YTHDF1 promotes gallbladder cancer progression via post-transcriptional regulation of the m6A/UHRF1 axis.

Gallbladder cancer is a rare but fatal malignancy. However, the mechanisms underlying gallbladder carcinogenesis and its progression are poorly understood. The function of m6A modification and its regulators was still unclear for gallbladder cancer. The current study seeks to investigate the function of YTH m6A RNA-binding protein 1 (YTHDF1) in gallbladder cancer. Transcriptomic analysis and immunochemical staining of YTHDF1 in gallbladder cancer tissues revealed its upregulation compared to paracancerous tissues. Moreover, YTHDF1 promotes the proliferation assays, Transwell migration assays, and Transwell invasion assays of gallbladder cancer cells in vitro. And it also increased tumour growth in xenograft mouse model and metastases in tail vein injection model in vivo. In vitro, UHRF1 knockdown partly reversed the effects of YTHDF1 overexpression. Mechanistically, dual-luciferase assays proved that YTHDF1 promotes UHRF1 expression via direct binding to the mRNA 3'-UTR in a m6A-dependent manner. Overexpression of YTHDF1 enhanced UHRF1 mRNA stability, as demonstrated by mRNA stability assays, and Co-IP studies confirmed a direct interaction between YTHDF1 and PABPC1. Collectively, these findings provide new insights into the progression of gallbladder cancer as well as a novel post-transcriptional mechanism of YTHDF1 via stabilizing target mRNA.

M6A RNA methylation in biliary tract cancer: the function roles and potential therapeutic implications.

Biliary tract cancers (BTCs) are relatively rare malignancies with a poor prognosis. For advanced BTCs, the efficacy of current chemotherapeutic approaches is limited. Consequently, there is an urgent need to deepen our understanding of the molecular mechanisms underlying BTC tumorigenesis and development for the exploration of effective targeted therapies. N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryotes, is found usually dysregulated and involved in tumorigenesis, progression, and drug resistance in tumors. Numerous studies have confirmed that aberrant m6A regulators function as either oncogenes or tumor suppressors in BTCs by the reversible regulation of RNA metabolism, including splicing, export, degradation and translation. In this review, we summarized the current roles of the m6A regulators and their functional impacts on RNA fate in BTCs. The improved understanding of m6A modification in BTCs also provides a reasonable outlook for the exploration of new diagnostic strategies and efficient therapeutic targets.

Fast growth of single-crystal covalent organic frameworks for laboratory x-ray diffraction.

The imine-exchange strategy makes single-crystal growth of covalent organic frameworks (COFs) with large size (>15 microns) possible but is a time-consuming process (15 to 80 days) that has had limited success (six examples) and restricts structural characterization to synchrotron-radiation sources for x-ray diffraction studies. We developed a CF3COOH/CF3CH2NH2 protocol to harvest single-crystal COFs within 1 to 2 days with crystal sizes of up to 150 microns. The generality was exemplified by the feasible growth of 16 high-quality single-crystal COFs that were structurally determined by laboratory single-crystal x-ray diffraction with resolutions of up to 0.79 angstroms. The structures obtained included uncommon interpenetration of networks, and the details of the structural evolution of conformational isomers and host-guest interaction could be determined at the atomic level.

A Comprehensive Analysis of Auxin Response Factor Gene Family in Melastoma dodecandrum Genome.

Auxin Response Factors (ARFs) mediate auxin signaling and govern diverse biological processes. However, a comprehensive analysis of the ARF gene family and identification of their key regulatory functions have not been conducted in Melastoma dodecandrum, leading to a weak understanding of further use and development for this functional shrub. In this study, we successfully identified a total of 27 members of the ARF gene family in M. dodecandrum and classified them into Class I-III. Class II-III showed more significant gene duplication than Class I, especially for MedARF16s. According to the prediction of cis-regulatory elements, the AP2/ERF, BHLH, and bZIP transcription factor families may serve as regulatory factors controlling the transcriptional pre-initiation expression of MedARF. Analysis of miRNA editing sites reveals that miR160 may play a regulatory role in the post-transcriptional expression of MeARF. Expression profiles revealed that more than half of the MedARFs exhibited high expression levels in the stem compared to other organs. While there are some specific genes expressed only in flowers, it is noteworthy that MedARF16s, MedARF7A, and MedARF9B, which are highly expressed in stems, also demonstrate high expressions in other organs of M. dodecandrum. Further hormone treatment experiments revealed that these MedARFs were sensitive to auxin changes, with MedARF6C and MedARF7A showing significant and rapid changes in expression upon increasing exogenous auxin. In brief, our findings suggest a crucial role in regulating plant growth and development in M. dodecandrum by responding to changes in auxin. These results can provide a theoretical basis for future molecular breeding in Myrtaceae.

General Analysis of Heat Shock Factors in the Cymbidium ensifolium Genome Provided Insights into Their Evolution and Special Roles with Response to Temperature.

Heat shock factors (HSFs) are the key regulators of heat stress responses and play pivotal roles in tissue development and the temperature-induced regulation of secondary metabolites. In order to elucidate the roles of HSFs in Cymbidium ensifolium, we conducted a genome-wide identification of CeHSF genes and predicted their functions based on their structural features and splicing patterns. Our results revealed 22 HSF family members, with each gene containing more than one intron. According to phylogenetic analysis, 59.1% of HSFs were grouped into the A subfamily, while subfamily HSFC contained only two HSFs. And the HSF gene families were differentiated evolutionarily between plant species. Two tandem repeats were found on Chr02, and two segmental duplication pairs were observed on Chr12, Chr17, and Chr19; this provided evidence for whole-genome duplication (WGD) events in C. ensifolium. The core region of the promoter in most CeHSF genes contained cis-acting elements such as AP2/ERF and bHLH, which were associated with plant growth, development, and stress responses. Except for CeHSF11, 14, and 19, each of the remaining CeHSFs contained at least one miRNA binding site. This included binding sites for miR156, miR393, and miR319, which were responsive to temperature and other stresses. The HSF gene family exhibited significant tissue specificity in both vegetative and floral organs of C. ensifolium. CeHSF13 and CeHSF15 showed relatively significant expression in flowers compared to other genes. During flower development, CeHSF15 exhibited markedly elevated expression in the early stages of flower opening, implicating critical regulatory functions in organ development and floral scent-related regulations. During the poikilothermic treatment, CeHSF14 was upregulated over 200-fold after 6 h of heat treatment. CeHSF13 and CeHSF14 showed the highest expression at 6 h of low temperature, while the expression of CeHSF15 and CeHSF21 continuously decreased at a low temperature. The expression patterns of CeHSFs further confirmed their role in responding to temperature stress. Our study may help reveal the important roles of HSFs in plant development and metabolic regulation and show insight for the further molecular design breeding of C. ensifolium.

The Genome-Level Survey of the WOX Gene Family in Melastoma dodecandrum Lour.

Though conserved in higher plants, the WOX transcription factors play crucial roles in plant growth and development of Melastoma dodecandrum Lour., which shows pioneer position in land ecosystem formation and produces nutritional fruits. Identifying the WOX family genes in M. dodecandrum is imperative for elucidating its growth and development mechanisms. However, the WOX genes in M. dodecandrum have not yet been characterized. In this study, by identification 22 WOX genes in M. dodecandrum based on current genome data, we classified family genes into three clades and nine types with homeodomains. We highlighted gene duplications of MedWOX4, which offered evidences of whole-genome duplication events. Promoter analysis illustrated that cis-regulatory elements related to light and stress responses and plant growth were enriched. Expression pattern and RT-qPCR results demonstrated that the majority of WOX genes exhibited expression in the stem. MedWOX13s displayed highest expression across various tissues. MedWOX4s displayed a specific expression in the stem. Collectively, our study provided foundations for elucidating WOX gene functions and further molecular design breeding in M. dodecandrum.

Bioinformatic Assessment and Expression Profiles of the AP2/ERF Superfamily in the Melastoma dodecandrum Genome.

AP2/ERF transcription factors play crucial roles in various biological activities, including plant growth, development, and responses to biotic and abiotic stressors. However, limited research has been conducted on the AP2/ERF genes of Melastoma dodecandrum for breeding of this potential fruit crop. Leveraging the recently published whole genome sequence, we conducted a comprehensive assessment of this superfamily and explored the expression patterns of AP2/ERF genes at a genome-wide level. A significant number of genes, totaling 218, were discovered to possess the AP2 domain sequence and displayed notable structural variations among five subfamilies. An uneven distribution of these genes was observed on 12 pseudochromosomes as the result of gene expansion facilitated by segmental duplications. Analysis of cis-acting elements within promoter sites and 87.6% miRNA splicing genes predicted their involvement in multiple hormone responses and abiotic stresses through transcriptional and post-transcriptional regulations. Transcriptome analysis combined with qRT-PCR results indicated that certain candidate genes are involved in tissue formation and the response to developmental changes induced by IAA hormones. Overall, our study provides valuable insights into the evolution of ERF genes in angiosperms and lays a solid foundation for future breeding investigations aimed at improving fruit quality and enhancing adaptation to barren land environments.

The Value of VR-PVEP in Objective Evaluation of Monocular Refractive Visual Impairment.

OBJECTIVES: To study the virtual reality-pattern visual evoked potential (VR-PVEP) P100 waveform characteristics of monocular visual impairment with different impaired degrees under simultaneous binocular perception and monocular stimulations. METHODS: A total of 55 young volunteers with normal vision (using decimal recording method, far vision ≥0.8 and near vision ≥0.5) were selected to simulate three groups of monocular refractive visual impairment by interpolation method. The sum of near and far vision ≤0.2 was Group A, the severe visual impairment group; the sum of near and far vision <0.8 was Group B, the moderate visual impairment group; and the sum of near and far vision ≥0.8 was Group C, the mild visual impairment group. The volunteers' binocular normal visions were set as the control group. The VR-PVEP P100 peak times measured by simultaneous binocular perception and monocular stimulation were compared at four spatial frequencies 16×16, 24×24, 32×32 and 64×64. RESULTS: In Group A, the differences between P100 peak times of simulant visual impairment eyes and simultaneous binocular perception at 24×24, 32×32 and 64×64 spatial frequencies were statistically significant (P<0.05); and the P100 peak time of normal vision eyes at 64×64 spatial frequency was significantly different from the simulant visual impairment eyes (P<0.05). In Group B, the differences between P100 peak times of simulant visual impairment eyes and simultaneous binocular perception at 16×16, 24×24 and 64×64 spatial frequencies were statistically significant (P<0.05); and the P100 peak time of normal vision eyes at 64×64 spatial frequency was significantly different from the simulant visual impairment eyes (P<0.05). In Group C, there was no significant difference between P100 peak times of simulant visual impairment eyes and simultaneous binocular perception at all spatial frequencies (P>0.05). There was no significant difference in the P100 peak times measured at all spatial frequencies between simulant visual impairment eyes and simultaneous binocular perception in the control group (P>0.05). CONCLUSIONS: VR-PVEP can be used for visual acuity evaluation of patients with severe and moderate monocular visual impairment, which can reflect the visual impairment degree caused by ametropia. VR-PVEP has application value in the objective evaluation of visual function and forensic clinical identification.

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A-dependent DAPK3 degradation.

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA-binding protein YT521-B homology domain-containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP-seq), m6A-modified RIP-seq, and RNA sequencing, which revealed that death-associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3'-UTR of DAPK3 mRNA and facilitates its degradation in an m6A-dependent manner. DAPK3 inhibition restores the tumor-suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A-dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC.

Predicting visual acuity with machine learning in treated ocular trauma patients.

AIM: To predict best-corrected visual acuity (BCVA) by machine learning in patients with ocular trauma who were treated for at least 6mo. METHODS: The internal dataset consisted of 850 patients with 1589 eyes and an average age of 44.29y. The initial visual acuity was 0.99 logMAR. The test dataset consisted of 60 patients with 100 eyes collected while the model was optimized. Four different machine-learning algorithms (Extreme Gradient Boosting, support vector regression, Bayesian ridge, and random forest regressor) were used to predict BCVA, and four algorithms (Extreme Gradient Boosting, support vector machine, logistic regression, and random forest classifier) were used to classify BCVA in patients with ocular trauma after treatment for 6mo or longer. Clinical features were obtained from outpatient records, and ocular parameters were extracted from optical coherence tomography images and fundus photographs. These features were put into different machine-learning models, and the obtained predicted values were compared with the actual BCVA values. The best-performing model and the best variable selected were further evaluated in the test dataset. RESULTS: There was a significant correlation between the predicted and actual values [all Pearson correlation coefficient (PCC)>0.6]. Considering only the data from the traumatic group (group A) into account, the lowest mean absolute error (MAE) and root mean square error (RMSE) were 0.30 and 0.40 logMAR, respectively. In the traumatic and healthy groups (group B), the lowest MAE and RMSE were 0.20 and 0.33 logMAR, respectively. The sensitivity was always higher than the specificity in group A, in contrast to the results in group B. The classification accuracy and precision were above 0.80 in both groups. The MAE, RMSE, and PCC of the test dataset were 0.20, 0.29, and 0.96, respectively. The sensitivity, precision, specificity, and accuracy of the test dataset were 0.83, 0.92, 0.95, and 0.90, respectively. CONCLUSION: Predicting BCVA using machine-learning models in patients with treated ocular trauma is accurate and helpful in the identification of visual dysfunction.

Risk control of host cell proteins in one therapeutic antibody produced by concentrated fed-batch (CFB) mode.

Multiple control strategies, including a downstream purification process with well-controlled parameters and a comprehensive release or characterization for intermediates or drug substances, were implemented to mitigate the potential risk of host cell proteins (HCPs) in one concentrated fed-batch (CFB) mode manufactured product. A host cell process specific enzyme-linked immunosorbent assay (ELISA) method was developed for the quantitation of HCPs. The method was fully validated and showed good performance including high antibody coverage. This was confirmed by 2D Gel-Western Blot analysis. Furthermore, a LC-MS/MS method with non-denaturing digestion and a long gradient chromatographic separation coupled with data dependent acquisition (DDA) on a Thermo/QE-HF-X mass spectrometer was developed as an orthogonal method to help identify the specific types of HCPs in this CFB product. Because of the high sensitivity, selectivity and adaptability of the new developed LC-MS/MS method, significantly more species of HCP contaminants were able to be identified. Even though high levels of HCPs were observed in the harvest bulk of this CFB product, the development of multiple processes and analytical control strategies may greatly mitigate potential risks and reduce HCPs contaminants to a very low level. No high-risk HCP was identified and the total amount of HCPs was very low in the CFB final product.

Integrin α6 Targeted Near Infrared Fluorescent Imaging and Photoacoustic Imaging of Hepatocellular Carcinoma in Mice.

Background and Aims: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death and ranks sixth in terms of incident cases worldwide. The purpose of this study was to develop an effective and sensitive method to distinguish liver cancer tissues from normal tissues in HCC patients. Integrin α6 is a promising cell surface target for molecular imaging of HCC, where it is overexpressed and is a prognostic biomarker. We previously identified an integrin α6-targeted peptide CRWYDENAC (RWY) that has been used for positron emission tomography (PET) imaging of HCC in mouse models. Methods: We labeled the integrin α6-targeted RWY peptide with cyanine 7 (Cy7) to form an optical probe (Cy7-RWY) for near infrared fluorescent (NIRF) and photoacoustic (PA) imaging in HCC. Mice transplanted with subcutaneous HCC-LM3 or orthotopic HCC-H22 cells that overexpressed integrin α6 were intravenously injected with Cy7-RWY and its corresponding Cy7-control. NIRF and PA images of mice were collected from 0 to 48 h after injection. Results: Both NIRF and PA signals started to accumulate in the tumor 2 h after injection of Cy7-RWY and peaked at 24 h. Conclusions: Cy7-RWY is a promising optical probe for NIRF and PA imaging of HCC in mice, and has potential clinical application for HCC detection.

The value of PMCTA in the diagnosis of coronary atherosclerosis in isolated human hearts.

Postmortem computed tomography (PMCT) has a limited value in investigating coronary artery disease, despite several obvious advantages over the conventional autopsy. To address this issue, postmortem computed tomography angiography (PMCTA) has been introduced into various studies, where it has been used to investigate natural and unnatural deaths involving vascular damage, occlusion, or other pathologies of the vascular system. To investigate the application value of PMCTA in the diagnosis of coronary artery stenosis in ex situ hearts, the water-based contrast media were injected into isolated hearts, scaned, and finally compared with gold standards (autopsy and histology findings of the coronary artery). This study involved 16 subjects from the Academy of Forensic Science who were suspected to have died of sudden death without traumatic injuries. Unenhanced PMCT was performed first, followed by PMCTA using a water-based contrast agent, injected into the coronary arteries of isolated hearts using a self-designed angiography device. The image data were reconstructed into three-dimensional (3D) angiography images using software in the angiography facility. The 3D images were recorded and evaluated by two radiologists and then statistically analysed. The results of PMCTA were consistent with the gold standards for the diagnosis of coronary artery stenosis (P > 0.05). However, water-based contrast media can only be used to examine the pathological changes of blood vessels, which may have limitations in the diagnosis of causes of death such as myocardial oedema. PMCTA can be used as a new method to evaluate the degree of coronary atherosclerosis in addition to traditional autopsy. The 3D reconstruction technique reveals the coronary artery lesions more objectively and vividly and provides the opportunity to re-read the data at any time. Key points: The methods and parameters for coronary angiography in isolated human hearts were standardized based on the previous researcher.PMCTA in isolated human hearts is including the 3D reconstruction technique that reveals the coronary artery lesions more objectively and vividly, and provides the opportunity to re-read the data at anytime.PMCTA could only be used to examine the pathological changes of blood vessels, which might have limitations for the diagnosis of causes of death.PMCTA in isolated human hearts can be viewed as an auxiliary method for establishing the cause of death, which can provide an assessment of degree and extent of arterial stenosis and accurately help determine the abnormal location.

Upregulation of hypothalamic POMC neurons after biliary diversion in GK rats.

Background: Bile acids are important signaling molecules that might activate hypothalamic neurons. This study aimed to investigate possible changes in hypothalamic pro-opiomelanocortin (POMC) neurons after biliary diversion in diabetic rats. Methods: Ten GK rats were randomly divided into the biliary diversion (BD) and sham groups. The glucose metabolism, hypothalamic POMC expression, serum bile acid profiles, and ileal bile acid-specific receptors of the two groups were analyzed. Results: Biliary diversion improved blood glucose (P = 0.001) and glucose tolerance (P = 0.001). RNA-Seq of the hypothalamus showed significantly upregulated expression of the POMC gene (log2-fold change = 4.1, P < 0.001), which also showed increased expression at the protein (P = 0.030) and mRNA (P = 0.004) levels. The POMC-derived neuropeptide α-melanocyte stimulating hormone (α-MSH) was also increased in the hypothalamus (2.21 ± 0.11 ng/g, P = 0.006). In addition, increased taurocholic acid (TCA) (108.05 ± 20.62 ng/mL, P = 0.003) and taurodeoxycholic acid (TDCA) (45.58 ± 2.74 ng/mL, P < 0.001) were found in the BD group and induced the enhanced secretion of fibroblast growth factor-15 (FGF15, 74.28 ± 3.44 pg/ml, P = 0.001) by activating farnesoid X receptor (FXR) that was over-expressed in the ileum. Conclusions: Hypothalamic POMC neurons were upregulated after BD, and the increased TCA, TDCA, and the downstream gut-derived hormone FGF15 might activate POMC neurons.

Effects of methanol and formic acid on CRYB, ALDH2, and ATP5A1 of RGCs.

OBJECTIVE: To explore the toxicity of methanol and its metabolite, formic acid on αB-crystallin(CRYB), aldehyde dehydrogenase (ALDH2), and ATPsynthase (ATP5A1) of rat retinal ganglion cells (RGCs). METHODS: RGCs are cultured in vitro in a toxic environment with 15/30/60 mM methanol or formic acid, respectively. Then, the morphological changes of RGCs and protein and mRNA levels of ALDH2, ATP5A1, and CRYB in rat RGCs were evaluated. RESULTS: 1) Compared to the toxicity of 15 mM formic acid on RGCs, 30 mM of formic acid environment significantly promoted apoptosis, and cell death occurred in the 60-mM formic acid group 24 h later. The toxicity of methanol for inducing apoptosis was not as obvious as formic acid. 2) In the 15-mM group, the level of CRYB protein was down-regulated after stimulating with both methanol and formic acid for 48 h, and ATP5A1 protein level decreased significantly with formic but not methanol. No change in ALDH2 was observed in methanol or formic acid. With a prolonged duration (>7 d) or high concentration (>30 mM) stimulation, cells treated with both methanol and formic acid showed severe apoptosis, rendering it challenging to collect a sufficient number of cells for protein detection. 3) In the 48-h group, no significant effect was detected on the mRNA of CRYB, ATP5A1, and ALDH2 by both 15/30 mM formic acid and 15 mM methanol. Conversely, 30 mM methanol had a significant up-regulation effect on the expression of the three genes, while no significant effect was observed in the 7-d groups. CONCLUSIONS: Formic acid exerted stronger toxicity on CRYB, ATP5A1, and ALDH2 than methanol and played a regulatory role at the translation level, while the effect of methanol is still uncertain, needing additional investigation.

Stable immobilization of uranium in iron containing environments with microbial consortia enriched via two steps accumulation method.

The stable stabilization of uranium (U) in iron (Fe) containing environments is restricted by the reoxidation of UO2. In the current study, based on air reoxidation tests, we propose a novel two steps accumulation method to enrich microbial consortia from paddy soil. The constructed microbial consortia, denoted as the Fe-U bacteria, can co-precipitate U and Fe to form stable Fe-U solids. Column experiments running for 4 months demonstrated the production of U(IV)-O-Fe(II) precipitates containing maximum of 39.51% uranium in the presence of Fe-U bacteria. The reoxidation experiments revealed the U(IV)-O-Fe(II) precipitates were more stable than UO2. 16S rDNA high throughput sequencing analysis demonstrated that Acinetobacter and Stenotrophomonas were responsible for Fe and U precipitation, while, Caulobacteraceae and Aminobacter were crucial for the formation of U(VI)-PO4 chemicals. The proposed two steps accumulation method has an extraordinary application potential in stable immobilization of uranium in iron containing environments.

Constructing new Fe3O4@MnOx with 3D hollow structure for efficient recovery of uranium from simulated seawater.

Enrichment of uranium from seawater is a promising method for addressing the energy crisis. Current technologies are generally not effective for enriching uranium from seawater because its concentration in seawater is low. In this study, new Fe3O4@MnOx with 3D hollow structure, which is capable of enriching low concentration uranium, was prepared via a novel redox etching method. The physicochemical characteristics of Fe3O4@MnOx were studied with TEM, HRTEM, SEAD, FTIR, XRD, and N2 adsorption-desorption analysis. Dynamic kinetic studies of different initial U(VI) concentrations revealed that the pseudo-second-order model fit the sorption process better, and the sorption rates of Fe3O4@MnOx in 1, 10, and 25 mg/L U(VI) solution were 0.0124, 0.00298, and 0.000867 g/mg·min, respectively. Isothermal studies showed that the maximum sorption amounts were 50.09, 56.27, and 64.62 mg/g for 1, 10, and 25 mg/L U(VI), respectively, at pH 5.0 and 313 K, suggesting that Fe3O4@MnOx could effectively enrich low concentration U(VI) from water. The sorption amount of U(VI) did not significantly decrease in the presence of Na+, Mg2+, and Ca2+. HRTEM, FTIR, and XPS results demonstrated that Fe(II) and Mn/Fe-O-H active sites in Fe3O4@MnOx were accounted for the high and specific enrichment efficiency. A column experiment was conducted to evaluate the U(VI) sorption efficiency of Fe3O4@MnOx in simulated seawater. The U(VI) sorption efficiency remained above 80% in 28 days run. Our findings demonstrate that Fe3O4@MnOx has extraordinary potential for the enrichment of uranium from simulated seawater.

Mevalonate Blockade in Cancer Cells Triggers CLEC9A+ Dendritic Cell-Mediated Antitumor Immunity.

Hyperactive mevalonate (MVA) metabolic activity is often observed in cancer cells, and blockade of this pathway inhibits tumor cell lipid synthesis and cell growth and enhances tumor immunogenicity. How tumor cell MVA metabolic blockade promotes antitumor immune responses, however, remains unclear. Here we show that inhibition of the MVA metabolic pathway in tumor cells elicits type 1 classical dendritic cells (cDC1)-mediated tumor recognition and antigen cross-presentation for antitumor immunity. Mechanistically, MVA blockade disrupted prenylation of the small GTPase Rac1 and induced cancer cell actin filament exposure, which was recognized by CLEC9A, a C-lectin receptor specifically expressed on cDC1s, in turn activating antitumor T cells. MVA pathway blockade or Rac1 knockdown in tumor cells induced CD8+ T-cell-mediated antitumor immunity in immunocompetent mice but not in Batf3 -/- mice lacking CLEC9A+ dendritic cells. These findings demonstrate tumor MVA metabolic blockade stimulates a cDC1 response through CLEC9A-mediated immune recognition of tumor cell cytoskeleton, illustrating a new immune surveillance mechanism by which dendritic cells monitor tumor metabolic dysregulation and providing insight into how MVA pathway inhibition may potentiate anticancer immunity. SIGNIFICANCE: These findings suggest that mevalonate blockade in cancer cells disrupts Rac1 prenylation to increase recognition and cross-presentation by conventional dendritic cells, suggesting this axis as a potential target for cancer immunotherapy.

Systemic characterization of the SLC family genes reveals SLC26A6 as a novel oncogene in hepatocellular carcinoma.

BACKGROUND: Solute carrier (SLC) transporters play important roles in various physiological and pathological processes, such as cellular uptake of nutrients, cellular metabolism, tumor initiation and chemotherapy resistance. However, little is known about the comprehensive expression profile of SLC genes in human cancers, especially in human hepatocellular carcinoma (HCC). METHODS: Comprehensive analysis was performed using the TCGA dataset to evaluate the expression profile and clinical significance of SLC family genes in HCC. Real-time PCR and immunohistochemistry (IHC) assays were conducted to validate the expression of solute carrier family 26 member 6 (SLC26A6) in clinical HCC tissues. Cell Counting Kit-8 (CCK8), colony formation and subcutaneous xenograft tumorigenesis assays were carried out to explore the functional role of SLC26A6 in HCC. Bioinformatic analyses were used to predict the potential molecular mechanism of SLC26A6 in HCC. RESULTS: We identified 118 differentially expressed SLC genes (DESLCs) and found that there was a preferential enrichment for activated DESLCs in HCC. Clinical-relevant DESLCs identified a poor prognostic HCC subtype exhibiting unique clinicopathological and genomic profiles. SLC26A6 was overexpressed in HCC tissues both in mRNA and protein levels. Knockdown of SLC26A6 suppressed HCC tumorigenesis both in vitro and in vivo, indicating it as a promising therapeutic target. Finally, multifaceted bioinformatic analyses indicated that SLC26A6 might associate with multiple cancer-related pathways. CONCLUSIONS: This study highlights the potential roles of SLC genes in HCC tumorigenesis, and suggested SLC26A6 as a promising therapeutic target in HCC patients.

Antibiotics and Food Safety in Aquaculture.

Antibiotics are widely used in aquaculture. Intensive farming drives indiscriminate use of antibiotics, which results in residues of antibiotics in cultured aquatic products and bacterial resistance. This perspective attempts to present a brief update on usage, regulations, residues, and potential human health risk of antibiotics used in aquaculture. Through the comprehensive literature review, we provide a view that the safety of aquatic products still requires further attention and more rigorous risk assessment. Finally, we make a few suggestions for future research directions: reduce the use of antibiotics to bring down the speed of resistance development and monitor resistant pathogens and genes, strictly manage the environmental sanitation of aquaculture and pay attention to the quality of water bodies introduced into aquaculture, seek international cooperation to establish an information bank of antibiotic residues and antibiotic-resistant genes, and set up a quantitative model to assess the risk of antibiotic resistance associated with the antibiotic residues.