YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths.

N6-methyladenosine (m6A) is a critical regulator in the fate of RNA, but whether and how m6A executes its functions in different tissues remains largely obscure. Here we report downregulation of a crucial m6A reader, YTHDF2, leading to tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, Bisphenol A (BPA) substitutes are widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m6A-gch1 for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m6A-sting1 decay for caudal vein plexus (CVP) apoptosis. The two distinct YTHDF2-mediated m6A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs, uncovering a new layer of PCD regulation. Since BHPF/YTHDF2-medaited PCD defects were also observed in mammals, BHPF exposure represents a potential health threat.

Development and validation of a simultaneous method for the analysis of benzothiazoles and organic ultraviolet filters in various environmental matrices by GC-MS/MS.

The presence of benzothiazoles (BTHs) and organic ultraviolet filters (UV filters) in aquatic ecosystems has emerged as a significant environmental issue, requiring urgent and efficient determination methods. A new, rapid, and sensitive determination method using gas chromatography triple quadrupole mass spectrometer (GC-MS/MS) was developed for the simultaneous extraction and analysis of 10 commonly used BTHs and 10 organic UV filters in surface water, wastewater, sediment, and sludge. For aqueous samples, solid-phase extraction (SPE) method was employed with optimizing of SPE cartridge type, pH, and elution solvent. For solid samples, ultrasonic extraction-solid-phase extraction purification (UE-SPE) and pressurized liquid extraction (PLE) methods were compared. And extraction conditions for ultrasonic extraction method (extraction solvents and extraction times) and PLE method (extraction temperatures and extraction cycles) were optimized. The limits of quantification for the 20 target compounds in surface water and wastewater were 0.01-2.12 ng/L and 0.05-6.14 ng/L, while those for sediment and sludge with UE-SPE method were 0.04-5.88 ng/g and 0.22-6.61 ng/g, respectively. Among the 20 target compounds, the recoveries ranged from 70 to 130% were obtained for 16, 15, 15, and 15 analytes in the matrix-spiked samples of surface water, wastewater, sediment, and sludge with three levels, respectively. And the precision was also acceptable with relative standard deviation (RSD) below 20% for all analytes. The developed methods were applied for the determination and quantification of target compounds in surface water, sediment, wastewater, and sludge samples collected from two wastewater treatment plants (WWTPs) and the Pearl River in Guangzhou, China. BTHs were frequently detected in surface water and wastewater, while UV filters were mainly found in sediment and sludge. Benzotriazole (BT) and 2-hydroxybenzothiazole (2-OH-BTH) were the two major BTHs in influent wastewater and surface water, respectively, with concentrations up to 966 and 189 ng/L. As for sediment and sludge, 2-(2'-hydroxy-5'-octylphenyl)-benzotriazole (UV-329) was a predominant chemical, detected at concentrations of 111 and 151 ng/g, respectively.

CC Chemokine Receptors in Lung Adenocarcinoma: The Inflammation-Related Prognostic Biomarkers and Immunotherapeutic Targets.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common type of lung cancer with a high incidence and increased mortality. CC chemokine receptors were participating in the modulation of the tumor microenvironment and involved in carcinogenesis and tumor development. However, the potential mechanistic values of CC chemokine receptors as clinical biomarkers and therapeutic targets in LUAD have not been fully clarified. METHODOLOGY: ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, SurvExpress, MethSurv, SurvivalMeth, cBioPortal, String, GeneMANIA, DAVID, Metascape, TRRUST, LinkedOmics, and Timer were applied in this work. RESULTS: The transcriptional levels of CCR1/10 in LUAD tissues were significantly reduced while the transcriptional levels of CCR3/6/7/8 were significantly elevated, and the expression of CCR1 was the highest in LUAD among these CC chemokine receptors. A significant correlation was found between the expression of CCR2/4/6/7 and the pathological stage of LUAD patients. There were significant associations between CCR2/3/4/5/6/10 expression levels and OS in LUAD, and LUAD patients with high transcriptional levels of CCR3/4 had inferior first-progression survival. In addition, the prognostic values of CC chemokine receptors signature in LUAD were explored in three independent cohorts, the high-risk group displayed unfavorable OS compared with the low-risk group, and the LUAD cases in the high-risk group also suffered inferior RFS than that in the low-risk group. And for the prognostic value of the DNA methylation of CC chemokine receptors, we found 1 CpG of CCR2, 2 CpGs of CCR3, 1 CpG of CCR4, 3 CpGs of CCR6, 3 CpGs of CCR7, 1 CpG of CCR8, and 3 CpGs of CCR9 were significantly associated with prognosis in LUAD patients. However, the DNA methylation signature analysis showed there was no statistically significant association between the high- and low-risk group. For potential mechanism, the neighbor gene networks, interaction analyses, functional enrichment analyses of CC chemokine receptors in LUAD were performed, the transcription factor targets, kinase targets, and miRNA targets of CC chemokine receptors were also identified in LUAD. We also found significant correlations among CC chemokine receptors expression and the infiltration of immune cells, the tumor infiltration levels among LUAD with different somatic copy number alterations of these chemokine receptors were also assessed. Moreover, the Cox proportional hazard model showed that CCR1/2/10, B_cell, CD4_Tcell were significantly related to the clinical outcome of LUAD patients. CONCLUSION: CC chemokine receptors might serve as immunotherapeutic targets and prognostic biomarkers in LUAD.

Identification of Prognostic Biomarkers and Molecular Targets Among JAK Family in Breast Cancer.

BACKGROUND: Janus kinases (JAKs) are a family of non-receptor tyrosine kinases involved in multiple malignancies. However, clinical values of JAKs as prognostic markers and potential mechanism as molecular targets in breast invasive carcinoma (BC) are not completely clarified. METHODOLOGY: TIMER, UALCAN and GEPIA were used to assess the expression and methylation levels of JAKs in BC. Kaplan-Meier Plotter, bc-GenExMiner, SurvExpress, TRGAted, MethSurv, and SurvivalMeth were used to assess the multilevel prognostic significance of JAKs in breast cancer patients. And cBioPortal, TIMER, STRING, GeneMANIA, NetworkAnalysis, LinkedOmics, DAVID 6.8, and Metascape were applied for multilayer networks and functional enrichment analyses. Correlations between immune cell infiltrates/their gene markers and JAKs were evaluated by TIMER. RESULTS: We first explored the expression and methylation level of JAKs in breast cancer and found significantly reduced JAK1 and JAK2 expression at mRNA and protein levels, significantly higher JAK3 protein expression, and significantly increased TYK2 expression at mRNA level but decreased at protein level. In addition, hypermethylation of JAK3 and TYK2 and hypomethylation of JAK1 were found in tumor samples. In terms of prognostic values of JAKs in BC patients, low transcriptional levels of JAK1, JAK2, JAK3, and TYK2 indicated worse OS/DMFS/PPS/RFS/DFS, inferior DFS, worse RFS, and shorter OS/DMFS/RFS, respectively. The mRNA signature analysis showed that high-risk group had unfavorable OS/RFS/MFS. Low JAK2 protein level indicated unfavorable DSS/PFS in BC patients. Five CpGs of JAK1, four CpGs of JAK2, 20 CpGs of JAK3, and 13 CpGs of TYK2 were significantly associated with prognosis in BC patients. The DNA methylation signature analysis also suggested worse prognosis in the high-risk group. For potential biological roles of JAKs, interaction analyses, functional enrichment analyses for biological process, cellular component, molecular function, and KEGG pathway analyses of JAKs and their neighbor genes in BC were conducted. Kinase targets, gene-miRNA interactions, and transcription factor-gene interactions of JAKs were also identified. Furthermore, JAKs were found to be significantly related to immune infiltrates as well as the expression levels of multiple immune markers in BC. CONCLUSION: JAKs showed multilevel prognostic value and important biological roles in BC. They might serve as promising prognostic markers and possible targets in breast cancer.

Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis.

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide. The prognosis of HCC remains poor. Currently, sorafenib is the first-line drug for advanced HCC. Although sorafenib's mechanism of action involving several established cancer-related protein kinase targets is well-characterized, the underlying molecular mechanism is still unclear. Here, we found that sorafenib inhibited viability, proliferation, and migration of HCC cells in a dose-dependent manner. Sorafenib treatment of HCC cells destroyed mitochondrial morphology, accompanied by decreased activity of oxidative phosphorylation, collapse of mitochondrial membrane potential, and reduced synthesis of ATP, with consequent cell death due to ferroptosis. Pharmacological utilization of glutathione (GSH) rescued the sorafenib-induced ferroptosis, eliminated the accumulation of cellular mitochondrial reactive oxygen species (ROS), and lipid peroxide. GSH depletion through cysteine deprivation or cysteinase inhibition exacerbated sorafenib-induced ferroptotic cell death and lipid peroxides generation, and enhanced oxidative stress and mitochondrial ROS accumulation. Collectively, these findings indicate that depletion of cysteine acts synergistically with sorafenib and renders HCC cells vulnerable to ferroptosis, presenting the potential value of new therapeutic combinations for advanced HCC.

Prognostic Value of Gastrokine-2 (GKN2) and Its Correlation with Tumor-Infiltrating Immune Cells in Lung Cancer and Gastric Cancers.

BACKGROUND: GKN2, as a secretory protein, is involved in the inflammation and immune modulation, and its aberrant expression is closely related to tumorigenesis. However, integrated studies on the value of GKN2 as a promising clinical biomarker and immunotherapy target in multiple tumors are still rare. METHODOLOGY: Multiple online databases, including ONCOMINE, SEGreg, UALCAN, GEPIA, K-M Plotter, cBioPortal, MethSurv, CellMarker, and Timer, were applied to assess the clinical significance of GKN2 and its correlation with tumor-infiltrating immune cells in differentially expressed cancers. RESULTS: Several databases confirmed that GKN2 was significantly down-regulated in lung and gastric cancers compared that in normal samples. GKN2 was altered in 3%, 5%, and 4% of the LUAD, LUSC, and STAD samples, respectively. Hyper-methylation of GKN2 was found in LUAD and LUSC samples. For the clinical values of GKN2, we found that the low transcription level of GKN2 was associated with worse OS in lung cancer, and inferior FP and PPS in gastric cancer, and the relationships between GKN2 expression and clinical variables regarding OS/FP/PPS in lung and gastric cancers were assessed. Moreover, the prognostic value of the DNA methylation patterns of GKN2 in LUAD, LUSC, and STAD was identified. Furthermore, GKN2 expression was found to be significantly correlated with the infiltrating multiple tumor immune cells, and statistically significant differences in the correlation between GKN2 expression and multiple markers of neutrophils and macrophage polarization were observed in LUAD, LUSC, and STAD. CONCLUSION: The study revealed the prognosis and risk factors for deterioration in patients with low expression of GKN2. GKN2 may be used as a valuable prognostic biomarker and therapeutic target in lung and gastric cancers.

Downregulation of CISD2 Has Prognostic Value in Non-Small Cell Lung Cancer and Inhibits the Tumorigenesis by Inducing Mitochondrial Dysfunction.

CISD2, a NEET protein that coordinates 2Fe-2S clusters through its CDGSH domain, is critical for normal development and iron homeostasis. CISD2 plays an important role in Fe-S cluster transfer and promotes cancer proliferation. However, its specific role in the development of non-small cell lung cancer (NSCLC) remains unclear. Bioinformatics of pan-cancer analysis from The Cancer Genome Atlas show that CISD2 has an aberrant expression in most types of human cancers. Moreover, CISD2 expression is associated with a higher hazard ratio and exhibits significantly poorer overall survival in lung adenocarcinoma (LUAD), uveal melanoma, head and neck squamous cell carcinoma, brain lower grade glioma, kidney chromophobe, and liver hepatocellular carcinoma. Further investigation revealed that CISD2 is highly expressed in LUAD and LUSC, which is associated with clinical pathological stages. In addition, survival data collected from GSE31210 and GSE13213, two datasets from the NCBI Gene Expression Omnibus, also confirmed that high CISD2 expression is associated with unfavorable survival in patients with LUAD. A cell-based assay indicated that the knockdown of CISD2 inhibited proliferation, invasion, and migration in A549 cells. Additionally, CISD2 knockdown accelerated the accumulation of cellular and mitochondrial reactive oxygen species, destroying the mitochondrial morphology and function. Moreover, CISD2 inhibition activated the iron starvation response, thus, accelerating iron accumulation in A549 cells. Pretreatment with DFO, the iron chelator, blocked mitochondrial dysfunction in CISD2-knockdown cells. Collectively, the present study provides novel insights into the regulatory role of CISD2 in NSCLC and presents a potential target to improve antitumor activity based on oxidative stress.

Design of a free-form diffuser for the entrance optic to correct the cosine error in the photometer.

The entrance optic is an important part of the photometer head. It can match the directional response of the photometer to the cosine function. In this paper, an entrance optic consisting of a free-form diffuser, a shadow ring, and an integrating cavity is introduced. An iterative optimization algorithm is presented to design a free-form diffuser that exhibits better cosine response characteristics. Diffusers of different materials and sizes are designed in a simulation experiment. After a finite number of iterations, in the absence of the shadow ring, the integral cosine error of the free-form diffuser is less than 1%. The directional cosine error is less than 3% for incidence angles between 0° and 70°. After adding a shadow ring to correct the directional response of the incident angle greater than 80°, for incident angles between 0° and 85°, the cosine errors are typically less than 3%, except that the cosine errors of very few large incident angles are close to 5%. The experimental results show the effectiveness and robustness of the proposed method. In addition, the influence of an important percentage constant σ on iterative optimization is studied. It is found that the larger the parameter σ, the fewer the number of iterations, and the directional cosine error may be slightly larger but still acceptable. The wide range of values of σ further embodies the versatility and flexibility of the proposed method.

Clinical characteristics and management of primary granulocytic sarcoma of the breast: A case report.

RATIONALE: Primary granulocytic sarcoma of the breast is a rare and poor-prognosis malignancy. Clinicians do not have sufficient knowledge of this disease and often misdirect it as other soft tissue sarcomas or inflammation. PATIENT CONCERNS: A 42-year-old female presented with a self-discovered asymptomatic growing and palpable right breast mass that had been present for 4 months. DIAGNOSES: The patient was diagnosed as primary myeloid sarcoma. INTERVENTIONS: The patient received modified radical mastectomy in the right breast and sentinel lymph node biopsy. Pathological diagnosis is primary granulocytic sarcoma. Then the patient accepted acute myeloid leukemia-induction chemotherapy. OUTCOMES: The follow-up of this patient has no evidence of disease progression or spread during 1 year. LESSONS: Granulocytic sarcoma in the breast tissue is rare. But it still should be considered in the differential diagnosis of any tumor in the breast. The present study discusses comprehensively the clinical and pathological characteristics to improve the understanding of myeloid sarcoma.

MicroRNA-765 alleviates the malignant progression of breast cancer via interacting with EZH1.

To detect the expression pattern of microRNA-765 in breast cancer (BCa) and its regulatory effect on the disease progression. Expression level of microRNA-765 in 66 paired BCa tissues and matched normal tissues was detected by qRT-PCR. The relationship between microRNA-765 level and clinical data of BCa patients was analyzed. Subsequently, microRNA-765 level in BCa cell lines was examined as well. Changes in proliferative, migratory and invasive abilities in MCF-7 and SKBR3 cells either overexpressing microRNA-765 or not were evaluated. Furthermore, expression level of EZH1 in BCa tissues and cell lines was determined. The regulatory interaction between microRNA-765 and EZH1 was identified. Finally, the role of microRNA-765/EZH1 axis in the progression of BCa was assessed. MicroRNA-765 was downregulated in BCa tissues relative to matched normal ones. BCa patients expressing low expression of microRNA-765 presented higher tumor stage, higher metastatic rate and worse overall survival. Overexpression of microRNA-765 attenuated proliferative, migratory and invasive abilities in MCF-7 and SKBR3 cells. In addition, EZH1 was upregulated in BCa tissues and cell lines. EZH1 level was negatively regulated by microRNA-765 in BCa. Overexpression of EZH1 reversed the inhibitory effects of microRNA-765 on malignant progression of BCa. MicroRNA-765 is downregulated in BCa and closely correlated to tumor stage, lymphatic metastasis, distant metastasis and poor prognosis of BCa patients. Overexpression of microRNA-765 attenuates the malignant progression of BCa through negatively regulating EZH1.

Reconstruction method based on the Hilbert fractal curve recovery sequence in a Fourier ptychography microscope.

Many Fourier ptychography microscopy techniques have been proposed to achieve higher recovery accuracy in the past few years, yet it is little known that their reconstructed quality is also dependent on the choice of recovery sequence, which is important for fast solution convergence during the Fourier ptychography reconstruction process. In this paper, we propose to use the Hilbert fractal curve, which is one of the most representative of classic space-filling curves, as a new kind of recovery sequence of mesh LED arrays and validate its effectiveness and robustness with both simulated and real experiments. Results show that the Hilbert fractal curve as the recovery sequence is a better choice for periodic LED arrays, compared with raster line, spiral line, and wave-shaped-curve three-recovery sequences.

The unexpected diversity of microbial communities associated with black corals revealed by high-throughput Illumina sequencing.

The microbes associated with black corals remain poorly studied. The present study is the first attempt to investigate microbial community structure in the black corals Antipathes ceylonensis and A. dichotoma from the South China Sea by using high-throughput Illumina sequencing. A total of 52 bacterial and 3 archaeal phyla were recovered in this study, suggesting the black corals harboured highly diverse microbial communities. Among the 55 microbial phyla, Proteobacteria, Firmicutes, Bacteroidetes, Chloroflexi, Acidobacteria and Actinobacteria dominated in the two black corals from the South China Sea. Although most of the microbial phyla recovered from the two black corals have been reported in previous studies on coral-associated microbes, eight bacterial phyla including Synergistetes, Thermi, AncK6, GNO2, NKB19, NC10, WWE1 and GAL15, and the archaeal phylum Parvarchaeota are reported for the first time from corals in this study, which expands our knowledge about the diversity of coral-associated microbes. The comparison of microbial communities in the different black coral species indicated that A. ceylonensis harboured few abundant bacterial genera such as Citrobacter and Pseudomonas, whereas a high diversity of rare bacterial genera (<1% abundance), such as Winogradskyella and Rubricoccus, was detected only in A. dichotoma. These results suggested that the microbial community in black corals exhibited species-specific variation.

Electromagnetic optimization of the integrated magnetorheological jet polishing tool and its application in millimeter-scale discontinuous structure processing.

To meet the special demands in small-scale discontinuous optical surface fabrication, the integrated magnetorheological jet polishing (IMJP) tool with multiple motion degrees is introduced in this paper. Four jetting models are implemented and investigated by means of the IMJP tool for practical manufacture. To ensure steady jetting in a long distance, ideal distribution characteristics of the magnetic field in the structure is proposed, based on electromagnetic theory. The magnetic field distribution is simulated subsequently using the finite element analysis method, and three key parameters in the IMJP tool structure are optimized through the simulations. The actual magnetic flux density is measured and spot polishing experiments are conducted in different standoff distances, verifying the effectiveness of the optimization. A processing experiment of a millimeter scale structure with milling tool marks located on a surface with nonuniform curvatures was conducted using the IMJP tool. The roughness of the polishing region converged to 4.86 nm Ra from a low initial quality after processing, and the tool marks have been efficiently removed. The experimental results reveal the reliability of the setup design and the remarkable roughness convergence ability of the IMJP tool for small complex structures.

Calibrating system errors of large scale three-dimensional profile measurement instruments by subaperture stitching method.

This study presents a subaperture stitching method to calibrate system errors of several ∼2 m large scale 3D profile measurement instruments (PMIs). The calibration process was carried out by measuring a Φ460 mm standard flat sample multiple times at different sites of the PMI with a length gauge; then the subaperture data were stitched together using a sequential or simultaneous stitching algorithm that minimizes the inconsistency (i.e., difference) of the discrete data in the overlapped areas. The system error can be used to compensate the measurement results of not only large flats, but also spheres and aspheres. The feasibility of the calibration was validated by measuring a Φ1070 mm aspheric mirror, which can raise the measurement accuracy of PMIs and provide more reliable 3D surface profiles for guiding grinding, lapping, and even initial polishing processes.