Identification of two novel variants in ALG11 causing congenital disorder of glycosylation.

BACKGROUND: Congenital disorders of glycosylation (CDG) represent a heterogeneous group of rare inherited metabolic disorders due to abnormalities in protein or lipid glycosylation pathways, affecting multiple systems, and frequently being accompanied by neurological symptoms. ALG11-CDG, also known as CDG-1p, arises from a deficiency in a specific mannosyltransferase encoded by the ALG11 gene. To date, only 17 cases have been documented, and these patients have prominent clinical phenotypes, including seizures, developmental delay, and microcephaly. METHODS: We describe a novel case of a four-month-old boy from a Chinese family exhibiting developmental delay, seizures, and microcephaly. Trio whole-exome sequencing (WES) and subsequent Sanger sequencing were employed to identify the potential genetic cause, and functional study was performed to evaluate the pathogenicity of genetic variant identified. RESULTS: Trio WES unveiled novel compound heterozygous variants: c.1307G>T (p.G436V) and c.1403G>A (p.R468H) within exon 4 of the ALG11 gene, inherited from the father and mother, respectively. Subsequent in vitro functional analysis revealed decreased stability of the mutant protein and concurrent hypoglycosylation of GP130, a hyperglycosylated protein. CONCLUSIONS: Our findings not only expand the clinical and variant spectrum of ALG11-CDG, but also emphasize the importance of WES as a first-tier genetic test in determining the molecular diagnosis.

DOR activation in mature oligodendrocytes regulates α-ketoglutarate metabolism leading to enhanced remyelination in aged mice.

The decreased ability of mature oligodendrocytes to produce myelin negatively affects remyelination in demyelinating diseases and aging, but the underlying mechanisms are incompletely understood. In the present study, we identify a mature oligodendrocyte-enriched transcriptional coregulator diabetes- and obesity-related gene (DOR)/tumor protein p53-inducible nuclear protein 2 (TP53INP2), downregulated in demyelinated lesions of donors with multiple sclerosis and in aged oligodendrocyte-lineage cells. Dor ablation in mice of both sexes results in defective myelinogenesis and remyelination. Genomic occupancy in oligodendrocytes and transcriptome profiling of the optic nerves of wild-type and Dor conditional knockout mice reveal that DOR and SOX10 co-occupy enhancers of critical myelinogenesis-associated genes including Prr18, encoding an oligodendrocyte-enriched, proline-rich factor. We show that DOR targets regulatory elements of genes responsible for α-ketoglutarate biosynthesis in mature oligodendrocytes and is essential for α-ketoglutarate production and lipid biosynthesis. Supplementation with α-ketoglutarate restores oligodendrocyte-maturation defects in Dor-deficient adult mice and improves remyelination after lysolecithin-induced demyelination and cognitive function in 17-month-old wild-type mice. Our data suggest that activation of α-ketoglutarate metabolism in mature oligodendrocytes can promote myelin production during demyelination and aging.

Phytoremediation efficiency of poplar hybrid varieties with diverse genetic backgrounds in soil contaminated by multiple toxic metals (Cd, Hg, Pb, and As).

Fifteen poplar varieties were used in a field trial to investigate the phytoremediation efficiency, stress resistance, and wood property of poplar hybrid varieties with diverse genetic backgrounds under the composite pollution of heavy metals. The coefficient of variation and clone repeatability for growth traits and Cd concentration were large. The Cd accumulation of poplar varieties 107 and QHQ reached 1.9 and 1.7 mg, respectively, followed by QHB, Ti, 69, and Pa, in which Cd accumulation reached 1.3 mg. Most of the intra-specific hybrid varieties (69, QH1, SL4, T3, and ZL46) had low Cd concentrations and small biomass, resulting in weak Cd accumulation and low phytoremediation efficiency for Cd-polluted soil. By contrast, the inter-sectional and inter-specific hybrid varieties exhibited better growth performance and accumulated higher concentrations of heavy metals than the intra-specific hybrids. The bioconcentration factor and translocation factor of Hg, As, and Pb were less than 1, indicating that poplars have low phytoremediation efficiency for these heavy metals. The hybrids between section Aigeiros and Tacamahaca (QHQ and QHB) and the inter-specific hybrid 107 within section Aigeiros were more resistant to composite heavy metal stress than the other poplar varieties were partially because of their high levels of free proline that exceeded 93 µg·g-1 FW. According to the correlation analysis of the concentrations of the different heavy metals, the poplar roots absorbed different heavy metals in a cooperative manner, indicating that elite poplar varieties with superior capacity for accumulating diverse heavy metals can be bred feasibly. Compared with the intra-specific hybrid varieties, the inter-sectional (QHQ and QHB) and inter-specific (107) hybrid varieties had higher pollution remediation efficiency, larger biomass, higher cellulose content, and lower lignin content, which is beneficial for pulpwood. Therefore, breeding and extending inter-sectional (QHQ and QHB) and inter-specific hybrid varieties can improve the phytoremediation of composite pollution.

Blocking TGFßR synergistically enhances anti-tumor effects of anti-PD-1 antibody in a mouse model of incomplete thermal ablation.

The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy is reported to be ineffective to prevent the progression of residual tumor resulted from iMWA. Transforming growth factor-ß (TGFß) signaling pathway plays an important role in tumorigenesis and development. We assume blocking transforming growth factor-ß receptor (TGFßR) after incomplete iMWA may synergistically enhance the effect of anti-PD-1 antibody to prevent the progression of residual tumor. We construct an iMWA model with mice harboring Hepa1-6 derived xenograft. The Tgfb1 expression and phosphorylated-Smad3 protein expression is upregulated in the residual tumor after iMWA. With the application of TGFßR inhibitor SB431542, the cell proliferation potential, the tumor growth, the mRNA expression of epithelial mesenchymal transition (EMT) markers including Cdh2, and Vim, and cancer stem cell marker Epcam, and the infiltrating Treg cells are reduced in the residual tumor tissue. In addition, iMWA combined with TGFßR blocker and anti-PD-1 antibody further decreases the cell proliferation, tumor growth, expression of EMT markers and cancer stem cell marker, and the infiltrating Treg cells in the residual tumor tissue. Blocking TGFßR may alleviate the pro-tumoral effect of tumor microenvironment thereby significantly prevents the progression of residual tumor tissue. Our study indicates that blocking TGFßR may be a novel therapeutic strategy to enhance the effect of anti-PD-1 antibody to prevent residual hepatocellular carcinoma (HCC) progression after iMWA.

Low storage temperature affects quality and volatile compounds in fresh tomatoes.

To investigate the impact of low temperature on the quality and flavor of ripe red tomatoes, we analyzed transcriptomes and volatile metabolomes of ripe red fruits stored at 0 °C and 20 °C for 8 days. The results showed that 0 °C maintained the sugar content by increasing the expression of sucrose synthetase (SUS) and sucrose transporter (SUT). Low expression of aroma synthesis-related genes, such as alcohol dehydrogenase 1 (ADH1), amino acid decarboxylase 1 A (AADC1A), and branched-chain amino acid aminotransferase 2 (BCAT2), were associated with reduced levels of pentanal, hexanal, 3-methylbutanal, 2-methylbutanal, and 2-phenylethanol. Additionally, the expression of pectinesterase (PE), beta-galactosidase (ß-GAL), and beta-glucosidase (ß-Glu), as well as phytoene synthase1 (PSY1) involved in carotenoid synthesis, was inhibited, thereby maintaining fruits texture and color. Furthermore, storage at 0 °C induced the expression of numerous genes regulating antioxidant and heat shock proteins, which further preserved the postharvest quality of tomatoes.

High­oxygen-modified atmospheric packaging delays flavor and quality deterioration in fresh-cut broccoli.

The purpose of this study was to investigate the impact of high­oxygen-modified atmospheric packaging (HOMAP) on aroma changes in fresh-cut broccoli during storage and to explore its regulatory mechanisms. The results showed that HOMAP reduced the levels of undesirable aroma substances hexanoic acid, isobutyric acid, cyclopentanone and increased glucosinolate accumulation by inhibiting the expression of arogenate/prephenate dehydratase (ADT), bifunctional aspartate aminotransferase and glutamate/aspartate-prephenate aminotransferase (PAT), thiosulfate/3-mercaptopyruvate Transferase (TST) to reduce the odor of fresh-cut broccoli. HOMAP inhibited the expression of respiratory metabolism related genes 6-phosphate fructokinase 1 (PFK), pyruvate kinase (PK), and NADH-ubiquinone oxidoreductase chain 6 (ND6). In HOMAP group, the low expression of phospholipase C (PLC), phospholipase A1 (PLA1), linoleate 9S-lipoxygenase 1 (LOX1) related to lipid metabolism and the high expression of naringenin 3-dioxygenase (F3H), trans-4-Hydroxycinnamate (C4H), glutaredoxin 3 (GRX3), and thioredoxin 1 (TrX1) in the antioxidant system maintained membrane stability while reducing the occurrence of membrane lipid peroxidation.

Dynamics and Internal Structure Evolution during the Glass Transition of the Ethylene-Cyclic Olefin Copolymers: A Molecular Dynamics Simulation.

Amorphous ethylene-cyclic olefin copolymers (COCs) which can be used in cell phone lenses and prefilled syringes have attracted increasing attention due to their excellent and tunable thermal properties. In order to better explain the influence of COC microstructure (cyclic olefin types and content) on the glass transition mechanism, we used molecular dynamics (MD) simulations to track the evolution of free volume, diffusion coefficients, atomic mobility, trans conformation probabilities, and characteristic parameters of α-relaxation kinetics during the quenching process. MD results show that for the classic COC E-co-NB (ethylene-norbornene copolymer), an increase in cyclic olefin content from 25 to 50 mol % reduces atomic mobility, limiting the molecular chain movement at higher temperatures and improving Tg. Compared to NB, the more rigid rings in tricyclopentadiene (TCPD) and exo-1,4,4a,9,9a,10-hexahydro-9,10(1',2')-bridged phenylidene-1,4-bridged methylideneanthracene (HBM) have the following effects: (1) reducing the thermal expansion coefficient and overall chain mobility; (2) enhancing the diffusion energy barrier; (3) promoting the formation of local ordered structures; (4) accelerating α-relaxation dynamics at high temperatures and improving the dynamic fragility m. These lead to an upward shift in the temperature region where chain movement is limited and thus improve Tg and high-temperature dimensional stability. In this simulation, the correlation equation between Tg, m, and the microstructural parameters of COCs is established, which is of great significance for the development of COCs with high performance.

Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Correction: Suppression of Mitochondrial Complex I Influences Cell Metastatic Properties.

[This corrects the article DOI: 10.1371/journal.pone.0061677.].

Effects of nitrate- and ammonium- nitrogen on anatomical and physiological responses of Catalpa bungei under full and partial root-zone drought.

Catalpa bungei is a precious timber species distributed in North China where drought often occurs. To clarify adaptive responses of C. bungei to partial- and full- root-zone drought under the influence of nitrogen forms, a two-factor experiment was conducted in which well-watered (WW), partial root-zone drought in horizontal direction (H-PRD) and in vertical direction (V-PRD), and full root-zone drought (FRD) were combined with nitrate-nitrogen (NN) and ammonium-nitrogen (AN) treatments. C. bungei responded to FRD by sharply closing stomata, decreasing gas exchange rate and increasing leaf instantaneous water use efficiency (WUEi). Under FRD condition, the growth of seedlings was severely inhibited and the effect of N forms was covered up by the drastic drought effect. In comparison, stomata conductance and gas exchanges were moderately inhibited by PRDs. WUEi in V-PRD treatment was superior to H-PRD due to the active stomata regulation resulting from a higher ABA level and active transcription of genes in abscisic acid (ABA) signaling pathway under V-PRD. Under both PRDs and FRD, nitrate benefited antioxidant defense, stomata regulation and leaf WUEi. Under V-PRD, WUEi in nitrate treatment was superior to that in ammonium treatment due to active stomata regulation by signaling network of nitric oxide (NO), Ca2+ and ABA. Under FRD, WUEi was higher in nitrate treatment due to the favoring photosynthetic efficiency resulting from active NO signal and antioxidant defense. The interactive effect of water and N forms was significant on wood xylem development. Superoxide dismutase (SOD) and catalase (CAT) largely contributes to stress tolerance and xylem development.

Multiomics analyses of the effects of LED white light on the ripening of apricot fruits.

INTRODUCTION: Apricot (Prunus armeniaca L.) fruits are highly perishable and prone to quality deterioration during storage and transportation. OBJECTIVES: To investigate the effects of LED white light treatment on postharvest ripening of fruits using metabolomics, transcriptomics, and ATAC-Seq analysis. METHODS: Fruits were exposed to 5 µmol m-2 s-1 LED white light for 12 h followed by 12 h of darkness at 20 °C daily for 12 days. The effects of the treatments on the physiological and nutritional quality of the fruits were evaluated. These data were combined with transcriptomic, metabolomic, and ATAC-Seq data from fruits taken on 8 d of treatment to provide insight into the potential mechanism by which LED treatment delays ripening. RESULTS: LED treatment activated pathways involved in ascorbate and aldarate metabolism and flavonoid and phenylpropanoid biosynthesis. Specifically, LED treatment increased the expression of UDP-sugar pyrophosphorylase (USP), L-ascorbate peroxidase (AO), dihydroflavonol 4-reductase (DFR), chalcone synthase (CHS), and caffeoyl-CoA O-methyltransferase (CCOAOMT1), leading to the accumulation of caffeoyl quinic acid, epigallocatechin, and dihydroquercetin and the activation of anthocyanin biosynthesis. LED treatment also affected the expression of genes associated with plant hormone signal transduction, fruit texture and color transformation, and antioxidant activity. The notable genes affected by LED treatment included 1-aminocyclopropane-1-carboxylate synthase (ACS), 1-aminocyclopropane-1-carboxylate oxidase (ACO), hexokinase (HK), lipoxygenase (LOX), malate dehydrogenase (MDH), endoglucanase (CEL), various transcription factors (TCP, MYB, EFR), and peroxidase (POD). ATAC-Seq analysis further revealed that LED treatment primarily regulated phenylpropanoid biosynthesis. CONCLUSION: The results obtained in this study provide insights into the effects of LED light exposure on apricot fruits ripening. LEDs offer a promising approach for extending the shelf life of other fruits and vegetables.

Revealing the Effect of the Molecular Weight Distribution on the Chain Diffusion and Crystallization Process under a Branched Trimodal Polyethylene System.

With the increasing demand for high-end materials, trimodal polyethylene (PE) has become a research hotspot in recent years due to its superior performance compared with bimodal PE. By means of molecular dynamics (MD) simulations, we aim to expound the effect of the molecular weight distribution (MWD) on the mechanism of nucleation and crystallization of trimodal PE. The crystallization rate is faster when short-chain branching is distributed on a single backbone compared to that on two backbones. In addition, as the content of high molecular weight backbone decreases, the time required for nucleation decreases, but the crystallization rate slows down. This is because low molecular weight backbones undergo intra-chain nucleation and crystallize earlier due to the high diffusion capacity, which leads to entanglement that prevents the movement of medium or high molecular weight backbones. Furthermore, crystallized short backbones hinder the movement and crystallization of other backbones. What is more, a small increase in the high molecular weight branched backbone of trimodal PE can make the crystallinity greater than that of bimodal PE, but when the content of high molecular weight backbone is too high, the crystallinity decreases instead, because the contribution of short and medium backbones to high crystallinity is greater than that of long backbones.

Activated phosphoinositide 3-kinase δ syndrome caused by PIK3CD mutations: expanding the phenotype.

BACKGROUND: Germline heterozygous gain-of-function (GOF) mutations in the PIK3CD gene lead to a rare primary immunodeficiency disease known as activated phosphoinositide 3-kinase (PI3K) δ syndrome type 1(APDS1). Affected patients present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation, increased levels of serum immunoglobulin (Ig) M, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia. Due to highly heterogeneous phenotypes of APDS1, it is very likely that suspected cases may be misdiagnosed. METHODS: Herein we reported three patients with different clinical presentations but harboring pathogenic variants in PIK3CD gene detected by trio whole-exome sequencing (trio-WES) and confirmed by subsequent Sanger sequencing. RESULTS: Two heterozygous mutations (c.3061G > A, p.E1021K and c.1574 A > G, p.E525G) in PIK3CD (NM_005026.3) were identified by whole exome sequencing (WES) in the three patients. One of two patients with the mutation (c.3061G > A) presented with abdominal pain and diarrhea as the first symptoms, which was due to intussusception caused by multiple polyps of colon. The patient with mutation (c.1574 A > G) had an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-like clinical manifestations, including multisystemic inflammation, acute nephritic syndrome, and positive perinuclear ANCA (p-ANCA), thus the diagnosis of ANCA-AAV was considered. CONCLUSIONS: Our study expands the spectrums of clinical phenotype and genotype of APDS, and demonstrates that WES has a high molecular diagnostic yield for patients with immunodeficiency related symptoms, such as respiratory infections, multiple ecchymosis, ANCA-associated vasculitis, multiple ileocecal polyps, hepatosplenomegaly, and lymphoid hyperplasia. TRIAL REGISTRATION: Retrospectively registered.

The Role of KDM2A and H3K36me2 Demethylation in Modulating MAPK Signaling During Neurodevelopment.

Intellectual disability (ID) is a condition characterized by cognitive impairment and difficulties in adaptive functioning. In our research, we identified two de novo mutations (c.955C>T and c.732C>A) at the KDM2A locus in individuals with varying degrees of ID. In addition, by using the Gene4Denovo database, we discovered five additional cases of de novo mutations in KDM2A. The mutations we identified significantly decreased the expression of the KDM2A protein. To investigate the role of KDM2A in neural development, we used both 2D neural stem cell models and 3D cerebral organoids. Our findings demonstrated that the reduced expression of KDM2A impairs the proliferation of neural progenitor cells (NPCs), increases apoptosis, induces premature neuronal differentiation, and affects synapse maturation. Through ChIP-Seq analysis, we found that KDM2A exhibited binding to the transcription start site regions of genes involved in neurogenesis. In addition, the knockdown of KDM2A hindered H3K36me2 binding to the downstream regulatory elements of genes. By integrating ChIP-Seq and RNA-Seq data, we made a significant discovery of the core genes' remarkable enrichment in the MAPK signaling pathway. Importantly, this enrichment was specifically linked to the p38 MAPK pathway. Furthermore, disease enrichment analysis linked the differentially-expressed genes identified from RNA-Seq of NPCs and cerebral organoids to neurodevelopmental disorders such as ID, autism spectrum disorder, and schizophrenia. Overall, our findings suggest that KDM2A plays a crucial role in regulating the H3K36me2 modification of downstream genes, thereby modulating the MAPK signaling pathway and potentially impacting early brain development.

Unraveling the influential mechanism of short-chain branching on the crystallization of trimodal polyethylene by molecular dynamics simulation.

Trimodal polyethylene (PE) has become the focus of research in recent years due to its excellent performance. By means of molecular dynamics simulations, we aim to expound the molecular mechanism of short-chain branching (SCB) in the nucleation process, crystallization process and chain entanglement of trimodal PE. In this study, a series of polyethylene models including different short-chain branching concentrations (SCBCs), short-chain branching lengths (SCBLs), and short-chain branching distributions (SCBDs) were considered. The increase of SCBCs greatly reduces the ability of flipping and movement of PE chains, resulting in more time for nucleation and crystallization and a significant reduction of crystallinity. In contrast, an increase in the SCBL only slightly slows down the diffusion rate of the chain, which leads to a little increase in crystallization time. Most important of all, in the study of SCBD, we find that the distribution of SCBs on a high molecular weight chain, which is the characteristic of trimodal PE, is conducive to the chain entanglement and prevents the occurrence of micro phase separation compared with the case where the SCBs are distributed on a medium molecular weight chain. The mechanism of chain entanglement is proposed to explain the effect of SCBs on tie chain entanglement.

Combined effects of high-fat diet and polystyrene microplastic exposure on microplastic bioaccumulation and lipid metabolism in zebrafish.

Extensive use of microplastics (MPs) threatens the safety of aquatic environments and hydrobionts. Increasing the weight of economic fish through high-fat diet (HFD) to increase production is common in aquaculture. However, little is known about the combined effects of MPs and HFD in fish. The aim of this study was to investigate the relationship between adiposity and MP bioaccumulation in fish. Using zebrafish as a vertebrate model, the content of polystyrene (PS) MPs in zebrafish tissues exposed to 5 and 50 µm of 1000 µg/L PS MPs was detected via confocal Raman spectroscopy in normal diet (ND) and HFD. The content of PS MPs in HFD group was significantly higher than that in ND group. The levels of hepatic lipids were significantly elevated in zebrafish subjected to HFD treatment, and this effect was aggravated by exposure to 5 µm PS MPs, and even caused liver injury. Transcriptomic analysis revealed that exposure to PS MPs interferes with hepatic lipid metabolism and energy homeostasis in zebrafish. These results suggests that in addition to controlling the use and performing proper recycling of plastic products in our daily life, we should not blindly increase the weight of fish through HFD. This aids protect the quality of economic fish and prevent MPs from being consumed by humans through the food chain. This study explored the interaction between fish feed culture and environmental pollutants to provide important reference for fish culture.

Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment.

Introduction: Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of metabolic disorders caused by abnormal protein or lpid glycosylation. DPM2 is one subunit of a heterotrimeric complex for dolichol-phosphatemannose synthase (DPMS), a key enzyme in glycosylation, and only four patients with DPM2-CDG have been reported. Methods: Whole-exome sequencing (WES) was performed in a Chinese family having two siblings with a mild form of DPM2-CDG with developmental delay, mild intellectual disability, hypotonia, and increased serum creatine kinase. Sanger sequencing was used to validate the variants identified in the siblings and their parents. In vitro functional study was performed. Results: A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863) was identified by whole exome sequencing (WES). In vitro functional analysis demonstrated that this variant increased the expression level of DPM2 protein and western blot revealed a significant decrease in ICAM1, a universal biomarker for hypoglycosylation in patients with CDG, suggesting abnormal N-linked glycosylation. We also reviewed the 4 previously reported patients carrying homozygous or compound heterozygous variants of DMP2 gene, and found that patients with variants within the region encoding the first domain had more severe clinical symptoms than those with variants within the second domain. However, the actual genotype-phenotype relationship needs more study. Discussion: Overall, our study broadens the variant spectrum of DPM2 gene, attempts to explain the different phenotypes in patients with different DPM2 variants, and emphasizes the need of further functional studies to understand the underlying pathophysiology of the phenotypic heterogeneity.

The potential of 1.5 T magnetic resonance imaging for the evaluation of fetal anomalies of the great vessels.

Purpose: To determine the efficacy of 1.5 T magnetic resonance imaging (MRI) for the diagnosis of anomalies of the fetal great arteries with comparison to fetal ultrasound, and to compare image quality between 1.5 T and 3.0 T MRI in fetal imaging of the great arteries. Methods: We compared the results of postnatal exam or surgery and evaluated the application value of prenatal 1.5 T MRI in the assessment of fetal great-vessel anomalies. To further determine the diagnostic potential of 1.5 T MRI, 23 pregnant women with suspected fetal cardiovascular abnormalities who had undergone ultrasound and 3.0 T MRI were enrolled and compared, respectively. Results: Prenatal MRI was superior to ultrasound in demonstrating aortic arch and branch abnormalities (sensitivity, 92.86% vs. 83.33%; specificity, 66.67% vs. 20%). The mean quality ratings for fetal MRI at 1.5 T was higher than 3.0 T (P < 0.001). Other than the fast scan speed afforded by 3.0 T MRI, the signal noise ratio (SNR) of 1.5 T MRI were higher than those of 3.0 T MRI; however, the difference in contrast to noise ratio (CNR) between the two imaging modalities was not statistically significant. Conclusions: 1.5 T MRI can achieve an overall assessment of fetal great-vessel anomalies, especially aortic arch and branch abnormalities. Therefore, 1.5 T MRI can be considered a supplementary imaging modality for the prenatal assessment of extracardiac great vessels malformations.

Functional characterization of a DNA-damage repair/tolerance 100 (DRT100) gene in Sedum alfredii Hance for genome stability maintenance and Cd hypertolerance.

Cd contamination is a world-wild concern for its toxicity and accumulation in food chain. Sedum alfredii Hance (Crassulaceae) is a zinc (Zn) and cadmium (Cd) hyperaccumulator native to China and widely applied for the phytoremediation at Zn or Cd contaminated sites. Although many studies report the uptake, translocation and storage of Cd in S. alfredii Hance, limited information is known about the genes and underlying mechanisms of genome stability maintenance under Cd stress. In this study, a gene resembling DNA-damage repair/toleration 100 (DRT100) was Cd inducible and designated as SaDRT100. Heterologous expression of SaDRT100 gene in yeasts and Arabidopsis thaliana enhanced Cd tolerance capability. Under Cd stress, transgenic Arabidopsis with SaDRT100 gene exhibited lower levels of reactive oxygen species (ROS), fewer Cd uptake in roots and less Cd-induced DNA damage. Evidenced by the subcellular location in cellular nucleus and expression in aerial parts, we suggested the involvement of SaDRT100 in combating Cd-induced DNA damage. Our findings firstly uncovered the roles of SaDRT100 gene in Cd hypertolerance and genome stability maintenance in S. alfredii Hance. The potential functions of DNA protection make SaDRT100 gene a candidate in genetic engineering for phytoremediation at multi-component contaminated sites.

HIF-1 inhibitor-based one-stone-two-birds strategy for enhanced cancer chemodynamic-immunotherapy.

Based on its ability to induce strong immunogenic cell death (ICD), chemodynamic therapy (CDT) was elaborately designed to combine with immunotherapy for a synergistic anticancer effect. However, hypoxic cancer cells can adaptively regulate hypoxia-inducible factor-1 (HIF-1) pathways, leading to a reactive oxygen species (ROS)-homeostatic and immunosuppressive tumor microenvironment. Consequently, both ROS-dependent CDT efficacy and immunotherapy are largely diminished, further lowering their synergy. Here, a liposomal nanoformulation co-delivering a Fenton catalyst copper oleate and a HIF-1 inhibitor acriflavine (ACF) was reported for breast cancer treatment. Through in vitro and in vivo experiments, copper oleate-initiated CDT was proven to be reinforced by ACF through HIF-1-glutathione pathway inhibition, thus amplifying ICD for better immunotherapeutic outcomes. Meanwhile, ACF as an immunoadjuvant significantly reduced the levels of lactate and adenosine, and downregulated the expression of programmed death ligand-1 (PD-L1), thereby promoting the antitumor immune response in a CDT-independent manner. Hence, the "one stone" ACF was fully taken advantage of to enhance CDT and immunotherapy (two birds), both of which contributed to a better therapeutic outcome.