Hepatitis E virus infection remodels the mature tRNAome in macrophages to orchestrate NLRP3 inflammasome response.

Hepatitis E virus (HEV) infection has been shown to activate NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in macrophages, a key mechanism of causing pathological inflammation, but the mechanisms regulating this response remain poorly understood. Here, we report that the mature tRNAome dynamically responds to HEV infection in macrophages. This directs IL-1ß expression, the hallmark of NLRP3 inflammasome activation, at mRNA and protein levels. Conversely, pharmacological inhibition of inflammasome activation abrogates HEV-provoked tRNAome remodeling, revealing a reciprocal interaction between the mature tRNAome and the NLRP3 inflammasome response. Remodeling the tRNAome results in improved decoding of codons directing leucine- and proline synthesis, which are the major amino acid constituents of IL-1ß protein, whereas genetic or functional interference with tRNAome-mediated leucine decoding impairs inflammasome activation. Finally, we demonstrated that the mature tRNAome also actively responds to lipopolysaccharide (a key component of gram-negative bacteria)-triggered inflammasome activation, but the response dynamics and mode of actions are distinct from that induced by HEV infection. Our findings thus reveal the mature tRNAome as a previously unrecognized but essential mediator of host response to pathogens and represent a unique target for developing anti-inflammatory therapeutics.

Estimating the key outcomes and hepatocellular carcinoma risk in patients in immune-tolerant phase of chronic hepatitis B virus infection: A systematic review and meta-analysis.

The question of whether patients in the immune-tolerant (IT) phase of chronic hepatitis B virus (HBV) infection should undergo antiviral therapy and determine the optimal regimen remains unclear. A comprehensive search of PubMed, Embase, MEDLINE, Cochrane Library, and Wanfang Data from inception to 5 December 2023, was conducted. Studies reporting on key outcomes such as HBV DNA undetectability, HBeAg loss or seroconversion, HBsAg loss or seroconversion, and hepatocellular carcinoma (HCC) incidence in patients in the IT phase of chronic HBV infection were included. In total, 23 studies were incorporated. Approximately 4% of patients in the IT phase achieved spontaneous HBeAg loss over 48 weeks of follow-up. Antiviral therapy demonstrated a favourable impact on HBV DNA negative conversion (Children: risk ratios [RR] = 6.83, 95% CI: 2.90-16.05; Adults: RR = 25.84, 95% CI: 6.47-103.31) and HBsAg loss rates (Children: RR = 9.49, 95% CI: 1.74-51.76; Adults: RR = 7.35, 95% CI: 1.41-38.27) for patients in the IT phase. Subgroup analysis revealed that in adult patients in the IT phase, interferon plus nucleos(t)ide analogues (NA)-treated patients exhibited a higher pooled rate of HBsAg loss or seroconversion than those treated with NA monotherapy (9% vs. 0%). Additionally, the pooled annual HCC incidence for patients in the IT phase was 3.03 cases per 1000 person-years (95% CI: 0.99-5.88). Adult patients in the IT phase had a significantly lower HCC incidence risk than HBeAg-positive indeterminate phase patients (RR = 0.46, 95% CI: 0.32-0.66), with no significant differences observed between IT and immune-active phases. Presently, there is insufficient evidence solely based on reducing the risk of HCC incidence, to recommend treating patients in the IT phase of chronic HBV infection. However, both adult and paediatric patients in the IT phase responded well to antiviral therapy, showing favourable rates of HBsAg loss or seroconversion.

Momentum-Resolved Electronic Structures and Strong Electronic Correlations in Graphene-like Nitride Superconductors.

Although transition-metal nitrides have been widely applied for several decades, experimental investigations of their high-resolution electronic band structures are rare due to the lack of high-quality single-crystalline samples. Here, we report on the first momentum-resolved electronic band structures of titanium nitride (TiN) films, which are remarkable nitride superconductors. The measurements of the crystal structures and electrical transport properties confirmed the high quality of these films. More importantly, from a combination of high-resolution angle-resolved photoelectron spectroscopy and first-principles calculations, the extracted Coulomb interaction strength of TiN films can be as large as 8.5 eV, whereas resonant photoemission spectroscopy yields a value of 6.26 eV. These large values of Coulomb interaction strength indicate that superconducting TiN is a strongly correlated system. Our results uncover the unexpected electronic correlations in transition-metal nitrides, potentially providing a perspective not only to understand their emergent quantum states but also to develop their applications in quantum devices.

Gstp1 negatively regulates blood pressure in hypertensive rat via promoting APLNR ubiquitination degradation mediated by Nedd4.

Hypertension is a leading risk factor for disease burden worldwide. Vascular contraction and remodeling contribute to the development of hypertension. Glutathione S-transferase P1 (Gstp1) plays several critical roles in both normal and neoplastic cells. In this study, we investigated the effect of Gstp1 on hypertension as well as on vascular smooth muscle cell (VSMC) contraction and phenotypic switching. We identified the higher level of Gstp1 in arteries and VSMCs from hypertensive rats compared with normotensive rats for the first time. We then developed Adeno-associated virus 9 (AAV9) mediated Gstp1 down-regulation and overexpression in rats and measured rat blood pressure by using the tail-cuff and the carotid catheter method. We found that the blood pressure of spontaneously hypertensive rats (SHR) rose significantly with Gstp1 down-regulation and reduced apparently after Gstp1 overexpression. Similar results were obtained from the observations of 2-kidney-1-clip renovascular (2K1C) hypertensive rats. Gstp1 did not influence blood pressure of normotensive Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats. Further in vitro study indicated that Gstp1 knockdown in SHR-VSMCs promoted cell proliferation, migration, dedifferentiation and contraction, while Gstp1 overexpression showed opposite effects. Results from bioinformatic analysis showed that the Apelin/APLNR system was involved in the effect of Gstp1 on SHR-VSMCs. The rise in blood pressure of SHR induced by Gstp1 knockdown could be reversed by APLNR antagonist F13A. We further found that Gstp1 enhanced the association between APLNR and Nedd4 E3 ubiquitin ligases to induce APLNR ubiquitination degradation. Thus, in the present study, we discovered a novel anti-hypertensive role of Gstp1 in hypertensive rats and provided the experimental basis for designing an effective anti-hypertensive therapeutic strategy.

Enhanced supercapacitor performance of porous carbon through tuning maceral composition proportion of coal.

Porous carbons (PCs) have been widely investigated as electrode materials for supercapacitors. However, during the preparation process, intense pore formation reactions result in an amorphous carbon structure, which limits the rate performance of the electrode material. Herein, coal is chosen as a carbon source and making use of different reaction characteristics of vitrinite and inertinite with a KOH activator, an interconnected porous structure carbon material with an abundant graphite microcrystalline structure is obtained; the organic relationships between the ratio of vitrinite and inertinite, carbonization conditions, material structure and capacity performance were researched. At the ratio of vitrinite to inertinite of 1 : 2, the sample shows a specific surface area of 2507 m2 g-1 and its ID1/IG is 1.31, which is lower than that of raw coal (1.36). Due to the synergistic effect of the pore structure and graphite microcrystals, PC-900-40 exhibits an improved specific capacitance of 229.40 F g-1 at a current density of 1.0 A g-1, and even at a high current density of 10.0 A g-1 it delivers a specific capacitance of 170.04 F g-1. The PC-900-40//PC-900-40 symmetrical capacitor retains 96% of its initial capacitance after 20 000 cycles.

Community-dwelling older adults' perspectives on health risks: a qualitative study exploring anxieties, priorities, and expectations in ageing.

BACKGROUND: With the conflict between the promise of ageing in health and longevity and the limited availability of health resources and social support, older adults in China inevitably experience anxieties surrounding health risks. This study aims to investigate how older adults perceive the health risks that come with getting older, explore the degree to which health risks affect older adults, and advocate for active engagement in practices for managing health risks. METHODS: Using purposive sampling, three districts of Beijing (Xicheng District, Fengtai District, and Daxing District, respectively) were selected for the research. Qualitative semi-structured and in-depth interviews were conducted with 70 community-dwelling older adults who participated in the study. Data were extracted and analyzed based on a thematic framework approach. RESULTS: Three main themes were identified: (i) the anxieties of older adults concerning health risks in ageing; (ii) the priorities of older adults for health risk management in ageing; (iii) the expectations of older adults for health risk management in ageing. The primary health concerns among older adults included disease incidence and function decline. It was found that basic health management emerged as a critical need for older adults to mitigate health risks. Moreover, it was observed that healthcare support for older adults from familial, institutional, and governmental levels exhibited varying degrees of inadequacy. CONCLUSIONS: The primary source of anxieties among older adults regarding health risks predominantly stems from a perceived sense of health deprivation. It is often compounded by persistent barriers to primary care of priorities in managing health risks among older adults. In addition, the expectations of older adults for health risk management emphasize the necessity for integrated care approaches. Therefore, further research should give priority to the prevention and management of health risks, aim to reduce anxieties, provide integrated care to meet the primary needs and expectations of older adults, and ultimately strive toward the overarching goal of promoting health and longevity.

People-centered Primary Care Measures (PCPCM) and health equity: a perspective of urban-rural comparison in Beijing, China.

BACKGROUND: Person-centered primary care measures (PCPCM) facilitate high-quality and culturally appropriate primary care. Access to PCPCM remains unequal between rural and urban areas, and the available evidence on rural PCPCM is still lacking. METHODS: A cross-sectional survey was conducted with stratified sampling by regions, and four districts (Xicheng, Fengtai, Huairou, and Daxing) in Beijing were selected to test the performance of PCPCM in both urban and rural areas. Descriptive statistical methods were used to compare the urban-rural differences in the demographic characteristics of PCPCM. Correlation and regression analyses were performed to determine the associations between PCPCM in demographics and utilization of primary care. RESULTS: The PCPCM showed good reliability and validity in both urban and rural areas (P< 0.001), slightly lower in rural areas, but scores of rural PCPCM (R-PCPCM) in all items were lower than urban PCPCM (U-PCPCM). The PCPCM score for preferring CHCs (U-PCPCM=3.31) or RHCs (R-PCPCM=3.10) was the highest. Patients in urban areas were more likely to receive higher-quality primary care than in rural areas (P < 0.001). Patients who preferred hospitals (ß=2.61, p<0.001) or CHCs (ß=0.71, p=0.003) as providers was a significant positive predictor of U-PCPCM, but it was the preference for hospitals (ß=2.95, p<0.001) for R-PCPCM. CONCLUSIONS: Urban-rural differences existed in the performance of PCPCM, with rural areas typically more difficult to access better PCPCM. To promote health equity in rural areas, healthcare providers should strive to minimize urban-rural differences in the quality and utilization of primary care services as much as feasible.

Network pharmacology to unveil the mechanism of suanzaoren decoction in the treatment of alzheimer's with diabetes.

BACKGROUND: Suanzaoren Decoction (SZRD), a well-known formula from traditional Chinese medicine, has been shown to have reasonable cognitive effects while relaxing and alleviating insomnia. Several studies have demonstrated significant therapeutic effects of SZRD on diabetes and Alzheimer's disease (AD). However, the active ingredients and probable processes of SZRD in treating Alzheimer's with diabetes are unknown. This study aims to preliminarily elucidate the potential mechanisms and potential active ingredients of SZRD in the treatment of Alzheimer's with diabetes. METHODS: The main components and corresponding protein targets of SZRD were searched on the TCMSP database. Differential gene expression analysis for diabetes and Alzheimer's disease was conducted using the Gene Expression Omnibus database, with supplementation from OMIM and genecards databases for differentially expressed genes. The drug-compound-target-disease network was constructed using Cytoscape 3.8.0. Disease and SZRD targets were imported into the STRING database to construct a protein-protein interaction network. Further, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed on the intersection of genes. Molecular docking and molecular dynamics simulations were conducted on the Hub gene and active compounds. Gene Set Enrichment Analysis was performed to further analyze key genes. RESULTS: Through the Gene Expression Omnibus database, we obtained 1977 diabetes related genes and 622 AD related genes. Among drugs, diabetes and AD, 97 genes were identified. The drug-compound-target-disease network revealed that quercetin, kaempferol, licochalcone a, isorhamnetin, formononetin, and naringenin may be the core components exerting effects. PPI network analysis identified hub genes such as IL6, TNF, IL1B, CXCL8, IL10, CCL2, ICAM1, STAT3, and IL4. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that SZRD in the treatment of Alzheimer's with diabetes is mainly involved in biological processes such as response to drug, aging, response to xenobiotic, and enzyme binding; as well as signaling pathways such as Pathways in cancer, Chemical carcinogenesis - receptor activation, and Fluid shear stress and atherosclerosis. Molecular docking results showed that licochalcone a, isorhamnetin, kaempferol, quercetin, and formononetin have high affinity with CXCL8, IL1B, and CCL2. Molecular dynamics simulations also confirmed a strong interaction between CXCL8 and licochalcone a, isorhamnetin, and kaempferol. Gene Set Enrichment Analysis revealed that CXCL8, IL1B, and CCL2 have significant potential in diabetes. CONCLUSION: This study provides, for the first time, insights into the active ingredients and potential molecular mechanisms of SZRD in the treatment of Alzheimer's with diabetes, laying a theoretical foundation for future basic research.

A Real-World Study on Safety and Efficacy of TAF Treatment in HBV Patients with High Risk of Osteoporosis or Osteopenia in China.

Objective: Long-term antiviral treatment is necessary for chronic hepatitis B (CHB) patients, and treatment safety is imperative for these patients. Previous studies showed tenofovir alafenamide (TAF) has shown efficacy non-inferior to that of tenofovir disoproxil fumarate (TDF) with improved renal and bone safety. However, there is still a lack of a rapid and convenient method to identify CHB patients at high risk of osteoporosis before initiating antiviral treatment. The International Osteoporosis Foundation (IOF) recommended a one-minute osteoporosis risk test to identify early high-risk patients. Our aim was to evaluate the feasibility of the one-minute osteoporosis risk test, along with evaluating the effectiveness and safety for virologically suppressed CHB patients switching to TAF. Methods: In this multicenter, prospective study, patients with chronic HBV infection who had been receiving TDF or Entecavir (ETV) for 48 weeks or more with HBV DNA less than 20 IU/mL for longer than 6 months were screened by one-minute osteoporosis risk test. Patients with a high risk of osteoporosis and then diagnosed with osteopenia or osteoporosis by dual-energy X-ray absorptiometry (DEXA) were enrolled. Safety in bone and bone turnover markers and antiviral efficacy of TAF were assessed respectively at 24 and 48 weeks. Results: 84.95% (175/206) CHB patients screened by one-minute osteoporosis risk test were at risk of osteoporosis.85.71% (150/175) were diagnosed with osteopenia by DEXA. The analysis included a total of 138 patients, of whom 92(62.3%) were male and 46 (37.7%) were female, with a mean age of 45 years old. HBV DNA was suppressed at 48 weeks at 88% (35/40) in the prior ETV group and 90% (88/98) at 48 weeks group in the prior TDF group. Bone mineral density (BMD) of the lumbar spine (L1-L4) from TDF switching to TAF was improved at 24 weeks (1.03±0.11 vs. 0.97±0.12, P = .001) than baseline. Propeptides of type I procollagen (PINP) and beta-C-terminal telopeptides of type 1 collagen (CTX) in serum at 24 weeks after switching from TDF to TAF declined compared with baseline (50.35±18.90 vs. 63.65±19.17, P = .016 and 0.21±0.13 vs. 0.32±0.10, P = .017). BMD, PINP, and CTX in ETV to TAF group remained stable during treatment. Conclusion: Attention should be paid to osteoporosis risk during lone-term nucleot(s)ide analogue treatment. One minute test of osteoporosis risk could rapidly identify most CHB patients at risk of osteoporosis. Given its convenience, we recommend using this test for early screening in CHB patients prior to initiating antiviral treatment. Our results further demonstrated that an improvement in bone safety after switching to TAF in virologically suppressed CHB patients with osteoporosis.

Flexible but Refractory Single-Crystalline Hyperbolic Metamaterials.

The fabrication of flexible single-crystalline plasmonic or photonic components in a scalable way is fundamentally important to flexible electronic and photonic devices with high speed, high energy efficiency, and high reliability. However, it remains a challenge. Here, we have successfully synthesized flexible single-crystalline optical hyperbolic metamaterials by directly depositing refractory nitride superlattices on flexible fluorophlogopite-mica substrates with magnetron sputtering. Interestingly, these flexible hyperbolic metamaterials show dual-band hyperbolic dispersion of dielectric constants with small dielectric losses and high figures of merit in the visible to near-infrared ranges. More importantly, the optical properties of these nitride-based flexible hyperbolic metamaterials show remarkable stability during 1000 °C heating or after being bent 1000 times. Therefore, the strategy developed in this work offers an easy and scalable route for fabricating flexible, high-performance, and refractory plasmonic or photonic components, which can significantly expand the applications of current electronic and photonic devices.

A case study of Duchenne muscular dystrophy caused by Alu element insertion in DMD gene and analysis of its gray-hair symptoms.

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive genetic disorder caused by mutations in the DMD gene, which leads to a deficiency of the dystrophin protein. The main mutation types of this gene include exon deletions and duplications, point mutations, and insertions. These mutations disrupt the normal expression of dystrophin, ultimately leading to the disease. In this study, we reported a case of DMD caused by an insertion mutation in exon 59 (E59) of the DMD gene. The affected child exhibited significant abnormalities in related biochemical markers, early symptoms of DMD, and multiple gray hair. His mother and sister were carriers with slightly abnormal biochemical markers. The mother had mild clinical symptoms, while the sister had no clinical symptoms. Other family members were genetically and physically normal. Sequencing and sequence alignment revealed that the inserted fragment was an Alu element from the AluYa5 subfamily. This insertion produced two stop codons and a polyadenylate (polyA) tail. To understand the impact of this insertion on the DMD gene and its association with clinical symptoms, exonic splicing enhancer (ESE) prediction indicated that the insertion did not affect the splicing of E59. Therefore, we speculated that the insertion sequence would be present in the mRNA sequence of the DMD gene. The two stop codons and polyA tail likely terminate translation, preventing the production of functional dystrophin protein, which may be the mechanism leading to DMD. In addition to typical DMD symptoms, the child also exhibited premature graying of hair. This study reports, for the first time, a case of DMD caused by the insertion of an Alu element into the coding region of the DMD gene. This finding provides clues for studying gene mutations induced by Alu sequence insertion and expands the understanding of DMD gene mutations.

AhR may be involved in Th17 cell differentiation in chronic hepatitis B.

Th17 cells which are crucial for host immunity have been demonstrated to increase HBV infection. However, the mechanism of the Th17 cell increase is unknown. Hence, the mechanism of Th17 cell enhancement is important to provide a theoretical foundation for chronic hepatitis B immunotherapy. This study included 15 instances in the healthy control (HC) and 15 cohorts in the chronic hepatitis B (CHB). Their CD4+ T cells were isolated from their peripheral blood and then subjected to RNA transcriptome sequencing. Then, to identify target genes linked to Th17-cell differentiation, DEGs associated with CHB were convergent with the Th17-cell-associated genes from the KEGG database. Hub genes of DEG and target genes linked to Th17 cells were analysed for correlation. The AhR-related genes were located using the GeneMANIA database. To analyse the function of the genes, GO and KEGG pathways were employed. Protein-protein interaction network analysis employed the Metascape, STRING and Cytoscape databases. Finally, Western blotting and RT-qPCR were used to validate AhR. A total of 348 differential genes were identified in CHB patients. CytoHubba was used for screening five hub genes associated with CHB: CXCL10, RACGAP1, TPX2, FN1 and GZMA. This study aimed to determine the mechanism of elevated Th17 cells in CHB. As a result, further investigation using the convergence of DGEs and Th17 cell-related genes identified three target genes: AhR, HLA-DQA1 and HLA-DQB1, all of which were elevated in CHB. The three genes were primarily involved in immune response-related processes, according to the GO enrichment analysis. Correlation analysis of CXCL10, RACGAP1, TPX2, FN1 and GZMA genes with AhR, HLA-DQA1 and HLA-DQB1 revealed that AhR was positively associated with CXCL10 and GZMA genes, which best respond to the severity of CHB disease. Combined with the role of AhR in Th17 cell differentiation, the genes AhR was chosen for confirmation by RT-qPCR and WB in this study. The results showed that the CHB group had higher expression levels of AhR at both RT-qPCR and WB levels. Furthermore, this study's findings revealed that AhR may contribute to the development of CHB by affecting the differentiation of Th17 cells.

Establishment and validation of an AI-aid method in the diagnosis of myocardial perfusion imaging.

BACKGROUND: This study aimed to develop and validate an AI (artificial intelligence)-aid method in myocardial perfusion imaging (MPI) to differentiate ischemia in coronary artery disease. METHODS: We retrospectively selected 599 patients who had received gated-MPI protocol. Images were acquired using hybrid SPECT-CT systems. A training set was used to train and develop the neural network and a validation set was used to test the predictive ability of the neural network. We used a learning technique named "YOLO" to carry out the training process. We compared the predictive accuracy of AI with that of physician interpreters (beginner, inexperienced, and experienced interpreters). RESULTS: Training performance showed that the accuracy ranged from 66.20% to 94.64%, the recall rate ranged from 76.96% to 98.76%, and the average precision ranged from 80.17% to 98.15%. In the ROC analysis of the validation set, the sensitivity range was 88.9 ~ 93.8%, the specificity range was 93.0 ~ 97.6%, and the AUC range was 94.1 ~ 96.1%. In the comparison between AI and different interpreters, AI outperformed the other interpreters (most P-value < 0.05). CONCLUSION: The AI system of our study showed excellent predictive accuracy in the diagnosis of MPI protocols, and therefore might be potentially helpful to aid radiologists in clinical practice and develop more sophisticated models.

Association between multiple vitamins and bone mineral density: a cross-sectional and population-based study in the NHANES from 2005 to 2006.

BACKGROUND: Bone mineral density (BMD) alterations in response to multivitamin exposure were rarely studied. Our study assessed the association of coexposure to six types of vitamins (i.e., vitamins B12, B9, C, D, A and E) with BMD measurements in adults in the US. METHODS: Data were collected from participants aged ≥ 20 years (n = 2757) in the U.S. National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2006. Multiple linear regression, restricted cubic splines, principal component analysis (PCA) and weighted quantile sum (WQS) regression were performed for statistical analysis. RESULTS: The circulating levels of vitamins B12 and C were positively associated with BMDs, and an inverted L-shaped exposure relationship was observed between serum vitamin C and BMDs. PCA identified two principal components: one for 'water-soluble vitamins', including vitamins B12, B9 and C, and one for 'fat-soluble vitamins', including vitamins A, D and E. The former was positively associated with total femur (ß = 0.009, 95%CI: 0.004, 0.015) and femoral neck (ß = 0.007, 95%CI: 0.002, 0.013) BMDs, and the latter was negatively associated with BMDs with non-statistical significance. The WQS index constructed for the six vitamins was significantly related to total femur (ß = 0.010, 95%CI: 0.001, 0.018) and femoral neck (ß = 0.008, 95%CI: 0.001, 0.015) BMDs, and vitamins B12 and C weighted the most. The WQS index was inversely related to BMDs with non-statistical significance, and vitamins E and A weighted the most. CONCLUSION: Our findings suggested a positive association between water-soluble vitamin coexposure and BMD, and the association was mainly driven by vitamins B12 and C. Negative association between fat-soluble vitamin coexposure and BMD was indicated, mainly driven by vitamins E and A. An inverted L-shaped exposure relationship was found between vitamin C and BMD.

Metal mixture and osteoporosis risk: Insights from plasma metabolite profiling.

The pathophysiology of osteoporosis (OP) is influenced by exposure to nonessential harmful metals and insufficient or excessive intake of necessary metals. Investigating multiple plasma metals, metabolites, and OP risk among older adults may reveal novel clues of underlying mechanisms for metal toxicity on bone mass. A total of 294 adults ≥ 55 years from Wuhan communities were included. Plasma concentrations of 23 metals and metabolites were measured via inductively coupled plasma-mass spectrometry and global metabolite detection. To investigate the relationships between plasma metals, OP risk, and OP-related metabolites, three different statistical techniques were used: generalized linear regression model, two-way orthogonal partial least-squares analysis (O2PLS), and weighted quantile sum (WQS). The mean ages were 66.82 and 66.21 years in OP (n = 115) and non-OP (n = 179) groups, respectively. Of all 2999 metabolites detected, 111 differential between-group members were observed. The OP risk decreased by 58.5% (OR=0.415, 95% CI: 0.237, 0.727) per quartile increment in the WQS index indicative of metal mixture exposure. Consistency remained for bone mineral density (BMD) measurements. The O2PLS model identified the top five OP-related metabolites, namely, DG(18:2_22:6), 3-phenoxybenzoic acid, TG(16:1_16:1_22:6), TG(16:0_16:0_20:4), and TG(14:1_18:2_18:3), contributing most to the joint covariation between the metal mixture and metabolites. Significant correlations between each of them and the metal mixture were found using WQS regression. Furthermore, the five metabolites mediated the associations of the metal mixtures, BMD, and OP risk. Our findings shed additional light on the mediation functions of plasma metabolites in the connection between multiple metal co-exposure and OP pathogenesis and offer new insights into the probable mechanisms underpinning the bone effects of the metal mixture.

VDVM: An automatic vertebrae detection and vertebral segment matching framework for C-arm X-ray image identification.

BACKGROUND: C-arm fluoroscopy, as an effective diagnosis and treatment method for spine surgery, can help doctors perform surgery procedures more precisely. In clinical surgery, the surgeon often determines the specific surgical location by comparing C-arm X-ray images with digital radiography (DR) images. However, this heavily relies on the doctor's experience. OBJECTIVE: In this study, we design a framework for automatic vertebrae detection as well as vertebral segment matching (VDVM) for the identification of vertebrae in C-arm X-ray images. METHODS: The proposed VDVM framework is mainly divided into two parts: vertebra detection and vertebra matching. In the first part, a data preprocessing method is used to improve the image quality of C-arm X-ray images and DR images. The YOLOv3 model is then used to detect the vertebrae, and the vertebral regions are extracted based on their position. In the second part, the Mobile-Unet model is first used to segment the vertebrae contour of the C-arm X-ray image and DR image based on vertebral regions respectively. The inclination angle of the contour is then calculated using the minimum bounding rectangle and corrected accordingly. Finally, a multi-vertebra strategy is applied to measure the visual information fidelity for the vertebral region, and the vertebrae are matched based on the measured results. RESULTS: We use 382 C-arm X-ray images and 203 full length X-ray images to train the vertebra detection model, and achieve a mAP of 0.87 in the test dataset of 31 C-arm X-ray images and 0.96 in the test dataset of 31 lumbar DR images. Finally, we achieve a vertebral segment matching accuracy of 0.733 on 31 C-arm X-ray images. CONCLUSIONS: A VDVM framework is proposed, which performs well for the detection of vertebrae and achieves good results in vertebral segment matching.

A Novel missense mutation of COL2A1 gene in a large family with stickler syndrome type I.

Stickler syndrome type I (STL1, MIM 108300) is characterized by ocular, auditory, skeletal and orofacial manifestations. Nonsyndromic ocular STL1 (MIM 609508) characterized by predominantly ocular features is a subgroup of STL1, and it is inherited in an autosomal dominant manner. In this study, a novel variant c.T100>C (p.Cys34Arg) in COL2A1 related to a large nonsyndromic ocular STL1 family was identified through Exome sequencing (ES). Bioinformatics analysis indicated that the variant site was highly conserved and the pathogenic mechanism of this variant may involve in affected structure of chordin-like cysteine-rich (CR) repeats of ColIIA. Minigene assay indicated that this variant did not change alternative splicing of exon2 of COL2A1. Moreover, the nonsyndromic ocular STL1 family with 16 affected members showed phenotype variability and certain male gender trend. None of the family members had hearing loss. Our findings would expand the knowledge of the COL2A1 mutation spectrum, and phenotype variability associated with nonsyndromic ocular STL1. Search for genetic modifiers and related molecular pathways leading to the phenotype variation warrants further studies.

Construction of TME and Identification of crosstalk between malignant cells and macrophages by SPP1 in hepatocellular carcinoma.

Liver cancer accounts for 6% of all malignancies causing death worldwide, and hepatocellular carcinoma (HCC) is the most common histological type. HCC is a heterogeneous cancer, but how the tumour microenvironment (TME) of HCC contributes to the progression of HCC remains unclear. In this study, we investigated the immune microenvironment by multiomics analysis. The tumour immune infiltration characteristics of HCC were determined at the genomic, epigenetic, bulk transcriptome and single-cell levels by data from The Cancer Genome Atlas portal and the Gene Expression Omnibus (GEO). An epigenetic immune-related scoring system (EIRS) was developed to stratify patients with poor prognosis. SPP1, one gene in the EIRS system, was identified as an immune-related predictor of poor survival in HCC patients. Through receptor-ligand pair analysis in single-cell RNA-seq, SPP1 was indicated to mediate the crosstalk between HCC cells and macrophages via SPP1-CD44 and SPP1-PTGER4 association. In vitro experiments further validate SPP1 can trigger the polarization of macrophages to M2-phenotype tumour-associated macrophages (TAMs).

Methylophaga pinxianii sp. nov., isolated from the Mariana Trench.

Two strains, TMB456T and TMB1265, were isolated from different locations in the Mariana Trench. Analysis of the 16S rRNA gene and genomic rRNA sequences indicated that they were from the same novel species and were affiliated with the genus Methylophaga of the class Gammaproteobacteria. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the most closely related validly published species were Methylophaga muralis Kr3T (98.1 % similarity) and Methylophaga nitratireducenticrescens JAM1T (97.3 % similarity). Digital DNA-DNA hybridization values of TMB456T with M. muralis Kr3T and M. nitratireducenticrescens JAM1T were <25 %. The average nucleotide identity value between strain TMB456T and M. muralis Kr3T was 80.9 %. The genomic DNA G+C contents of strains TMB456T and TMB1265 were both 44.9 mol %. Strains TMB456T and TMB1265 could grow at 4-37 °C (optimum at 20-28 °C), at pH 3-10 (optimum at pH 7-9) and in the presence of 0-10 % (w/v) NaCl (optimum at 0-1 %). Cells of strains TMB456T and TMB1265 were Gram-negative rods (0.3-0.6 µm×0.7-1.3 µm). Chemotaxonomic analysis showed that ubiquinone 8 was the sole quinone produced by strain TMB456T and that the major cellular fatty acids were iso-C16 : 0, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c) and summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c). The polar lipid profile of this strain included phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphoglycolipids and two unidentified polar lipids. Based on the phenotypic, chemotaxonomic and molecular features, strains TMB456T and TMB1265 belong to a novel species within the genus Methylophaga, for which the name Methylophaga pinxianii sp. nov. is proposed. The type strain is TMB456T (=KCTC 82622T= MCCC 1K05898T).

L-Theanine inhibits melanoma cell growth and migration via regulating expression of the clock gene BMAL1.

PURPOSE: L-Theanine is a unique non-protein amino acid found in green tea, which has been identified as a safe dietary supplement. It has been reported that L-theanine exerts various biological activities. In this study, we explored the anti-cancer effects of L-theanine on melanoma cells. METHODS: A375, B16-F10, and PIG1 cell lines were used in the present study. EdU labeling, TUNEL and Annexin V/PI staining, wound-healing, and transwell migration assay were performed to detect the effects of L-theanine on melanoma cell proliferation, apoptosis, and migration. Brain and muscle Arnt-like protein 1 (BMAL1) was knocked down in melanoma cells to evaluate if L-theanine plays the anti-cancer role through regulating circadian rhythm of melanoma cells. The western blot, qRT-PCR, and dual luciferase assay were performed to explore the mechanism involved in the effects of L-theanine on melanoma cells. RESULTS: L-Theanine apparently reduced the viability of melanoma cells. Further experiments showed that L-theanine attenuated the proliferation and migration, and promoted apoptosis of melanoma cells. L-Theanine significantly enhanced the expression of BMAL1, a clock gene in melanoma cells. Down-regulation of BMAL1 suppressed the anti-cancer effects of L-theanine on melanoma cells. Further experiments indicated that the p53 transcriptional activity raised by L-theanine was dependent on BMAL1 expression in melanoma cells. CONCLUSION: L-Theanine exerts the anti-cancer effect on melanoma cells through attenuating the proliferation and migration, and promoting apoptosis of them, which is dependent on the regulation of the clock gene Bmal1 in melanoma cells.