Thyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase ...(D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of ∼165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-activated receptor-γ expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB-D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10–20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet-induced steatosis, hypertriglyceridemia, and obesity.
DNA methylation is an important epigenetic modification involved in many biological processes and diseases. Many studies have mapped DNA methylation changes associated with embryogenesis, cell ...differentiation, and cancer at a genome-wide scale. Our understanding of genome-wide DNA methylation changes in a developmental or disease-related context has been steadily growing. However, the investigation of which CpGs are variably methylated in different normal cell or tissue types is still limited. Here, we present an in-depth analysis of 54 single-CpG-resolution DNA methylomes of normal human cell types by integrating high-throughput sequencing-based methylation data. We found that the ratio of methylated to unmethylated CpGs is relatively constant regardless of cell type. However, which CpGs made up the unmethylated complement was cell-type specific. We categorized the 26,000,000 human autosomal CpGs based on their methylation levels across multiple cell types to identify variably methylated CpGs and found that 22.6% exhibited variable DNA methylation. These variably methylated CpGs formed 660,000 variably methylated regions (VMRs), encompassing 11% of the genome. By integrating a multitude of genomic data, we found that VMRs enrich for histone modifications indicative of enhancers, suggesting their role as regulatory elements marking cell type specificity. VMRs enriched for transcription factor binding sites in a tissue-dependent manner. Importantly, they enriched for GWAS variants, suggesting that VMRs could potentially be implicated in disease and complex traits. Taken together, our results highlight the link between CpG methylation variation, genetic variation, and disease risk for many human cell types.
Since the severity and frequency of extreme events have seriously threatened the stability of fossil energy markets, this paper conducts multilayer dynamic network analysis to demonstrate the ...evolution of the entire market structure during extreme events. Based on the data of 64 Chinese energy firms ranging from March 2018 to February 2023, this paper examines the sectoral discrepancies, and identifies systemically important companies during different crises. The results indicate that the risk transmission mechanisms among fossil energy markets are different induced by the two crises, namely the COVID-19 pandemic and the Russia–Ukraine conflict. Specifically, the COVID-19 has rendered greater influence on the oil and gas industry, while the Russia–Ukraine conflict has brought instability to the coal industry. Additionally, the heterogeneous effects of these events on individual energy firms are identified, and the results suggest that both small and large firms have played prominent roles in risk transmission.
•Extreme risk contagions among fossil energy firms are examined.•The dynamic evolution of market structure is demonstrated by multilayer network.•Topological characteristics are presented from market, sector, and firm levels.•The COVID-19 has rendered significant impacts on the oil and gas sectors.•The Russia–Ukraine conflict has brought instability to the coal sectors.
Purpose: To establish a rat flexor tendon laceration and repair model to investigate the molecular mechanisms of flexor tendon healing.
Methods: Surgery was performed on rat flexor digitorum longus ...tendons from both hind feet. Repaired tendons were harvested at 0, 3, 7, 14, 21, 28, 42, 56, and 84 days after surgery. Histologic study (first 84 days) and gene expression study (first 28 days) of several collagens and matrix metalloproteinases (MMPs) were performed.
Results: In the histologic study pre-existing collagen bundles were degraded between days 7 to 21. Newly formed collagen fibers crossed the repair site by day 28. Remodeling of the collagen fibers continued until day 84. Gene expression of type I collagen decreased initially and then returned gradually to the initial level by day 28, whereas expression levels of types III, V, and XII collagen were increased after surgery. The expression levels of MMP-9 and MMP-13 peaked between days 7 to 14, whereas MMP-2, MMP-3, and MMP-14 levels increased after surgery and maintained high levels until day 28.
Conclusions: The rat tendon laceration model represented the entire tendon healing process. The results of this study suggest that MMP-9 and MMP-13 participate only in collagen degradation, whereas MMP-2, MMP-3, and MMP-14 participate not only in collagen degradation but also in collagen remodeling.
Site-1 protease (S1P) has an essential function in the conversion of latent, membrane-bound transcription factors to their free, active form. In mammals, abundant expression of S1P in chondrocytes ...suggests an involvement in chondrocyte function. To determine the requirement of S1P in cartilage and bone development, we have created cartilage-specific S1P knockout mice (S1Pcko). S1Pcko mice exhibit chondrodysplasia and a complete lack of endochondral ossification even though Runx2 expression, Indian hedgehog signaling, and osteoblastogenesis is intact. However, there is a substantial increase in chondrocyte apoptosis in the cartilage of S1Pcko mice. Extraction of type II collagen is substantially lower from S1Pcko cartilage. In S1Pcko mice, the collagen network is disorganized and collagen becomes entrapped in chondrocytes. Ultrastructural analysis reveals that the endoplasmic reticulum (ER) in S1Pcko chondrocytes is engorged and fragmented in a manner characteristic of severe ER stress. These data suggest that S1P activity is necessary for a specialized ER stress response required by chondrocytes for the genesis of normal cartilage and thus endochondral ossification.
Due to the close production link between clean energy and non-ferrous metals, their price and market dynamics can easily affect one another through production costs. Furthermore, with the increased ...financialization of clean energy and non-ferrous metals markets, investment risk can easily spread between them. Therefore, this paper intends to explore the risk contagion between the two markets through the spillover index model and the minimum spanning tree (MST) method. Employing the data collected in China, this paper quantifies the magnitude of risk transfer by the volatility spillovers of eight clean energy stock markets as identified in The Energy Conservation and Environmental Protection Clean Industry Statistical Classification 2021 and the eight corresponding non-ferrous metals futures markets, while fully considering the heterogeneity between sub-markets. First, we find that risk is mainly transmitted from clean energy to non-ferrous metals. Second, this paper identifies not only the most influential market but also the shortest path of risk contagion based on the MST topology analysis. Last, the empirical results show that the COVID-19 has increased the scale of risk transmission between the two markets and their connectivity. During the COVID-19 period, the shortest path between the two markets shifted from “hydropower–gold” to “smartgrid–zinc”, and the systematically influential markets correspondingly become smartgrid and zinc. The results obtained in this paper might have practical implications for policymakers seeking to achieve effective risk management, which could also facilitate investors for diversification benefits.
•Risk contagion between clean energy and non-ferrous metals markets is examined.•The magnitude of risk transfer is quantified by DY spillover index.•The shortest risk transmission path is identified through topology analysis.•The COVID-19 has caused changes to risk spillover and transmission path.
The rapid development of green energy would render a profound impact on the non-ferrous metals markets in China. This paper adopts the quantile vector autoregression (QVAR) to investigate the ...spillover effects between China’s green energy and non-ferrous metals markets as well as their dynamic pattern under normal and extreme conditions. Furthermore, GARCH-MIDAS model and quantile regression method are applied to examine the impact of China’s climate policy uncertainty on the spillovers between the two markets. In doing so, we find that green energy markets mainly act as transmitters of return spillover effects to non-ferrous metals markets during normal market times and periods of downturns. However, in upturns, the non-ferrous metals markets would easily transit spillover effects to green energy ones. It is further indicated that China’s climate policy uncertainty exacerbates the spillover effect, and the exacerbated effect of high uncertainty on the market relationship when the spillover effect is at high level is the most significant.
•The spillover between green energy and non-ferrous metals markets across quantiles is examined.•China’s climate policy uncertainty index is constructed through text analysis.•The impact of climate policy uncertainty on market spillovers would be heterogeneous.•The intensifying effect is the most significant when the market spillovers are at high quantiles.
Climate policies such as carbon tax and green finance policy are critical measures to promote low-carbon transition worldwide. These policies are, however, likely to interact with each other and ...create unintentional consequences. This paper adopts a stock-flow consistent model to theoretically explore the effects of policy interactions. Specifically, commercial banks, as the key credit creators and critical players in providing source of finance, are included. Based on the numerical simulations of the dynamic model, we find that both carbon tax and green finance policies render positive impacts on low-carbon transition. In addition, green credit incentives, if imposed simultaneously with carbon tax, can enhance the positive effects. Although low-carbon transition could generate higher net government revenues, our results show that banking sector tends to expose to higher financial risks when firms’ debt-equity ratio rises. Further analysis shows that subsidies on green loans can support green transition and bring positive consequences to debt rollover and social welfare, indicating the needs for active government intervention to improve policy effectiveness. The framework proposed in this paper provides a useful way to understand policy dilemmas in pursuing low-carbon transition and give important implications to form optimal policy mix.
•A stock-flow consistent model is developed to examine climate policy interactions.•We show that climate policy-mix can generate both positive and negative effects.•Green finance policies can enhance green investment and induce higher financial risks.•Active government intervention such as green subsidies can ease financial distress and improve policy effectiveness.
With the purpose of performing a simple and original analysis on the impact of carbon tax on low-carbon transition, this paper presents a stock-flow consistent model, paying special attention to the ...role of commercial banks. Through theoretical analysis, we find that the reduction effect of carbon tax on carbon emissions is amplified by commercial banks via financing more green investments. Moreover, such effect is altered by commercial banks’ capability to issue green loans. The results obtained in this paper facilitate the understandings about carbon tax and its coordination with bank-centered financial policies.
•A stock-flow consistent model is constructed to examine the impact of carbon tax.•This paper employs carbon intensity to quantify the low-carbon level of the economy.•Commercial banks act as credit creators in financing brown and green investments.•Commercial banks could amplify the effect of carbon tax on carbon intensity.•The reduction effect is altered by banks’ capability to issue green loans.
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