An activatable fluorescence probe for rapid detection and in situ imaging of ß-galactosidase activity in cabbage roots under heavy metal stress.

ß-Galactosidase (ß-gal), an enzyme related to cell wall degradation, plays an important role in regulating cell wall metabolism and reconstruction. However, activatable fluorescence probes for the detection and imaging of ß-gal fluctuations in plants have been less exploited. Herein, we report an activatable fluorescent probe based on intramolecular charge transfer (ICT), benzothiazole coumarin-bearing ß-galactoside (BC-ßgal), to achieve distinct in situ imaging of ß-gal in plant cells. It exhibits high sensitivity and selectivity to ß-gal with a fast response (8 min). BC-ßgal can be used to efficiently detect the alternations of intracellular ß-gal levels in cabbage root cells with considerable imaging integrity and imaging contrast. Significantly, BC-ßgal can assess ß-gal activity in cabbage roots under heavy metal stress (Cd2+, Cu2+, and Pb2+), revealing that ß-gal activity is negatively correlated with the severity of heavy metal stress. Our work thus facilitates the study of ß-gal biological mechanisms.

Identification of cell-specific epigenetic patterns associated with chondroitin sulfate treatment response in an endemic arthritis, Kashin-Beck disease.

Aims: To assess the alterations in cell-specific DNA methylation associated with chondroitin sulphate response using peripheral blood collected from Kashin-Beck disease (KBD) patients before initiation of chondroitin sulphate treatment. Methods: Peripheral blood samples were collected from KBD patients at baseline of chondroitin sulphate treatment. Methylation profiles were generated using reduced representation bisulphite sequencing (RRBS) from peripheral blood. Differentially methylated regions (DMRs) were identified using MethylKit, while DMR-related genes were defined as those annotated to the gene body or 2.2-kilobase upstream regions of DMRs. Selected DMR-related genes were further validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to assess expression levels. Tensor composition analysis was performed to identify cell-specific differential DNA methylation from bulk tissue. Results: This study revealed 21,060 hypermethylated and 44,472 hypomethylated DMRs, and 13,194 hypermethylated and 22,448 hypomethylated CpG islands for differential global methylation for chondroitin sulphate treatment response. A total of 12,666 DMR-related genes containing DMRs were identified in their promoter regions, such as CHL1 (false discovery rate (FDR) = 2.11 × 10-11), RIC8A (FDR = 7.05 × 10-4), and SOX12 (FDR = 1.43 × 10-3). Additionally, RIC8A and CHL1 were hypermethylated in responders, while SOX12 was hypomethylated in responders, all showing decreased gene expression. The patterns of cell-specific differential global methylation associated with chondroitin sulphate response were observed. Specifically, we found that DMRs located in TESPA1 and ATP11A exhibited differential DNA methylation between responders and non-responders in granulocytes, monocytes, and B cells. Conclusion: Our study identified cell-specific changes in DNA methylation associated with chondroitin sulphate response in KBD patients.

Modulatory interactions of T-2 and deoxynivalenol mycotoxins on murine femoral development and osteological integrity.

In this study, we conducted a systematic assessment of the effectsof deoxynivalenol (DON) and T-2 mycotoxins (T-2) on the developmental processes and structural integrity of murine femurs, considering both the isolated and synergistic effects of these toxins. To this end, we divided 72 male mice into nine groups, each subjected to varying dosages of T-2, DON, or their combinations. Over a four-week experimental period, meticulous monitoring was undertaken regarding the mice's body weight, biochemical markers of bone formation and resorption, and the activity of relevant cells. To comprehensively evaluate alterations in bone structure, we employed biomechanical analysis, micro-computed tomography (micro-CT), and transmission electron microscopy.Our findings unveiled a significant revelation: the mice exhibited a dose-dependent decrease in body weight upon exposure to individual mycotoxins, while the combined use of these toxins manifested an atypical antagonistic effect. Furthermore, we observed variations in the levels of calcium, phosphorus, and vitamin D, as well as adjustments in the activities of osteoblasts and osteoclasts, all intricately linked to the dosage and ratio of the toxins. Alterations in biomechanical properties were also noted to correlate with the dosage and combination of toxins. Analyses via micro-CT and transmission electron microscopy further corroborated the substantial impact of toxin dosage and combinations on both cortical and trabecular bone structures.In summation, our research unequivocally demonstrates the dose- and ratio-dependent detrimental effects of DON and T-2 mycotoxins on the growth and structural integrity of murine femurs. These insights accentuate the importance of a profound understanding of the potential risks these toxins pose to bone health, offering pivotal guidance for future toxicological research and public health preventative strategies.

Identification and Verification of Hub Mitochondrial Dysfunction Genes in Osteoarthritis Based on Bioinformatics Analysis.

Objective: Age-related mitochondrial dysfunction and associated oxidative stress may contribute to the development of osteoarthritis. The aim of this study was to identify hub genes associated with mitochondrial dysfunction in osteoarthritis (OA) patients, helping predict the risk of OA, and revealing the mechanism of OA progression. Methods: OA expression data and mitochondrial dysfunction genes were downloaded from GEO (GSE55235, GSE82107, and GSE114007) and GeneCard databases. The differentially expressed mitochondrial dysfunction genes (DEMDFGs) between OA and control samples were screened. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathways were analyzed for DEMDFGs. The hub genes were determined by WGCNA and LASSO regression analysis. ROC curves manifested the diagnostic efficacy of each hub gene. A nomogram model was constructed and validated to predict OA risk. The expression of hub genes in OA and normal chondrocytes was verified by external datasets, qRT-PCR and western blotting. Results: A total of 31 DEMDFGs were identified, with 15 genes upregulated and 16 genes downregulated. GO functional enrichment analysis revealed that DEMDFGs were enriched in biological processes related to energy metabolism and cellular respiration. By employing weighted gene coexpression network analysis, we identified four distinct coexpression modules, among which the blue module exhibited the strongest correlation with OA. The intersection between DEMDFGs and this module yielded eight candidate genes. After LASSO analysis of the data, four hub genes (ACADL, CYBA, SLC19A2, and UCP2) were identified as potential biomarkers for OA. The expression levels of these four genes were externally validated in the GSE114007 dataset. And the biologically differential expression of these four genes has been verified in OA and normal chondrocytes. Moreover, the four hub genes had good sensitivity and specificity by ROC curve analysis, and the risk model constructed with these four genes showed promising performance. In conclusion, our study may provide novel mitochondrial dysfunction hub genes with potential clinical applications for understanding the pathology, diagnosis, and treatment of OA.

Consuming intracellular glucose and regulating the levels of O2/H2O2 via the closed cascade catalysis system of Cu-CeO2 nanozyme and glucose oxidase.

Imbalances in the intracellular environment caused by high levels of glucose, H2O2, and hypoxia can greatly impact cancer development and treatment. However, there is limited research on regulating the levels of these species simultaneously in tumor cells. Here, a pH-responsive nanozyme-enzyme hybrid system was developed to regulate intracellular glucose, H2O2 and O2. The system, named DMSN@Cu-CeO2@GOx, consists of Cu-CeO2 nanoparticles and glucose oxidase (GOx) immobilized in dendritic mesoporous silica (DMSN) spheres. GOx efficiently consumes glucose in tumor cells, causing a drop in pH and producing a significant amount of H2O2. Cu-CeO2 then catalyzes the conversion of H2O2 to O2 due to its high catalase-like (CAT) activity in weakly acidic conditions. The process was monitored by fluorescence probes, and the mechanism was investigated through fluorescence spectroscopy and confocal laser scanning microscopy. The cascade catalytic system with excellent biocompatibility continuously consumes glucose and elevates the level of O2 in cells. This hybrid nanomaterial offers a means to regulate the glucose/H2O2/O2 levels in cells and may provide insights into starvation therapy by modulating reactive species within cells.

A large Stokes shift NIR fluorescent probe for visual monitoring of mitochondrial peroxynitrite during inflammation and ferroptosis and in an Alzheimer's disease model.

The excessive formation of peroxynitrite (ONOO-) in mitochondria has been implicated in various pathophysiological processes and diseases. However, owing to short emission wavelengths and small Stokes shifts, previously reported fluorescent probes pose significant challenges for mitochondrial ONOO- imaging in biological systems. In this study, a near-infrared (NIR) fluorescent probe, denoted as DCO-POT, is designed for the visual monitoring of mitochondrial ONOO-, displaying a remarkable Stokes shift of 170 nm. The NIR fluorophore of DCO-CHO is released by DCO-POT upon the addition of ONOO-, resulting in off-on NIR fluorescence at 670 nm. This phenomenon facilitates the high-resolution confocal laser scanning imaging of ONOO- generated in biological systems. The practical applications of DCO-POT as an efficient fluorescence imaging tool are verified in this study. DCO-POT enables the fluorometric visualization of ONOO- in organelles, cells, and organisms. In particular, ONOO- generation is analyzed during cellular and organism-level (zebrafish) inflammation during ferroptosis and in an Alzheimer's disease mouse model. The excellent visual monitoring performance of DCO-POT in vivo makes it a promising tool for exploring the pathophysiological effects of ONOO-.

Evaluating the genetic interaction effects of gut microbiome and diet on the risk of neuroticism in the UK Biobank cohort.

OBJECTIVES: In this study designed to investigate the effect of diet and gut microbiome on neuropsychiatric disorders, we explored the mechanisms of the interaction between diet and gut microbiome on the risk of neuroticism. METHODS: First, using the individual genotype data from the UK Biobank cohort (N = 306 165), we calculated the polygenic risk score (PRS) based on 814 dietary habits single nucleotide polymorphisms (SNPs), 21 diet compositions SNPs and 1001 gut microbiome SNPs, respectively. Gut microbiome and diet-associated SNPs were collected from three genome-wide association studies (GWAS), including the gut microbiome (N = 3890), diet compositions (over 235 000 subjects) and dietary habits (N = 449 210). The neuroticism score was calculated by 12 questions from the Eysenck Personality Inventory Neuroticism scale. Then, regression analysis was performed to evaluate the interaction effects between diet and the gut microbiome on the risk of neuroticism. RESULTS: Our studies demonstrated multiple candidate interactions between diet and gut microbiome, such as protein vs. Bifidobacterium (ß = 4.59 × 10-3; P = 9.45 × 10-3) and fat vs. Clostridia (ß = 3.67 × 10-3; P = 3.90 × 10-2). In addition, pieces of fresh fruit per day vs. Ruminococcus (ß = -5.79 × 10-3, P = 1.10 × 10-3) and pieces of dried fruit per day vs. Clostridiales (ß = -5.63 × 10-3, P = 1.49 × 10-3) were found to be negatively associated with neuroticism in fruit types. We also identified several positive interactions, such as tablespoons of raw vegetables per day vs. Veillonella (ß = 5.92 × 10-3, P = 9.21 × 10-4) and cooked vegetables per day vs. Acidaminococcaceae (ß = 5.69 × 10-3, P = 1.24 × 10-3). CONCLUSIONS: Our results provide novel clues for understanding the roles of diet and gut microbiome in the development of neuroticism.

A turn-on NIR fluorescent probe for risk-assessing oxidative stress in cabbage roots under abiotic stress.

Oxidative stress is closely related to the crop health status under stress conditions. H2O2 is an important signaling molecule in plants under stress. Therefore, monitoring H2O2 fluctuations is of great significance when risk-assessing oxidative stress. However, few fluorescent probes have been reported for the in situ tracking of H2O2 fluctuations in crops. Herein, we designed a "turn-on" NIR fluorescent probe (DRP-B) to detect and in situ-image H2O2 in living cells and crops. DRP-B exhibited good detection performance for H2O2 and could image endogenous H2O2 in living cells. More importantly, it could semi-quantitatively visualize H2O2 in cabbage roots under abiotic stress. Visualization of H2O2 in cabbage roots revealed H2O2 upregulation in response to adverse environments (metals, flood, and drought). This study provides a new method for risk-assessing oxidative stress in plants under abiotic stress and is expected to provide guidance for the development of new antioxidant defense strategies to enhance plant resistance and crop productivity.

Mitochondria-targeting fluorescent sensor with high photostability and permeability for visualizing viscosity in mitochondrial malfunction, inflammation, and AD models.

Viscosity changes in mitochondria are closely associated with numerous cellular processes and diseases. Currently available fluorescence probes used in mitochondrial viscosity imaging are not very photostable or sufficiently permeable. Herein, a highly photostable and permeable mitochondria-targeting red fluorescent probe (Mito-DDP) was designed and synthesized for viscosity sensing. Viscosity was imaged in living cells using a confocal laser scanning microscope, and the results suggested that Mito-DDP penetrated the membrane and stained the living cells. Importantly, practical applications of Mito-DDP were demonstrated: viscosity visualization was realized for mitochondrial malfunction, cellular and zebrafish inflammation, and Drosophila Alzheimer's disease models, i.e., for subcellular organelles, cells, and organisms. The excellent analytical and bioimaging performance of Mito-DDP in vivo makes it an effective tool for exploring the physiological and pathological effects of viscosity.

Evaluating the interactive effects of dietary habits and human gut microbiome on the risks of depression and anxiety.

BACKGROUND: Gut microbiome and dietary patterns have been suggested to be associated with depression/anxiety. However, limited effort has been made to explore the effects of possible interactions between diet and microbiome on the risks of depression and anxiety. METHODS: Using the latest genome-wide association studies findings in gut microbiome and dietary habits, polygenic risk scores (PRSs) analysis of gut microbiome and dietary habits was conducted in the UK Biobank cohort. Logistic/linear regression models were applied for evaluating the associations for gut microbiome-PRS, dietary habits-PRS, and their interactions with depression/anxiety status and Patient Health Questionnaire (PHQ-9)/Generalized Anxiety Disorder-7 (GAD-7) score by R software. RESULTS: We observed 51 common diet-gut microbiome interactions shared by both PHQ score and depression status, such as overall beef intake × genus Sporobacter [hurdle binary (HB)] (PPHQ = 7.88 × 10-4, Pdepression status = 5.86 × 10-4); carbohydrate × genus Lactococcus (HB) (PPHQ = 0.0295, Pdepression status = 0.0150). We detected 41 common diet-gut microbiome interactions shared by GAD score and anxiety status, such as sugar × genus Parasutterella (rank normal transformed) (PGAD = 5.15 × 10-3, Panxiety status = 0.0347); tablespoons of raw vegetables per day × family Coriobacteriaceae (HB) (PGAD = 6.02 × 10-4, Panxiety status = 0.0345). Some common significant interactions shared by depression and anxiety were identified, such as overall beef intake × genus Sporobacter (HB). CONCLUSIONS: Our study results expanded our understanding of how to comprehensively consider the relationships for dietary habits-gut microbiome interactions with depression and anxiety.

Self-Cascade Nanoenzyme of Cupric Oxide Nanoparticles (CuO NPs) Induced in Situ Catalysis Formation of Polyelectrolyte as Template for the Synthesis of Near-Infrared Fluorescent Silver Nanoclusters and the Application in Glutathione Detection and Bioimaging.

In this work, near-infrared fluorescent silver nanoclusters (Ag NCs) were prepared based on the in situ formed poly methacrylic acid (PMAA) as the template and stabilizer, which is synthesized by methacrylic acid (MAA) and hydroxyl radical (·OH) that is generated by the cascade nanoenzyme reaction of cupric oxide nanoparticles (CuO NPs). CuO NPs possess the intrinsic glutathione-like (GPx-like) and peroxidase-like (POD-like) activities, which can catalyze glutathione (GSH) and O2 to produce hydrogen peroxide (H2O2), and then transform into ·OH. The fluorescence intensity of Ag NCs decreases with the addition of GSH, because the -SH can easily anchor on the surface, resulting in the PMAA leaving the Ag NCs, and the coeffect of GSH and PMAA results in the aggregation to form larger Ag NPs. A good linear relationship between the fluorescence quenching rate and the GSH concentration was found in the range 0.01-40 µM with the detection limit 8.0 nM. The Ag NCs can be applied in the detection of GSH in the serum, as well as bioimaging of endogenous and exogenous GSH in cells with high sensitivity. Moreover, the normal and cancer cells can be distinguished through bioimaging because of the different GSH levels. The new method for the preparation of biocompatible nanoprobe based on the nanozyme tandem catalysis and the in situ formed template can avoid the direct usage of polymers or protein templates that hinder preparation and separation, providing a reliable approach for the synthesis, biosensing, and bioimaging of nanoclusters.

MMP-10 Deficiency Effects Differentiation and Death of Chondrocytes Associated with Endochondral Osteogenesis in an Endemic Osteoarthritis.

OBJECTIVE: The objective of this study was to determine the matrix metalloproteinase-10 (MMP-10) expression pattern and to assess how it contributes to endochondral osteogenesis in Kashin-Beck disease (KBD). DESIGN: The cartilages of KBD patients, Sprague-Dawley rats fed with selenium (Se)-deficient diet and/or T-2 toxin, and ATDC5 cells were used in this study. ATDC5 cells were induced into hypertrophic chondrocytes using a 1% insulin-transferrin-selenium (ITS) culture medium for 21 days. The expressions of MMP-10 in the cartilages were visualized by immunohistochemistry. The messenger RNA (mRNA) and protein expression levels were determined by real-time polymerase chain reaction (RT-PCR) and Western blotting. MMP-10 short hairpin RNA (shRNA) was transfected into hypertrophic chondrocytes to knock down the gene expression of MMP-10. Meanwhile, the cell death of MMP-10-knockdown chondrocyte was detected using flow cytometry. RESULTS: The expression of MMP-10 was decreased in the growth plates of children with KBD. A decreased expression of MMP-10 also was observed in the growth plates of rats fed with an Se-deficient diet and/or T-2 toxin exposure. The mRNA and protein expression levels of MMP-10 increased during the chondrogenic differentiation of ATDC5 cells. MMP-10 knockdown in hypertrophic chondrocytes significantly decreased the gene and protein expression of collagen type II (Col II), Col X, Runx2, and MMP-13. Besides, the percentage of cell apoptosis was significantly increased after MMP-10 knockdown in hypertrophic chondrocytes. CONCLUSION: MMP-10 deficiency disrupts chondrocyte terminal differentiation and induces the chondrocyte's death, which impairs endochondral osteogenesis in the pathogenesis of KBD.

Construction of a unique fluorescent probe for rapid and highly sensitive detection of glutathione in living cells and zebrafish.

A rhodamine-based fluorescent probe (Rho-GSH) was rationally designed and synthesized, using nitrobenzene as recognition group for monitoring and imaging GSH in vitro and in vivo. In the presence of GSH, Rho-GSH undergoes sequential nucleophilic substitution and spiro-ring-opening reaction, resulting the fluorescence increase of probe, which enables quantitative detection of GSH with "off-on" fluorescence. The cascade reaction also enables Rho-GSH to rapidly detect GSH (3 s). In addition, Rho-GSH exhibited outstanding selectivity in detecting GSH vs cysteine (Cys) and homocysteine (Hcy). Based on the outstanding detection performance and superior biocompatibility of Rho-GSH, it was used to visualize GSH in vitro and in vivo, demonstrating its highly selectivity for GSH detection (with respect to Cys and Hcy). Rho-GSH can help visually distinguishing cancer cells from normal cells by fluorescence imaging, demonstrating the overexpression of GSH in cancer cells. Because of the outstanding analytical capabilities of Rho-GSH for GSH detection, Rho-GSH may be useful for cancer diagnosis and clinical evaluation.

The associations between sleep behaviors, lifestyle factors, genetic risk and mental disorders: A cohort study of 402 290 UK Biobank participants.

BACKGROUND: Sleep behaviors were believed to be associated with mental disorders (MD). However, the underlying mechanism of such association relationship, especially the role of multiple lifestyle factors in it remains unclear. METHODS: A total of 402,290 participants from UK Biobank who don't have MD at baseline were included. They were divided into poor, intermediate and healthy sleep patterns according to the sleep score, which was calculated based on the data collecting from five sleep behaviors. Cox proportional hazard model was used to estimate the associations between sleep behaviors and MD. The associations were further estimated when taking lifestyle factors such as physical activity, coffee intake, tea intake and genetic susceptibility into account. RESULTS: Healthy sleep pattern was associated with lower risk of overall MD status (HR,0.41, 95%CI,0.39-0.43), depressive disorders (HR,0.34, 95%CI,0.31-0.37) and anxiety disorders (HR,0.46, 95%CI,0.41-0.79), compared with poor sleep pattern. And in each subgroup of physical activity, tea intake, coffee intake, age and genetic risk scores (GRS), healthy sleep pattern could partly offset the risk of diseases. CONCLUSIONS: Our study suggested healthy sleep behaviors could diminish the negative effect from genetic predisposition and lifestyle factors on the risk of MD, highlighting the benefit of healthy sleep pattern.

A fluorescence nanoplatform for the determination of hydrogen peroxide and adenosine triphosphate via tuning of the peroxidase-like activity of CuO nanoparticle decorated UiO-66.

A novel nanocomposite of CuO nanoparticle-modified Zr-MOF (CuO/UiO-66) was synthesized and developed as a fluorescence nanoplatform for H2O2 and adenosine triphosphate (ATP) via the "turn-on-off" mode in the presence of terephthalic acid (TA). The structure of CuO/UiO-66 was thoroughly characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), and other techniques. The CuO/UiO-66 with enhanced peroxidase-like (POD) activity obtained due to the Zr4+ in UiO-66 is beneficial to the aggregation of CuO NPs on its surface. As a result, the strengthened fluorescence at 425 nm with the excitation of 300 nm was found due to the highly fluorescent species of TAOH. This is produced by the oxidation of TA by ·OH that came from the catalysis of H2O2 via the peroxidase mimic of CuO/UiO-66. Hence the modification of CuO NPs on porous UiO-66 can provide a friendly and sensitive physiological condition for H2O2 detection. However, upon addition of ATP, the fluorescence intensity of TAOH at 425 nm effectively declined owing to the formation of complexation of Zr4+-ATP and the interaction of CuO to ATP which hampers the catalytic reaction of CuO/UiO-66 to H2O2. The specific interaction induced "inhibition of the peroxide-like activity" endows the sensitive and selective recognition of ATP. The detection limits were 16.87 ± 0.2 nM and 0.82 ± 0.1 nM, and linear analytical ranges were 0.02-100 µM and 0.002-30 µM for H2O2 and ATP, respectively. The novel strategy was successfully applied to H2O2 and ATP determination in serum samples with recoveries of 97.2-103.8% for H2O2 and 97.6-101.7% for ATP, enriching the avenue to design functional MOFs and providing new avenue of multicomponent bioanalysis.

Abnormal Level of Manganese, Iron, Iodine, and Selenium in the Hair of Children Living in Kashin-Beck Disease Endemic Areas.

Biological geochemistry is a main suggested cause of Kashin-Beck disease (KBD), due to the absence or excess of elements in the environment. Initially, Se deficiency is regarded as the most key role in the etiology of KBD, and selenium supplementation effectively helps to prevent and control KBD. However, several elements are reported to be relevant to KBD or selenium in succession, which indicated selenium deficiency is not the original etiology of KBD. The study comprehensively analyzed the characteristics of the bio-element profile of KBD and further re-examined the unique role of selenium in etiology. The study measured 14 elements, including sodium, potassium, calcium, phosphorus, magnesium, copper, iron, zinc, selenium, iodine, manganese, lead, arsenic, and mercury, which were detected from hair samples collected from 150 boys. Research participants were separated based on whether they had received any preventative treatment (with and without selenium supplementation). From endemic areas, 30 KBD and 30 healthy children without any preventative treatment were selected alongside 30 KBD and 30 healthy children with selenium supplementation. The participants from endemic areas were then compared to 30 healthy children living in non-endemic areas. Compared to the non-endemic group, the levels of iron and manganese were all significantly higher in the endemic groups and were further elevated in KBD participants (p < 0.05). In contrast, selenium and iodine levels in endemic areas were much lower than those of the control group (p < 0.05). The proportions of selenium excess (p < 0.05) and iodine deficiency (p < 0.05) in endemic groups were significantly lower than participants from non-endemic areas. Meanwhile, excess levels of iron (p < 0.05) and manganese (p < 0.05) were higher in the endemic groups. Moreover, the proportions of Zn/Fe and Se/Mn were found to be significantly lower in endemic area participants than those in the control group (p < 0.05). Three pairs of elements had a correlation coefficient value of more than 0.6: 0.7423 for manganese and calcium, 0.6446 for potassium and sodium, and 0.6272 for manganese and iron. The ratios of Se/Mn and Zn/Fe were associated with a correlation coefficient value of 0.8055. Magnesium, sodium, copper, and iodine levels were meticulously examined using binary regression analysis. This was also used to determine the ratios of Ca/Mg, Ca/P, Zn/Fe, Se/Mn, and Se/I. Thus, the study largely revealed the vital role of manganese, iron, and iodine (in conjunction with selenium) in KBD etiology and pathogenesis. High manganese and iron levels with low selenium and iodine levels were identified as characteristic features of the bio-element profile of KBD. The different element ratios reflect the interaction between several elements. The most significant of these were the proportions of Se/Mn and Zn/Fe, which may be significant in the occurrence and development of KBD.

Genome-Wide Association Study and Genetic Correlation Scan Provide Insights into Its Genetic Architecture of Sleep Health Score in the UK Biobank Cohort.

PURPOSE: Most previous genetic studies of sleep behaviors were conducted individually, without comprehensive consideration of the complexity of various sleep behaviors. Our aim is to identify the genetic architecture and potential biomarker of the sleep health score, which more powerfully represents overall sleep traits. PATIENTS AND METHODS: We conducted a genome-wide association study (GWAS) of sleep health score (overall assessment of sleep duration, snoring, insomnia, chronotype, and daytime dozing) using 336,463 participants from the UK Biobank. Proteome-wide association study (PWAS) and transcriptome-wide association study (TWAS) were then performed to identify candidate genes at the protein and mRNA level, respectively. We finally used linkage disequilibrium score regression (LDSC) to estimate the genetic correlations between sleep health score and other functionally relevance traits. RESULTS: GWAS identified multiple variants near known candidate genes associated with sleep health score, such as MEIS1, FBXL13, MED20 and SMAD5. HDHD2 (PPWAS = 0.0146) and GFAP (PPWAS = 0.0236) were identified associated with sleep health score by PWAS. TWAS identified ORC4 (PTWAS = 0.0212) and ZNF732 (PTWAS = 0.0349) considering mRNA expression level. LDSC found significant genetic correlations of sleep health score with 3 sleep behaviors (including insomnia, snoring, dozing), 4 psychiatry disorders (major depressive disorder, attention deficit/hyperactivity disorder, schizophrenia, autism spectrum disorder), and 9 plasma protein (such as Stabilin-1, Stromelysin-2, Cytochrome c) (all LDSC PLDSC < 0.05). CONCLUSION: Our results advance the comprehensive understanding of the aetiology and genetic architecture of the sleep health score, refine the understanding of the relationship of sleep health score with other traits and diseases, and may serve as potential targets for future mechanistic studies of sleep phenotype.

The first human induced pluripotent stem cell line of Kashin-Beck disease reveals involvement of heparan sulfate proteoglycan biosynthesis and PPAR pathway.

Kashin-Beck disease (KBD) is an endemic osteochondropathy. Due to a lack of suitable animal or cellular disease models, the research progress on KBD has been limited. Our goal was to establish the first disease-specific human induced pluripotent stem cell (hiPSC) cellular disease model of KBD, and to explore its etiology and pathogenesis exploiting transcriptome sequencing. HiPSCs were reprogrammed from dermal fibroblasts of two KBD and one healthy control donor via integration-free vectors. Subsequently, hiPSCs were differentiated into chondrocytes through three-week culture. Gene expression profiles in KBD, normal primary chondrocytes, and hiPSC-derived chondrocytes were defined by RNA sequencing. A Venn diagram was constructed to show the number of shared differentially expressed genes (DEGs) between KBD and normal. Gene oncology and Kyoto Encyclopedia of Genes and Genomes annotations were performed, and six DEGs were further validated in other individuals by RT-qPCR. KBD cellular disease models were successfully established by generation of hiPSC lines. Seventeen consistent and significant DEGs present in all compared groups (KBD and normal) were identified. RT-qPCR validation gave consistent results with the sequencing data. Glycosaminoglycan biosynthesis-heparan sulfate/heparin; PPAR signaling pathway; and cell adhesion molecules (CAMs) were identified to be significantly altered in KBD. Differentiated chondrocytes derived from KBD-origin hiPSCs provide the first cellular disease model for etiological studies of KBD. This study also provides new sights into the pathogenesis and etiology of KBD and is likely to inform the development of targeted therapeutics for its treatment.

Simultaneous visualization and quantification of copper (II) ions in Alzheimer's disease by a near-infrared fluorescence probe.

The abnormal accumulation of copper ions (Cu2+) is considered to be one of the pathological factors of Alzheimer's disease (AD), but the internal relationship between Cu2+ and AD progression is still not fully clear. In this work, a sensitive and selective near-infrared fluorescent copper ion probe (DDP-Cu) was designed for quantification and visualization of Cu2+ level in lysates, living cells, living zebrafish and brain tissues of drosophila and mice with AD. By using this probe, we demonstrated that the content of Cu2+ in the brains of AD mice and drosophila enhanced nearly 3.5-fold and 4-fold than that of normal mice and drosophila, respectively. More importantly, pathogenesis analysis revealed that elevated Cu2+ led to changes in factors closely associated with AD, such as the increasing of reactive oxygen species(ROS), the aggregation of amyloid-ß protein (Aß) and nerve cell cytotoxicity. These findings could promote the understanding of the roles between Cu2+ and AD.

Associations between electronic devices use and common mental traits: A gene-environment interaction model using the UK Biobank data.

BACKGROUND: Electronic devices use has been reported to be associated with depression. However, limited effort has been provided to elucidate the associations between electronic devices use and mental traits in interaction with genetic factors. METHODS: We first conducted an observational study consisting of 138 976-383 742 participants for TV watching, 29 636-38 599 participants for computer using and 118 61-330 985 participants for computer playing in the UK Biobank cohort. A linear regression model was used to evaluate the associations between common mental traits and electronic devices use. Subsequently, a genome-wide gene-environment interaction study (GWEIS) was performed by PLINK2.0 to estimate the interaction effects of genes and electronic devices use on the risks of the four mental traits. RESULTS: In the UK Biobank cohort, significant associations were observed between electronic devices use and mental traits (all P < 1.0 × 10-9 ), including depression score (B = 0.094 for TV watching), anxiety score (B = 0.051 for TV watching), cigarette smoking (B = 0.046 for computer using) and alcohol drinking (B = 0.010 for computer playing). GWEIS identified multiple mental traits associated loci, interacting with electronic devices use, such as DCDC2 (rs115986722, P = 4.10 × 10-10 ) for anxiety score and TV watching, PRKCE (rs56181965, P = 9.64 × 10-10 ) for smoking and computer using and FRMD4A (rs56227933, P = 7.42 × 10-11 ) for depression score and computer playing. CONCLUSIONS: Our findings suggested that electronic devices use was associated with common mental traits and provided new clues for understanding genetic architecture of mental traits.