CT-based radiomics for predicting lymph node metastasis in esophageal cancer: a systematic review and meta-analysis.

Objective: We aimed to evaluate the diagnostic effectiveness of computed tomography (CT)-based radiomics for predicting lymph node metastasis (LNM) in patients diagnosed with esophageal cancer (EC). Methods: The present study conducted a comprehensive search by accessing the following databases: PubMed, Embase, Cochrane Library, and Web of Science, with the aim of identifying relevant studies published until July 10th, 2023. The diagnostic accuracy was summarized using the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC). The researchers utilized Spearman's correlation coefficient for assessing the threshold effect, besides performing meta-regression and subgroup analysis for the exploration of possible heterogeneity sources. The quality assessment was conducted using the Quality Assessment of Diagnostic Accuracy Studies-2 and the Radiomics Quality Score (RQS). Results: The meta-analysis included six studies conducted from 2018 to 2022, with 483 patients enrolled and LNM rates ranging from 27.2% to 59.4%. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC, along with their corresponding 95% CI, were 0.73 (0.67, 0.79), 0.76 (0.69, 0.83), 3.1 (2.3, 4.2), 0.35 (0.28, 0.44), 9 (6, 14), and 0.78 (0.74, 0.81), respectively. The results demonstrated the absence of significant heterogeneity in sensitivity, while significant heterogeneity was observed in specificity; no threshold effect was detected. The observed heterogeneity in the specificity was attributed to the sample size and CT-scan phases (P < 0.05). The included studies exhibited suboptimal quality, with RQS ranging from 14 to 16 out of 36. However, most of the enrolled studies exhibited a low-risk bias and minimal concerns relating to applicability. Conclusion: The present meta-analysis indicated that CT-based radiomics demonstrated a favorable diagnostic performance in predicting LNM in EC. Nevertheless, additional high-quality, large-scale, and multicenter trials are warranted to corroborate these findings. Systematic Review Registration: Open Science Framework platform at https://osf.io/5zcnd.

In Addition to Damaging the Plasma Membrane, Phenolic Monoterpenoid Carvacrol Can Bind to the Minor Groove of DNA of Phytopathogenic Fungi to Potentially Control Tea Leaf Spot Caused by Lasiodiplodia theobromae.

Carvacrol expresses a wide range of biological activities, but the studies of its mechanisms focused on bacteria, mainly involving the destruction of the plasma membrane. In this study, carvacrol exhibited strong activities against several phytopathogenic fungi and demonstrated a novel antifungal mechanism against Lasiodiplodia theobromae. RNA sequencing indicated that many genes of L. theobromae hyphae were predominately induced by carvacrol, particularly those involved in replication and transcription. Hyperchromic, hypsochromic, and bathochromic effects in the UV-visible absorption spectrum were observed following titration of calf thymus DNA (ctDNA) and carvacrol, which indicated the formation of a DNA-carvacrol complex. Circular dichroism (CD) spectroscopy indicated that the response of DNA to carvacrol was similar to that of 4',6-diamidino-2-phenylindole (DAPI) but different from that of ethidium bromide (EB), implying the ionic bonds between carvacrol and ctDNA. Fluorescence spectrum (FS) analysis indicated that carvacrol quenched the fluorescence of double-stranded DNA (dsDNA) more than single-stranded DNA, indicating that carvacrol mainly bound to dsDNA. A displacement assay showed that carvacrol reduced the fluorescence intensity of the DNA-DAPI complex through competition with DAPI, but this did not occur for DNA-EB. The FS assay revealed that carvacrol bound to the AAA sequence on the minor groove of ds-oligonucleotides. The hydroxyl of carvacrol was verified to bind to ctDNA through a comparative test in which structural analogs of carvacrol, including thymol and 4-ethyl-1,2-dimethyl, were analyzed. The current study indicated carvacrol can destruct plasma membranes and bind to the minor groove of DNA, inhibiting fungal proliferation by disturbing the stability of dsDNA.

Mechanism of the Treatment of Irritable Bowel Syndrome with Sini Powder and Tong Xie Yao Fang Decoction Based on Network Pharmacology.

This study used a network pharmacology approach to investigate the potential active ingredients of Sini Powder and Tong xie yao fang decoction and the underlying mechanisms in irritable bowel syndrome (IBS) treatment. The potential active ingredients of Sini Powder and Tong xie yao fang decoction were obtained from TCMSP databases, and the potential targets of the active ingredients were predicted and analyzed by using the Swiss Target Prediction database. T Genecard, DisGeNET, and OMIM databases were processed to screen the potential therapeutic targets in IBS. The interaction of overlapped candidates between the potential biotarget of herb extracts and the potential therapeutic target of IBS were analyzed by STRING website and visualized by the Cytoscape V3.8.0 software. Gene ontology (GO) analysis and Kyoto Genomics and Genomics Encyclopedia (KEGG) pathway were processed to categorize and map the potential biofunctions and effects of these candidates by using David database. Result. There were 139 predicted active components and 248 related biotargets of Sini Powder and Tong xie yao fang decoction which were involved in IBS treatment, and 522 annotations and 101 related pathways are obtained by enrichment analysis (P < 0.01, FDR < 0.05). The underlying mechanisms of Sini Powder and Tong xie yao fang decoction may be related to neuroactive ligand-receptor interaction, calcium, cAMP, and HIF-1 signaling pathways. In conclusion, our results showed that the effect and mechanism of Sini Powder and Tong xie yao fang decoction in IBS treatment were in multi-ingredient, multitargets and multipathways, which would provide several potential and promising strategies for the further research and development of Sini Powder and Tong xie yao fang decoction on IBS treatment.

Biomechanical analysis of lumbar spine with interbody fusion surgery and U-shaped lumbar interspinous spacers.

Previous research indicates whole-body vibration may lead to low back pain. The aim of this study is assessing the dynamic characteristics of a lumbar spine with Coflex and Coflex-F (commercial implants used as lumbar interspinous spacers) and effect of lumbar interbody fusion surgery. A transient dynamic analysis is performed on three numerical lumbar spine models under the loading condition of a vertical sinusoidal force of ±40 N with a compressive follower preload of 400 N. Also, Coflex-F model with and without interbody fusion surgery is analyzed under the same loading condition. The results show that the maximum value and vibration amplitude of von Mises stress in annulus ground substance (AGS) and intradiscal pressure (IDP) at implanted segment decrease from healthy model to Coflex model, and Coflex-F model. By contrast, for adjacent segments the maximum value of implanted models are larger than that of healthy model. The maximum value of endplates with and without cage are 2.44 MPa and 1.73 MPa (L4 inferior endplate), 1.94 MPa and 1.42 MPa (L5 superior endplate), respectively. The vibration amplitude of Coflex-F model with fusion surgery is smaller than that without fusion surgery. Coflex and Coflex-F not only protect implanted segment but also have a negative effect on adjacent segments. Inserting cage for Coflex-F model can absorb vibration energy at adjacent segments.

Optimisation of double-enzymatic extraction of arabinoxylan from fresh corn fibre.

Enzymatic extraction of arabinoxylans (AXs) is an attractive and environmentally friendly extraction option, in which technical considerations (yield and purity) have been coupled with environmental concerns. Amano HC 90 and Cellulase were combined to evaluate their interactive effects on AX extraction from destarched, deproteinised bran (DSDPB). A response surface methodology was used to obtain the optimal extraction conditions. The experimental data fit well with the predicted values and the model adequately represented the actual relationship among the measured parameters. The extraction yield and AX content in the extract under optimal conditions (double-enzyme dose of 920 U/g, pH of 3.0, extraction temperature of 35.0 °C; extraction time of 6 h; and DSDPB to liquid ratio of 1:30) were 40.73 ± 0.09% and 75.88 ± 0.11%, respectively. The double-enzymatic extraction method of AX from fresh corn fibre was more efficient than the chemical method.

Setosphapyrone C and D accelerate macrophages cholesterol efflux by promoting LXRα/ABCA1 pathway.

LXRα agonists have attracted significant attention due to their potential biological activities on promoting cholesterol efflux. This study was designed to investigate whether setosphapyrone C and D have potential lipid-lowering capacity and the underlying mechanisms in vitro. Our data showed that setosphapyrone C and D had weak cytotoxicity compared to the liver X receptor α (LXRα) agonist T0901317. In RAW 264.7 macrophages, setosphapyrone C and D significantly enhanced [3H]-cholesterol efflux by ~ 21.3% and 32.4%, respectively; furthermore, setosphapyrone C and D enhanced the protein levels of ATP-binding cassette transporter (ABC) A1 and LXRα by 58% and 69%, and 60% and 70% (8 µM), respectively; however, they had no effect on the protein levels of ABCG1 and scavenger receptor B type 1; additionally, they had minor effect on the mRNA expression of lipogenic genes. Of note, setosphapyrone C and D significantly enhanced LXRα/ABCA1pathway in mice primary macrophages. In BRL cells, setosphapyrone C and D significantly improved the protein levels of ABCA1 and ABCG1; setosphapyrone D significantly enhanced the protein expression of low-density lipoprotein. Collectively, setosphapyrone C and D with weak cytotoxicity exhibited effective lipid-lowering effect via enhancing LXRα/ABC pathways. Setosphapyrones possess potential application for the treatment of hyperlipidemic diseases.

Publisher Correction: Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Protective mechanisms of hydrogen sulfide in myocardial ischemia.

Hydrogen sulfide (H2 S), which has been identified as the third gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO), plays an important role in maintaining homeostasis in the cardiovascular system. Endogenous H2 S is produced mainly by three endogenous enzymes: cystathionine ß-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfur transferase. Numerous studies have shown that H2 S has a significant protective role in myocardial ischemia. The mechanisms by which H2 S affords cardioprotection include the antifibrotic and antiapoptotic effects, regulation of ion channels, protection of mitochondria, reduction of oxidative stress and inflammatory response, regulation of microRNA expression, and promotion of angiogenesis. Amplification of NO- and CO-mediated signaling through crosstalk between H2 S, NO, and CO may also contribute to the cardioprotective effect. Exogenous H2 S donors are expected to become effective drugs for the treatment of cardiovascular diseases. This review article focuses on the protective mechanisms and potential therapeutic applications of H2 S in myocardial ischemia.

Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction.

DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Here we show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state-effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.

MicroRNA regulatory networks in the pathogenesis of sarcopenia.

Sarcopenia is an age-related disease characterized by disturbed homeostasis of skeletal muscle, leading to a decline in muscle mass and function. Loss of muscle mass and strength leads to falls and fracture, and is often accompanied by other geriatric diseases, including osteoporosis, frailty and cachexia, resulting in a general decrease in quality of life and an increase in mortality. Although the underlying mechanisms of sarcopenia are still not completely understood, there has been a marked improvement in the understanding of the pathophysiological changes leading to sarcopenia in recent years. The role of microRNAs (miRNAs), especially, has been clearer in skeletal muscle development and homeostasis. miRNAs form part of a gene regulatory network and have numerous activities in many biological processes. Intervention based on miRNAs may develop into an innovative treatment strategy to conquer sarcopenia. This review is divided into three sections: firstly, the latest understanding of the pathogenesis of sarcopenia is summarized; secondly, increasing evidence for the involvement of miRNAs in the regulation of muscle quantity or quality and muscle homeostasis is highlighted; and thirdly, the possibilities and limitations of miRNAs as a treatment for sarcopenia are explored.

Ezetimibe promotes CYP7A1 and modulates PPARs as a compensatory mechanism in LDL receptor-deficient hamsters.

BACKGROUND: The LDL-C lowering effect of ezetimibe has been attributed primarily to increased catabolism of LDL-C via up-regulation of LDL receptor (LDLR) and decreased cholesterol absorption. Recently, ezetimibe has been demonstrated to have reverse cholesterol transport (RCT) promoting effects in mice, hamsters and humans. However, the underlying mechanisms are still not clear. The aim of this study is to investigate whether ezetimibe improves RCT-related protein expression in LDLR-/- hamsters. METHODS: A high-fat diet was used to induce a human-like hyperlipidemia in LDLR-/- hamsters. Lipid profiles were assayed by commercially available kits, and the effects of ezetimibe on lipid metabolism-related protein expression were carried out via western blot. RESULTS: Our data demonstrated that ezetimibe administration significantly reduced plasma total cholesterol (~ 51.6% reduction, P < 0.01) and triglyceride (from ~ 884.1 mg/dL to ~ 277.3 mg/dL) levels in LDLR-/- hamsters fed a high-fat diet. Ezetimibe administration (25 mg/kg/d) significantly promoted the protein expression of cholesterol 7 alpha-hydroxylase A1 (CYP7A1), LXRß and peroxisome proliferator-activated receptor (PPAR) γ; and down-regulated the protein expression of PPARα and PPARß. However, it showed no significant effect on sterol regulatory element-binding protein (SREBP)-1c, SREBP-2, proprotein convertase subtilisin/kexin type 9 (PCSK9), Niemann-Pick C1-like 1 (NPC1L1), and ATP-biding cassette (ABC) G5/G8. CONCLUSION: Ezetimibe may accelerate the transformation from cholesterol to bile acid via promoting CYP7A1 and thereby enhance RCT. As a compensatory mechanism of TG lowering, ezetimibe promoted the protein expression of PPARγ and decreased PPARα and ß. These results are helpful in explaining the lipid-lowering effects of ezetimibe and the potential compensatory mechanisms.

The marine-derived furanone reduces intracellular lipid accumulation in vitro by targeting LXRα and PPARα.

Recent studies have demonstrated that commercially available lipid-lowering drugs cause various side effects; therefore, searching for anti-hyperlipidaemic compounds with lower toxicity is a research hotspot. This study was designed to investigate whether the marine-derived compound, 5-hydroxy-3-methoxy-5-methyl-4-butylfuran-2(5H)-one, has an anti-hyperlipidaemic activity, and the potential underlying mechanism in vitro. Results showed that the furanone had weaker cytotoxicity compared to positive control drugs. In RAW 264.7 cells, the furanone significantly lowered ox-LDL-induced lipid accumulation (~50%), and its triglyceride (TG)-lowering effect was greater than that of liver X receptor (LXR) agonist T0901317. In addition, it significantly elevated the protein levels of peroxisome proliferator-activated receptors (PPARα) and ATP-binding cassette (ABC) transporters, which could be partially inhibited by LXR antagonists, GSK2033 and SR9243. In HepG2 cells, it significantly decreased oleic acid-induced lipid accumulation, enhanced the protein levels of low-density lipoprotein receptor (LDLR), ABCG5, ABCG8 and PPARα, and reduced the expression of sterol regulatory element-binding protein 2 (~32%). PPARα antagonists, GW6471 and MK886, could significantly inhibit the furanone-induced lipid-lowering effect. Furthermore, the furanone showed a significantly lower activity on the activation of the expression of lipogenic genes compared to T0901317. Taken together, the furanone exhibited a weak cytotoxicity but had powerful TC- and TG-lowering effects most likely through targeting LXRα and PPARα, respectively. These findings indicate that the furanone has a potential application for the treatment of dyslipidaemia.

The fucoidan from the brown seaweed Ascophyllum nodosum ameliorates atherosclerosis in apolipoprotein E-deficient mice.

Hyperlipidemia is a major cause of atherosclerosis. Reverse cholesterol transport (RCT) is believed to attenuate hyperlipidemia and the progression of atherosclerosis. Although fucoidans are reported to have hypolipidemic effects, the underlying mechanisms are unclear. Furthermore, few reports have revealed the anti-atherosclerotic effects and the underlying mechanisms of fucoidans. This study was designed to investigate the anti-atherosclerotic effect and mechanisms of the fucoidan from seaweed A. nodosum. Our results demonstrated that the fucoidan administration ameliorated atherosclerotic lesion and lipid profiles in a dose-dependent manner in the apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet. In the apoE-/- mice liver, the fucoidan treatment significantly increased the expression of scavenger receptor B type 1 (SR-B1), peroxisome proliferator-activated receptor (PPAR) α and ß, liver X receptor (LXR) α, ATP-binding cassette transporter (ABC) A1 and ABCG8; and markedly decreased the expression of PPARγ and sterol regulatory element-binding protein (SREBP) 1c, but not low-density lipoprotein receptor, proprotein convertase subtilisin/kexin type 9, cholesterol 7 alpha-hydroxylase A1, LXRß and ABCG1. In the small intestine of the apoE-/- mice, the fucoidan treatment significantly reduced the expression of Niemann-Pick C1-like 1 (NPC1L1) and dramatically improved ABCG8 levels. These results demonstrated for the first time that the fucoidan from A. nodosum attenuated atherosclerosis by regulating RCT-related genes and proteins expression in apoE-/- mice. In summary, this fucoidan from A. nodosum may be explored as a potential compound for prevention or treatment of hyperlipidemia-induced atherosclerosis.

New insights into the pathogenesis and treatment of sarcopenia in chronic heart failure.

Sarcopenia is an age-related geriatric syndrome that is characterized by a progressive loss of muscle mass, strength and function. Chronic heart failure (CHF), the final stage of various cardiovascular diseases, may be closely correlated with the occurrence of sarcopenia. Accumulating evidence has demonstrated that CHF can promote the development of sarcopenia through multiple pathophysiological mechanisms, including malnutrition, inflammation, hormonal changes, oxidative stress, autophagy, and apoptosis. Additionally, CHF can aggravate the adverse outcomes associated with sarcopenia, including falls, osteoporosis, frailty, cachexia, hospitalization, and mortality. Sarcopenia and CHF are mutually interacting clinical syndromes. Patients with these two syndromes seem to endure a double burden, with no particularly effective way to hinder their progression. However, the combination of physical exercise, nutritional supplements, and drug therapy may counteract the development of these maladies. In this review, we will summarize the latest progress in the pathogenesis and treatment of sarcopenia in patients with CHF.

Fucoidan A2 from the Brown Seaweed Ascophyllum nodosum Lowers Lipid by Improving Reverse Cholesterol Transport in C57BL/6J Mice Fed a High-Fat Diet.

Reverse cholesterol transport (RCT) is a physiological process, in which excess peripheral cholesterol is transported to the liver and further excreted into the bile and then feces. Recently, fucoidans are reported to have a lipid-lowering effect. This study was designed to investigate whether fucoidan from the brown seaweed Ascophyllum nodosum lowers lipid by modulating RCT in C57BL/6J mice fed a high-fat diet. Our results indicated that fucoidan intervention significantly reduced plasma triglyceride, total cholesterol, and fat pad index and markedly increased high-density lipoprotein cholesterol in a dose-dependent manner. In the liver, fucoidan significantly increased the expression of peroxisome proliferator-activated receptor (PPAR)α, PPARγ, liver X receptor (LXR)ß, adenosine triphosphate (ATP) binding cassette (ABC)A1, ABCG8, low-density lipoprotein receptor (LDLR), scavenger receptor B type 1 (SR-B1), and cholesterol 7-α-hydroxylase A1 (CYP7A1) and decreased the triglyceride level and expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and PPARß but had no effect on LXRα, ABCG1, and ABCG5. In the small intestine, the fucoidan treatment significantly reduced the expression of Niemann-Pick C1-like 1 (NPC1L1) and improved ABCG5 and ABCG8. These results demonstrated that fucoidan can improve lipid transfer from plasma to the liver by activating SR-B1 and LDLR and inactivating PCSK9 and upregulate lipid metabolism by activating PPARα, LXRß, ABC transporters, and CYP7A1. In the small intestine, this fucoidan can decrease cholesterol absorption and increase cholesterol excretion by activating NPC1L1 and ABCG5 and ABCG8, respectively. In conclusion, fucoidan from A. nodosum may lower lipids by modulating RCT-related protein expression and can be explored as a potential compound for prevention or treatment of hyperlipidemia-related diseases.

The fucoidan A3 from the seaweed Ascophyllum nodosum enhances RCT-related genes expression in hyperlipidemic C57BL/6J mice.

Reverse cholesterol transport (RCT) has been demonstrated to reduce hyperlipidemia, and fucoidans are found to possess hypolipidemic effect. This study was designed to investigate the lipid-lowering effect of the fucoidan from the brown seaweed A. nodosum and whether it improves RCT-related genes expression in C57 BL/6J mice. Our results indicated that fucoidan A3 (100 mg/kg/day) intervention significantly reduced plasma total cholesterol (~23.2%), triglyceride (~48.7%) and fat pad index. This fucoidan significantly increased the mRNA expression of low-density lipoprotein receptor (LDLR), scavenger receptor B type 1 (SR-B1), cholesterol 7 alpha-hydroxylase A1 (CYP7A1), liver X receptor (LXR) ß, ATP-binding cassette transporter (ABC) A1 and sterol regulatory element-binding protein (SREBP) 1c, and decreased the expression of peroxisome proliferator-activated receptor (PPAR) γ, however, it had no effect on the expression of proprotein convertase subtilisin/kexin type 9, PPARα, LXRα, SREBP-2, ABCG1, ABCG8 and Niemann-Pick C1-like 1. These results demonstrated that this fucoidan improved lipid transfer from plasma to the liver by activating SR-B1 and LDLR, and up-regulated lipid metabolism by activating LXRß, ABCA1 and CYP7A1. In conclusion, this fucoidan lowers lipid by enhancing RCT-related genes expression, and it can be explored as a potential candidate for prevention or treatment of lipid disorders.

Inorganic Salts Induce Thermally Reversible and Anti-Freezing Cellulose Hydrogels.

Inspired by the anti-freezing mechanisms found in nature, ionic compounds (ZnCl2 /CaCl2 ) are integrated into cellulose hydrogel networks to enhance the freezing resistance. In this work, cotton cellulose is dissolved by a specially designed ZnCl2 /CaCl2 system, which endows the cellulose hydrogels specific properties such as excellent freeze-tolerance, good ion conductivity, and superior thermal reversibility. Interestingly, the rate of cellulose coagulation could be promoted by the addition of extra water or glycerol. This new type of cellulose-based hydrogel may be suitable for the construction of flexible devices used at temperature as low as -70 °C.

Structural characterisation and cholesterol efflux improving capacity of the novel polysaccharides from Cordyceps militaris.

Water extracts of the edible mushroom Cordyceps militaris possess a lipid-lowering effect. However, the types of components and how they exert this effect are not clear. In this study, two novel polysaccharides, CM1 and CMS, were isolated, and their cholesterol efflux improving capacity was investigated in vitro. The molecular weight of CM1 was approximately 700 kDa, and its main chain was consisted of (1 → 4)-ß-D-Glcp and (1 → 2)-α-D-manp branched at the O-6 positions of (1 → 2,6)-α-D-manp with (1 → 2) linked-ß-D-galf, (1 → 2)-α-D-manp or methyl and terminated with ß-D-Galf and α-D-Manp. The molecular weight of CMS was approximately 18.2 kDa, and it was a novel (1 → 6)-ß-D-Glcp linked glucan. Both CM1 and CMS significantly increased [3H]-cholesterol efflux by activating the protein expression of ATP-binding cassette (ABC) G1. However, they showed no significant influence on the proteins expression of ABCA1 and scavenger receptor B type 1. Therefore, CM1 and CMS are effective water-soluble components with potential lipid-lowering activity. They may be exploited as potential candidates for dyslipidaemia-related diseases such as atherosclerosis.

The DNA modification N6-methyl-2'-deoxyadenosine (m6dA) drives activity-induced gene expression and is required for fear extinction.

DNA modification is known to regulate experience-dependent gene expression. However, beyond cytosine methylation and its oxidated derivatives, very little is known about the functional importance of chemical modifications on other nucleobases in the brain. Here we report that in adult mice trained in fear extinction, the DNA modification N6-methyl-2'-deoxyadenosine (m6dA) accumulates along promoters and coding sequences in activated prefrontal cortical neurons. The deposition of m6dA is associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with extinction-induced gene expression. The accumulation of m6dA is associated with transcriptional activation at the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV messenger RNA expression and for the extinction of conditioned fear. These results expand the scope of DNA modifications in the adult brain and highlight changes in m6dA as an epigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.