Assessing intracellular and extracellular distribution of antibiotic resistance genes in the commercial organic fertilizers.

Compost-based organic fertilizers often contain high levels of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs). Previous studies focused on quantification of total ARGs and MGEs. For a more accurate risk assessment of the dissemination risk of antibiotic resistance, it is necessary to quantify the intracellular and extracellular distribution of ARGs and MGEs. In the present study, extracellular ARGs and MGEs (eARGs and eMGEs) and intracellular ARGs and MGEs (iARGs and iMGEs) were separately analyzed in 51 commercial composts derived from different raw materials by quantitative polymerase chain reaction (qPCR) and metagenomic sequencing. Results showed that eARGs and eMGEs accounted for 11-56% and 4-45% of the total absolute abundance of ARGs and MGEs, respectively. Comparable diversity, host composition and association with MGEs were observed between eARGs and iARGs. Contents of high-risk ARGs were similar between eARGs and iARGs, with high-risk ARGs in the two forms accounting for 6.7% and 8.2% of the total abundances, respectively. Twenty-four percent of the overall ARGs were present in plasmids, while 56.7% of potentially mobile ARGs were found to be associated with plasmids. Variation partitioning analysis, null model and neutral community model indicated that the compositions of both eARGs and iARGs were largely driven by deterministic mechanisms. These results provide important insights into the cellular distribution of ARGs in manure composts that should be paid with specific attention in risk assessment and management.

Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity.

An important epigenetic component of tyrosine kinase signaling is the phosphorylation of histones, and epigenetic readers, writers, and erasers. Phosphorylation of protein arginine methyltransferases (PRMTs), have been shown to enhance and impair their enzymatic activity. In this study, we show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates tyrosine residues (Y149 and Y334) in coactivator-associated arginine methyltransferase 1 (CARM1), an important target in hematologic malignancies, increasing its methyltransferase activity and altering its target specificity. While non-phosphorylatable CARM1 methylates some established substrates (e.g. BAF155 and PABP1), only phospho-CARM1 methylates the RUNX1 transcription factor, on R223 and R319. Furthermore, cells expressing non-phosphorylatable CARM1 have impaired cell-cycle progression and increased apoptosis, compared to cells expressing phosphorylatable, wild-type CARM1, with reduced expression of genes associated with G2/M cell cycle progression and anti-apoptosis. The presence of the JAK2-V617F mutant kinase renders acute myeloid leukemia (AML) cells less sensitive to CARM1 inhibition, and we show that the dual targeting of JAK2 and CARM1 is more effective than monotherapy in AML cells expressing phospho-CARM1. Thus, the phosphorylation of CARM1 by hyperactivated JAK2 regulates its methyltransferase activity, helps select its substrates, and is required for the maximal proliferation of malignant myeloid cells.

Soil redox status governs within-field spatial variation in microbial arsenic methylation and rice straighthead disease.

Microbial arsenic (As) methylation in paddy soil produces mainly dimethylarsenate (DMA), which can cause physiological straighthead disease in rice. The disease is often highly patchy in the field, but the reasons remain unknown. We investigated within-field spatial variations in straighthead disease severity, As species in rice husks and in soil porewater, microbial composition and abundance of arsM gene encoding arsenite S-adenosylmethionine methyltransferase in two paddy fields. The spatial pattern of disease severity matched those of soil redox potential, arsM gene abundance, porewater DMA concentration, and husk DMA concentration in both fields. Structural equation modelling identified soil redox potential as the key factor affecting arsM gene abundance, consequently impacting porewater DMA and husk DMA concentrations. Core amplicon variants that correlated positively with husk DMA concentration belonged mainly to the phyla of Chloroflexi, Bacillota, Acidobacteriota, Actinobacteriota, and Myxococcota. Meta-omics analyses of soil samples from the disease and non-disease patches identified 5129 arsM gene sequences, with 71% being transcribed. The arsM-carrying hosts were diverse and dominated by anaerobic bacteria. Between 96 and 115 arsM sequences were significantly more expressed in the soil samples from the disease than from the non-disease patch, which were distributed across 18 phyla, especially Acidobacteriota, Bacteroidota, Verrucomicrobiota, Chloroflexota, Pseudomonadota, and Actinomycetota. This study demonstrates that even a small variation in soil redox potential within the anoxic range can cause a large variation in the abundance of As-methylating microorganisms, thus resulting in within-field variation in rice straighthead disease. Raising soil redox potential could be an effective way to prevent straighthead disease.

The interpositional bypass with a parietal branch of superficial temporal artery graft for symptomatic atherosclerotic anterior cerebral artery stenosis or occlusion.

Background: For nonmoyamoya patients with anterior cerebral artery (ACA) stenosis or occlusion, whether direct revascularization of the ACA territory can prevent stroke is still unclear. The objective of this study was to investigate the efficacy and safety of a parietal branch of superficial temporal artery-interposed superficial temporal artery-to-ACA bypass (PISAB) for preventing stroke in patients with symptomatic atherosclerotic ACA stenosis or occlusion (SAASO). Methods: We retrospectively analyzed the data from patients with SAASO who had undergone PISAB in our center between April 2016 and November 2021. The rates of patency, satisfaction (revascularization grades A and B) of bypass, perioperative complications, recurrence of ischemic stroke, changes in bypass flow, and improvements in cerebral blood perfusion were analyzed. Results: A total of 19 SAASO patients were involved in this study. Sixteen out of 19 (84.2%) patients were free from any cerebral ischemic events after surgery. Only 3 patients (15.8%) had recurrent stroke postoperatively. Two (10.5%) surgery-related complications occurred, including hyperperfusion syndrome and minor stroke. No skin ischemic complications occurred. The average follow-up period was 50.6 ± 18.3 months. The flow rate of the bypass was significantly increased half a year after surgery (56.2 ± 8.0 mL/min vs. 44.3 ± 5.3 mL/min, p < 0.001). The ratio of ipsilateral/contralateral mean transit time in the superior frontal gyrus was decreased significantly after bypass (1.08 ± 0.07 vs. 1.23 ± 0.05, p < 0.001) and continued to decrease 6 months after surgery (1.05 ± 0.04 vs. 1.08 ± 0.07, p = 0.002). The patency rate of PISAB was 94.7% (18/19) 2 years after surgery. The satisfaction rate of bypass was 89.5% (17/19). Conclusion: The results of this study indicate that PISAB, as a safe superficial bypass, can effectively reduce the risk of stroke in SAASO patients. More precise conclusions will require randomized control studies.

Large language model for horizontal transfer of resistance gene: From resistance gene prevalence detection to plasmid conjugation rate evaluation.

The burgeoning issue of plasmid-mediated resistance genes (ARGs) dissemination poses a significant threat to environmental integrity. However, the prediction of ARGs prevalence is overlooked, especially for emerging ARGs that are potentially evolving gene exchange hotspot. Here, we explored to classify plasmid or chromosome sequences and detect resistance gene prevalence by using DNABERT. Initially, the DNABERT fine-tuned in plasmid and chromosome sequences followed by multilayer perceptron (MLP) classifier could achieve 0.764 AUC (Area under curve) on external datasets across 23 genera, outperforming 0.02 AUC than traditional statistic-based model. Furthermore, Escherichia, Pseudomonas single genera based model were also be trained to explore its predict performance to ARGs prevalence detection. By integrating K-mer frequency attributes, our model could boost the performance to predict the prevalence of ARGs in an external dataset in Escherichia with 0.0281-0.0615 AUC and Pseudomonas with 0.0196-0.0928 AUC. Finally, we established a random forest model aimed at forecasting the relative conjugation transfer rate of plasmids with 0.7956 AUC, drawing on data from existing literature. It identifies the plasmid's repression status, cellular density, and temperature as the most important factors influencing transfer frequency. With these two models combined, they provide useful reference for quick and low-cost integrated evaluation of resistance gene transfer, accelerating the process of computer-assisted quantitative risk assessment of ARGs transfer in environmental field.

A calix[3]carbazole-based cavitand: synthesis, structure and its complexation with fullerenes.

A calix[3]carbazole-based cavitand was conveniently synthesized. It was found that the cavitand with adjustable conformation could show excellent complexation with fullerenes C60 and C70 in both solution and the solid state. Moreover, the crystal structures of the host-guest complexes show that the cavitand can stack into channel-like architectures, in which fullerenes are orderly arranged inside.

Prognostic effect of DNA methylation of BTG2 gene in Chinese hepatocellular carcinoma.

Background: This study aims to develop a prognostic model for overall survival based on potential methylation sites within B-cell translocation gene 2 (BTG2) in Chinese patients with hepatocellular carcinoma (HCC). Methods: This is a retrospective study. The beta values of nine CpG sites and RSEM normalized count values of BTG2 gene were extracted from the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) (TCGA-LIHC) dataset, with the beta value representing the methylation level by indicating the ratio of the intensity of the methylated bead type to the combined locus intensity. Pyrosequencing was performed to determine the range of methylation values surrounding cg01798157 site in BTG2 gene. A weighted linear model was developed to predict the overall survival (OS). Results: The beta value of cg01798157 was significantly negatively associated with the mRNA expression of BTG2 in the TCGA-LIHC dataset (Spearman's rho = -0.5306, P = 2.27 × 10-27). The methylation level of cg01798157 was significantly associated with OS in the cohort of 51 Chinese HCC patients (Hazard ratio = 0.597, 95% CI: 0.434-0.820, P = 0.001). Multivariate Cox regression analysis identified methylation level of cg01798157, cirrhosis, and microvascular invasion as independent prognostic factors. The prognostic efficiency of death risk score was superior to that of cirrhosis or microvascular invasion alone. Conclusions: The methylation level of cg01798157 in BTG2 may be an epigenetic biomarker in Chinese patients with resectable HCC.

Berberine inhibits NLRP3 inflammasome activation and proinflammatory macrophage M1 polarization to accelerate peripheral nerve regeneration.

Berberine (BBR) has demonstrated potent anti-inflammatory effects by modulating macrophage polarization. Nevertheless, the precise mechanisms through which berberine regulates post-injury inflammation within the peripheral nerve system remain elusive. This study seeks to elucidate the role of BBR and its underlying mechanisms in inflammation following peripheral nerve injury (PNI). Adult male C57BL/6J mice subjected to PNI were administered daily doses of berberine (0, 60, 120, 180, 240 â€‹mg/kg) via gavage from day 1 through day 28. Evaluation of the sciatic function index (SFI) and paw withdrawal threshold revealed that BBR dose-dependently enhanced both motor and sensory functions. Immunofluorescent staining for anti-myelin basic protein (anti-MBP) and anti-neurofilament-200 (anti-NF-200), along with histological staining comprising hematoxylin-eosin (HE), luxol fast blue (LFB), and Masson staining, demonstrated that BBR dose-dependently promoted structural regeneration. Molecular analyses including qRT-PCR, Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence confirmed that inactivation of the NLRP3 inflammasome by MCC950 shifted macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, while also impeding macrophage infiltration. Furthermore, BBR significantly downregulated the expression of the NLRP3 inflammasome and its associated molecules in macrophages, thereby mitigating NLRP3 inflammasome activation-induced macrophage M1 polarization and inflammation. In summary, BBR's neuroprotective effects were concomitant with the suppression of inflammation after PNI, achieved through the inhibition of NLRP3 inflammasome activation-induced macrophage M1 polarization.

Unveiling the next generation of MRI contrast agents: current insights and perspectives on ferumoxytol-enhanced MRI.

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a pivotal tool for global disease diagnosis and management. Since its clinical availability in 2009, the off-label use of ferumoxytol for ferumoxytol-enhanced MRI (FE-MRI) has significantly reshaped CE-MRI practices. Unlike MRI that is enhanced by gadolinium-based contrast agents, FE-MRI offers advantages such as reduced contrast agent dosage, extended imaging windows, no nephrotoxicity, higher MRI time efficiency and the capability for molecular imaging. As a leading superparamagnetic iron oxide contrast agent, ferumoxytol is heralded as the next generation of contrast agents. This review delineates the pivotal clinical applications and inherent technical superiority of FE-MRI, providing an avant-garde medical-engineering interdisciplinary lens, thus bridging the gap between clinical demands and engineering innovations. Concurrently, we spotlight the emerging imaging themes and new technical breakthroughs. Lastly, we share our own insights on the potential trajectory of FE-MRI, shedding light on its future within the medical imaging realm.

Migrate demographic group for fair Graph Neural Networks.

Graph Neural networks (GNNs) have been applied in many scenarios due to the superior performance of graph learning. However, fairness is always ignored when designing GNNs. As a consequence, biased information in training data can easily affect vanilla GNNs, causing biased results toward particular demographic groups (divided by sensitive attributes, such as race and age). There have been efforts to address the fairness issue. However, existing fair techniques generally divide the demographic groups by raw sensitive attributes and assume that are fixed. The biased information correlated with raw sensitive attributes will run through the training process regardless of the implemented fair techniques. It is urgent to resolve this problem for training fair GNNs. To tackle this problem, we propose a brand new framework, FairMigration, which is able to migrate the demographic groups dynamically, instead of keeping that fixed with raw sensitive attributes. FairMigration is composed of two training stages. In the first stage, the GNNs are initially optimized by personalized self-supervised learning, and the demographic groups are adjusted dynamically. In the second stage, the new demographic groups are frozen and supervised learning is carried out under the constraints of new demographic groups and adversarial training. Extensive experiments reveal that FairMigration achieves a high trade-off between model performance and fairness.

Macrocycle-Based Charge Transfer Cocrystals with Dynamically Reversible Chiral Self-Sorting Display Chain Length-Selective Vapochromism to Alkyl Ketones.

Chirality-driven self-sorting plays an essential role in controlling the biofunction of biosystems, such as the chiral double-helix structure of DNA from self-recognition by hydrogen bonding. However, achieving precise control over the chiral self-sorted structures and their functional properties for the bioinspired supramolecular systems still remains a challenge, not to mention realizing dynamically reversible regulation. Herein, we report an unprecedented saucer[4]arene-based charge transfer (CT) cocrystal system with dynamically reversible chiral self-sorting synergistically induced by chiral triangular macrocycle and organic vapors. It displays efficient chain length-selective vapochromism toward alkyl ketones due to precise modulation of optical properties by vapor-induced diverse structural transformations. Experimental and theoretical studies reveal that the unique vapochromic behavior is mainly attributed to the formation of homo- or heterochiral self-sorted assemblies with different alkyl ketone guests, which differ dramatically in solid-state superstructures and CT interactions, thus influencing their optical properties. This work highlights the essential role of chiral self-sorting in controlling the functional properties of synthetic supramolecular systems, and the rarely seen controllable chiral self-sorting at the solid-vapor interface deepens the understanding of efficient vapochromic sensors.

The ARPKD Protein DZIP1L Regulates Ciliary Protein Entry by Modulating the Architecture and Function of Ciliary Transition Fibers.

Serving as the cell's sensory antennae, primary cilia are linked to numerous human genetic diseases when they malfunction. DZIP1L, identified as one of the genetic causes of human autosomal recessive polycystic kidney disease (ARPKD), is an evolutionarily conserved ciliary basal body protein. Although it has been reported that DZIP1L is involved in the ciliary entry of PKD proteins, the underlying mechanism remains elusive. Here, an uncharacterized role of DZIP1L is reported in modulating the architecture and function of transition fibers (TFs), striking ciliary base structures essential for selective cilia gating. Using C. elegans as a model, C01G5.7 (hereafter termed DZIP-1) is identified as the sole homolog of DZIP1L, which specifically localizes to TFs. While DZIP-1 or ANKR-26 (the ortholog of ANKRD26) deficiency shows subtle impact on TFs, co-depletion of DZIP-1 and ANKR-26 disrupts TF assembly and cilia gating for soluble and membrane proteins, including the ortholog of ADPKD protein polycystin-2. Notably, the synergistic role for DZIP1L and ANKRD26 in the formation and function of TFs is highly conserved in mammalian cilia. Hence, the findings illuminate an evolutionarily conserved role of DZIP1L in TFs architecture and function, highlighting TFs as a vital part of the ciliary gate implicated in ciliopathies ARPKD.

A hyper-knowledge graph system for research on AI ethics cases.

Current studies on the artificial intelligence (AI) ethics focus either on very broad guidelines or on a very special domain. Therefore, the research outcome can hardly be converted into actionable measures or transferred to other domains. Potential correlations between various cases of AI ethics at different granularity levels are unexplored. To overcome these deficiencies, the authors designed a case-oriented ontological model (COOM) and a hyper-knowledge graph system (HKGS) for the research of collected AI ethics cases. COOM describes criteria for modelling cases by attributes from three perspectives: event attributes, relational attributes, and positional attributes on the value chain. Based on it, HKGS stores the correlation between cases as knowledge and allows advanced visual analysis. The correlations between cases and their dynamic changes on value chain can be observed and explored. In HKGS's implementation part, one of the collected ethics cases is used as an example to demonstrate how to generate a hyper-knowledge graph and to visually analyze it. The authors also anticipated how different practitioners of AI ethics, can achieve the desired outputs from HKGS in their diverse scenarios.

Cost-effectiveness of immune checkpoint inhibitors in treating metastatic urothelial cancer.

Objectives: Immune checkpoint inhibitor (ICI) is an important treatment option for metastatic urothelial carcinoma (mUC) patients. A lot of clinical evidence proved the survival benefits of ICI, but cost-effectiveness of the treatment remains unclear. This study evaluates the cost-effectiveness of the ICIs treatment in different sequences among mUC patients. Methods: We retrospectively analyzed mUC patients who had been treated at our hospital between January 2016 and December 2020. These patients received chemotherapy with or without ICI treatment (Pembrolizumab, Atezolizumab, Nivolumab, Durvalumab, or Avelumab). The patients were divided into three different groups: receiving chemotherapy alone, receiving a combination of first-line ICI and chemotherapy (ICI combination therapy), and receiving chemotherapy as the first-line treatment followed by second-line ICI therapy (Subsequent ICI therapy). The primary endpoint was cost per life day, while lifetime medical costs and overall survival were also evaluated. Results: The 74 enrolled patients had a median age of 67.0 years, with 62.2% being male. Of these patients, 23 had received chemotherapy only, while the remaining patients had received combined therapy with ICI in either first-line or as subsequent agents (37 patients had ever received atezolizumab, 18 pembrolizumab, 1 Durvalumab, 1 Nivolumab, and 1 Avelumab separately.). Fifty-five patients (74.3%, 55/74) received cisplatin amongst all the patients who underwent chemotherapy. Median overall survival was 27.5 months (95% CI, 5.2-49.9) in the first-line ICI combination therapy group, and 8.9 months (95% CI, 7.1-10.8) in the chemotherapy only. Median overall survival for the subsequent ICI therapy group was not reached. The median lifetime cost after metastatic UC diagnosis was USD 31,221. The subsequent ICI therapy group had significantly higher costs when compared with the ICI combination therapy group (155.8 USD per day, [IQR 99.0 to 220.5] v 97.8 USD per day, [IQR 60.8 to 159.19], p = 0.026). Higher insurance reimbursement expenses for the subsequent ICI therapy group were observed when compared with the ICI combination therapy group. Conclusion: Our real-world data suggests that first line use of ICI combined with chemotherapy demonstrates better cost-effectiveness and similar survival outcomes for mUC patients, when compared with subsequent ICI therapy after chemotherapy.

Prognostic Molecular Biomarkers in Breast Cancer Lesions with Non-Mass Enhancement on MR.

Clustered ring enhancement (CRE) is a new lexicon for non-mass enhancement (NME) of breast MR in the 5th BIRADS, indicating a high suspicion of malignancy. We wonder if the presence of CRE correlates with expression of prognostic molecular biomarkers of breast cancer. A total of 58 breast lesions, which MRI reported with NME, were collected between July 2013 and December 2018. The patterns of enhancement including CRE were reviewed and the pathological results with expression of molecular biomarkers were collected. The association between MRI NME, pathological, and IHC stain findings were investigated under univariate analysis. A total of 58 breast lesions were pathologically proven to have breast cancer, comprising 31 lesions with CRE and 27 lesions without CRE on breast MRI. The expression of the estrogen receptor (ER) (p = 0.017) and the progesterone receptor (PR) (p = 0.017) was significantly lower in lesions with CRE as compared with those without CRE. The expression of Ki-67 (≥25%) was significantly higher in lesions with CRE (p = 0.046). The lesions with CRE had a lower expression ratio of ER (50.71 ± 45.39% vs. 74.26 ± 33.59%, p = 0.028). Our study indicated that lesions with CRE may possess different features from those without CRE in molecular expression, bearing a more aggressive behavior.

A functional variant of ALDH1A2 is associated with hand osteoarthritis in the Chinese population.

Genome-wide association study identified common variants within the ALDH1A2 gene as the susceptible loci of hand osteoarthritis (HOA) in UK and Iceland populations. Located in chromosome 15, ALDH1A2 encodes aldehyde dehydrogenase family 1 member A2, which is an enzyme that catalyses the synthesis of retinoic acid from retinaldehyde. Our purposes were to replicate the association of functional variant in ALDH1A2 with the development of HOA in the Chinese population. Variant rs12915901 of ALDH1A2 was genotyped in 872 HOA patients and 1223 healthy controls. Subchondral bone samples were collected from 40 patients who had undergone a trapeziectomy, and the tissue expression of ALDH1A2 was analysed. The chi-square analysis was used to compare the frequency of genotype and risk allele between the HOA cases and controls. The Student t test was used to compare the mRNA expression of ALDH1A2 between patients with genotype AA/AG and those with genotype GG. The frequency of genotype AA was significantly higher in HOA patients than in the controls (7.6% vs. 5.1%, p = .01). The frequency of allele A was significantly higher in the patients than in the controls (28.9% vs. 24.6%, p = .005). The mRNA expression of ALDH1A2 was 1.31-folds higher in patients with genotype GG than in the patients with genotype AA/AG (0.000617 ± 0.000231 vs. 0.000471 ± 0.000198, p = .04). Variant rs12915901 of ALDH1A2 contributed to the susceptibility of HOA in the Chinese population. Allele A of rs12915901 can add to the risk of HOA possibly via down-regulation of ALDH1A2 expression.

An autocatalytic CRISPR-Cas amplification effect propelled by the LNA-modified split activators for DNA sensing.

CRISPR-Cas systems with dual functions offer precise sequence-based recognition and efficient catalytic cleavage of nucleic acids, making them highly promising in biosensing and diagnostic technologies. However, current methods encounter challenges of complexity, low turnover efficiency, and the necessity for sophisticated probe design. To better integrate the dual functions of Cas proteins, we proposed a novel approach called CRISPR-Cas Autocatalysis Amplification driven by LNA-modified Split Activators (CALSA) for the highly efficient detection of single-stranded DNA (ssDNA) and genomic DNA. By introducing split ssDNA activators and the site-directed trans-cleavage mediated by LNA modifications, an autocatalysis-driven positive feedback loop of nucleic acids based on the LbCas12a system was constructed. Consequently, CALSA enabled one-pot and real-time detection of genomic DNA and cell-free DNA (cfDNA) from different tumor cell lines. Notably, CALSA achieved high sensitivity, single-base specificity, and remarkably short reaction times. Due to the high programmability of nucleic acid circuits, these results highlighted the immense potential of CALSA as a powerful tool for cascade signal amplification. Moreover, the sensitivity and specificity further emphasized the value of CALSA in biosensing and diagnostics, opening avenues for future clinical applications.

Characterization and function of PTEN-induced putative kinase 1 (PINK1) in process of Zinc alleviates hepatic lipid deposition of yellow catfish (Pelteobagrus fulvidraco).

PTEN-induced putative kinase 1 (PINK1) is a key regulator of mitophagy, however, the relevant information remains poorly understood on aquatic animals. Here, a PINK1 gene was cloned, characterized and functionally studied in yellow catfish. PINK1 encoded a protein containing 570 amino acids, 2 functional domains. High fat (15.66%) fed fish showed a downregulation trend of liver PINK1 expression than that of normal fat (10.14%) group, and was reversed by the addition of Zn. In the in vitro study, high fat (HF) can increase lipid deposition and decrease by addition Zn (HFZ) in hepatocytes, whereas above phenomena reversed by overexpression/interference of PINK1, respectively. In addition, the addition of Zn can significantly affect mitochondrial activity, increase mitophagy, and improve the antioxidant activity of hepatocytes. Together, these findings illustrated that yellow catfish PINK1 is conserve, and it participated in mitochondria control of fish. These findings indicate Zn could alleviate high fat-induced hepatic lipid deposition of fish by activating PINK1-mediated mitophagy and provide basis for further exploring new approach for decreasing lipid deposition in fish products during aquaculture.

ADNP modulates SINE B2-derived CTCF-binding sites during blastocyst formation in mice.

CTCF is crucial for chromatin structure and transcription regulation in early embryonic development. However, the kinetics of CTCF chromatin occupation in preimplantation embryos have remained unclear. In this study, we used CUT&RUN technology to investigate CTCF occupancy in mouse preimplantation development. Our findings revealed that CTCF begins binding to the genome prior to zygotic genome activation (ZGA), with a preference for CTCF-anchored chromatin loops. Although the majority of CTCF occupancy is consistently maintained, we identified a specific set of binding sites enriched in the mouse-specific short interspersed element (SINE) family B2 that are restricted to the cleavage stages. Notably, we discovered that the neuroprotective protein ADNP counteracts the stable association of CTCF at SINE B2-derived CTCF-binding sites. Knockout of Adnp in the zygote led to impaired CTCF binding signal recovery, failed deposition of H3K9me3, and transcriptional derepression of SINE B2 during the morula-to-blastocyst transition, which further led to unfaithful cell differentiation in embryos around implantation. Our analysis highlights an ADNP-dependent restriction of CTCF binding during cell differentiation in preimplantation embryos. Furthermore, our findings shed light on the functional importance of transposable elements (TEs) in promoting genetic innovation and actively shaping the early embryo developmental process specific to mammals.

FOXO3/Rab7-Mediated Lipophagy and Its Role in Zn-Induced Lipid Metabolism in Yellow Catfish (Pelteobagrus fulvidraco).

Lipophagy is a selective autophagy that regulates lipid metabolism and reduces hepatic lipid deposition. However, the underlying mechanism has not been understood in fish. In this study, we used micronutrient zinc (Zn) as a regulator of autophagy and lipid metabolism and found that Ras-related protein 7 (rab7) was involved in Zn-induced lipophagy in hepatocytes of yellow catfish Pelteobagrus pelteobagrus. We then characterized the rab7 promoter and identified binding sites for a series of transcription factors, including Forkhead box O3 (FOXO3). Site mutation experiments showed that the -1358/-1369 bp FOXO3 binding site was responsible for Zn-induced transcriptional activation of rab7. Further studies showed that inhibition of rab7 significantly inhibited Zn-induced lipid degradation by lipophagy. Moreover, rab7 inhibitor also mitigated the Zn-induced increase of cpt1α and acadm expression. Our results suggested that Zn exerts its lipid-lowering effect partly through rab7-mediated lipophagy and FA ß-oxidation in hepatocytes. Overall, our findings provide novel insights into the FOXO3/rab7 axis in lipophagy regulation and enhance the understanding of lipid metabolism by micronutrient Zn, which may help to reduce excessive lipid accumulation in fish.