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Abstract Accurate segmentation of the tumor area is crucial for the treatment and prognosis of patients with bladder cancer. Cystoscopy is the gold standard for diagnosing bladder tumors. However, The vast majority of current work uses deep learning to identify and segment tumors from CT and MRI findings, and rarely involves cystoscopy findings. Accurately segmenting bladder tumors remains a great challenge due to their diverse morphology and fuzzy boundaries. In order to solve the above problems, this paper proposes a medical image segmentation network with boundary guidance called boundary guidance network. This network combines local features extracted by CNNs and long-range dependencies between different levels inscribed by Parallel ViT, which can capture tumor features more effectively. The Boundary extracted module is designed to extract boundary features and utilize the boundary features to guide the decoding process. Foreground-background dual-channel decoding is performed by boundary integrated module. Experimental results on our proposed new cystoscopic bladder tumor dataset (BTD) show that our method can efficiently perform accurate segmentation of tumors and retain more boundary information, achieving an IoU score of 91.3%, a Hausdorff Distance of 10.43, an mAP score of 85.3%, and a F1 score of 94.8%. On BTD and three other public datasets, our model achieves the best scores compared to state-of-the-art methods, which proves the effectiveness of our model for common medical image segmentation.

Abstract Background Circular RNAs (circRNAs), which are a new type of single-stranded circular RNA, have significant involvement in progression of many diseases, including tumors. Currently, multiple circRNAs have been identified in hepatocellular carcinoma (HCC). Our study aims to investigate the function and mechanism of circDCAF8 in HCC. Methods The expression of circDCAF8 (hsa_circ_0014879) in HCC and para-carcinoma tissue samples was determined using quantitative real-time polymerase chain reaction (qRT-PCR). The biological function of circDCAF8 in HCC was confirmed by experiments conducted both in vitro and in vivo. And the relationship between circDCAF8, miR-217 and NAP1L1 was predicted by database and verified using qRT-PCR, RNA-binding protein immunoprecipitation (RIP) and dual-luciferase reporter assays. Exosomes isolated from HCC cells were utilized to assess the connection of exosomal circDCAF8 with HCC angiogenesis and regorafenib resistance. Results CircDCAF8 is upregulated in HCC tissues and cell lines, and is linked to an unfavourable prognosis for HCC patients. Functionally, circDCAF8 was proved to facilitate proliferation, migration, invasion and Epithelial-Mesenchymal Transformation (EMT) in HCC cells. Animal examinations also validated the tumor-promoting characteristics of circDCAF8 on HCC. Besides, exosomal circDCAF8 promoted angiogenesis in HUVECs. Mechanistically, circDCAF8 interacted with miR-217 and NAP1L1 was a downstream protein of miR-217. CircDCAF8 promoted NAP1L1 expression by sponging miR-217. In addition, exosomes may transfer circDCAF8 from regorafenib-resistant HCC cells to sensitive cells, where it would confer a resistant phenotype. Conclusion CircDCAF8 facilitates HCC proliferation and metastasis via the miR-217/NAP1L1 axis. Meanwhile, circDCAF8 can promote angiogenesis and drive resistance to regorafenib, making it a viable therapeutic target for HCC patients.

Abstract Osteoarthritis (OA) is the most prevalent form of arthritis, characterized by a complex pathogenesis. One of the key factors contributing to its development is the apoptosis of chondrocytes triggered by oxidative stress. Involvement of peroxisome proliferator-activated receptor gamma (PPARγ) has been reported in the regulation of oxidative stress. However, there remains unclear mechanisms that through which PPARγ influences the pathogenesis of OA. The present study aims to delve into the role of PPARγ in chondrocytes apoptosis induced by oxidative stress in the context of OA. Primary human chondrocytes, both relatively normal and OA, were isolated and cultured for the following study. Various assessments were performed, including measurements of cell proliferation, viability and cytotoxicity. Additionally, we examined cell apoptosis, levels of reactive oxygen species (ROS), nitric oxide (NO), mitochondrial membrane potential (MMP) and cytochrome C release. We also evaluated the expression of related genes and proteins, such as collagen type II (Col2a1), aggrecan, inducible nitric oxide synthase (iNOS), caspase-9, caspase-3 and PPARγ. Compared with relatively normal cartilage, the expression of PPARγ in OA cartilage was down-regulated. The proliferation of OA chondrocytes decreased, accompanied by an increase in the apoptosis rate. Down-regulation of PPARγ expression in OA chondrocytes coincided with an up-regulation of iNOS expression, leading to increased secretion of NO, endogenous ROS production, and decrease of MMP levels. Furthermore, we observed the release of cytochrome C, elevated caspase-9 and caspase-3 activities, and reduction of the components of extracellular matrix (ECM) Col2a1 and aggrecan. Accordingly, utilization of GW1929 (PPARγ Agonists) or Z-DEVD-FMK (caspase-3 inhibitor) can protect chondrocytes from mitochondrial-related apoptosis and alleviate the progression of OA. During the progression of OA, excessive oxidative stress in chondrocytes leads to apoptosis and ECM degradation. Activation of PPARγ can postpone OA by down-regulating caspase-3-dependent mitochondrial apoptosis pathway.

Abstract N6-methyladenosine (m6A) and 5-methylcytosine (m5C) RNA modifications have garnered significant attention in the field of epigenetic research due to their close association with human cancers. This study we focus on elucidating the expression patterns of m6A/m5C-related long non-coding RNAs (lncRNAs) in esophageal squamous cell carcinoma (ESCC) and assessing their prognostic significance and therapeutic potential. Transcriptomic profiles of ESCC were derived from public resources. m6A/m5C-related lncRNAs were obtained from TCGA using Spearman’s correlations analysis. The m6A/m5C-lncRNAs prognostic signature was selected to construct a RiskScore model for survival prediction, and their correlation with the immune microenvironment and immunotherapy response was analyzed. A total of 606 m6A/m5C-lncRNAs were screened, and ESCC cases in the TCGA cohort were stratified into three clusters, which showed significantly distinct in various clinical features and immune landscapes. A RiskScore model comprising ten m6A/m5C-lncRNAs prognostic signature were constructed and displayed good independent prediction ability in validation datasets. Patients in the low-RiskScore group had a better prognosis, a higher abundance of immune cells (CD4 + T cell, CD4 + naive T cell, class-switched memory B cell, and Treg), and enhanced expression of most immune checkpoint genes. Importantly, patients with low-RiskScore were more cline benefit from immune checkpoint inhibitor treatment (P

Abstract Background Most genetic skeletal disorders (GSD) were complex, disabling and life-threatening without effective diagnostic and treatment methods. However, its impacts on health system have not been well studied. The study aimed to systematically evaluate the health-care utilization and economic burden in GSD patients. Methods The patients were derived from 2018 Nationwide Inpatient Sample and Nationwide Readmissions Database. GSD patients were extracted based on International Classification of Diseases-10th revision codes. Results A total of 25,945 (0.12%) records regarding GSD were extracted from all 21,400,282 records in NIS database. GSD patients were likely to have significantly longer length of stay (6.50 ± 0.08 vs. 4.63 ± 0.002, P

Abstract The significance means of the seismic reinforcement effect of a pile-anchor system for slope reinforcement has been widely recognized. However, cases of deformation failure and instability sliding of the pile-anchor system itself and the reinforced slope under seismic action continue to be recorded. Therefore, it is crucial to evaluate the seismic performance of slopes reinforced by a pile-anchor system to prevent the system’s failure. Current evaluation models of a slope reinforced by a pile-anchor system mainly focus on slope stability; however, the safety of the pile-anchor system itself is not sufficiently considered in these models. Consequently, in this study, we propose a multi-objective optimization evaluation (MOE) model for evaluating the seismic performance of slopes reinforced by a pile-anchor system that considers slope stability, safety of the pile-anchor system, and dynamic response of the slope. This model considers slope displacement, acceleration amplification factor of a slope, pile displacement, and anchor displacement as negative indexes, and anti-slide pile bending moment, shear force, and anchor axial force as intermediate indexes. The comprehensive weight of relevant indexes is obtained by combining subjective and objective weights, and the seismic reinforcement effect of the pile-anchor system is evaluated subsequently. In conclusion, the MOE model proposed in this study provides a novel solution for the optimization evaluation of a slope reinforced by a pile-anchor system in forthcoming projects.

Abstract We aimed to investigate the clinico-radiologic features of acute Marchiafava-Bignami disease (MBD) and its evolutionary process after effective treatment through subgroup comparison. The clinical and MRI data of 23 patients with acute MBD were retrospectively analyzed and divided into type A (12 cases, with entire callosal involvement) and type B (11 cases, with focal callosal involvement). The clinical assessments and MRI findings (before and after treatment) were compared between the two subtypes. Compared with type B, type A had lower MoCA (Montreal Cognitive Assessment) scores at admission (16.50 ± 1.73 vs 18.27 ± 1.68, P = 0.021) and were more common with extracallosal involvement (66.67% vs 18.18%, P = 0.036) and longer illness duration (18.3 ± 2.1 days vs 15.6 ± 2.4 days, P = 0.012). During the treatment, the residual lesion in the splenium was more common in type A (58.33% vs 9.09%, P = 0.027). After treatment, the MoCa scores of both subtypes gradually increased (P

Abstract The sustainable development of urban agglomerations plays a pivotal role in national and global efforts to reduce emissions. By focusing on the efficient exchange and optimization of energy consumption across various sectors, the sustainable development of energy systems within urban agglomerations can be achieved. However, the overall impact of the cross-sector energy optimization and complementarity has not been quantitatively analyzed. Here, we focused on the Yangtze River Delta (YRD) urban agglomeration in China and proposed an optimization framework for energy, environment, and economy. The framework considered four sectors: transportation sector, power sector, industry sector, and building sector, in order to determine the most sustainable development pathway for the urban agglomeration. The optimization model considers total costs and greenhouse gas emissions reduction as the objectives and utilizes technologies as constraints to optimize the pathway. We found that this optimization strategy resulted in a 53.1 billion tons increase in CO2 emissions reduction in the region. The results of emission reduction varied across sectors, ranging from 4.5 to 22.2 billion tons CO2 equivalent, and across cities, ranging from 7.1 to 4688.1 Mt. The results suggest that the core cities in the urban agglomeration can take on a leadership role. By promoting cross-sector collaboration and implementing energy recycling, the energy efficiency of surrounding cities can be greatly improved, leading to the sustainable development of the urban agglomeration.

Abstract Dry processing is ineffective in preserving fresh jujubes (Zizyphus jujuba Mill.), contributing largely to the delayed jujube harvest in Xinjiang. However, no studies have evaluated the impact of delayed harvest periods on processing quality. Therefore, the present study investigated the effects of different delayed harvest periods on the characteristics of the quality of jujubes in Xinjiang after hot air drying. Six batches (S1–S6) were sampled over a 7-d period. Various indicators of jujubes changed significantly during the extended harvest period (P

Abstract Osteogenesis imperfecta (OI) is a connective tissue disorder affecting the skeleton and other organs, which has multiple genetic patterns, numerous causative genes, and complex pathogenic mechanisms. The previous classifications lack structure and scientific basis and have poor applicability. In this paper, we summarize and sort out the pathogenic mechanisms of OI, and analyze the molecular pathogenic mechanisms of OI from the perspectives of type I collagen defects(synthesis defects, processing defects, post-translational modification defects, folding and cross-linking defects), bone mineralization disorders, osteoblast differentiation and functional defects respectively, and also generalize several new untyped OI-causing genes and their pathogenic mechanisms, intending to provide the evidence of classification and a scientific basis for the precise diagnosis and treatment of OI.

Abstract VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner. Mechanistically, as an RNA binding protein, BICC1 bounds to the 3’UTR of Lipocalin-2 (LCN2) mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells. When its level is elevated, LCN2 binds to its receptor 24p3R, which directly phosphorylates JAK2 and activates JAK2/STAT3 signal, leading to increased production of an angiogenic factor CXCL1. Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice, and increased the tumor suppressive effect of gemcitabine. In conclusion, BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer, leading to resistance to VEGF inhibitors. BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.

The Guangdong-Hong Kong-Macao Greater Bay Area has attracted attention for its extraordinary pace of economic development and is considered to be leading the way in China's transformation from a manufacturing to an innovation cluster. However, due to rapid economic expansion and rapid urbanization, the Great Bay Area still struggles with low energy efficiency and environmental degradation, which has slowed down the pace of development. Therefore, in order to alleviate energy pressure, promote the country's sustainable development and gain a competitive advantage in the global market, researching energy efficiency and improving energy utilization efficiency is crucial. In this study, macro-level energy efficiency indicators are constructed using energy consumption data from various cities in the Greater Bay Area for the period from 2000 to 2020, and the spatio-temporal evolution of energy efficiency is analysed. The results show that all cities in the Greater Bay Area experienced an increasing trend in energy efficiency from 2000 to 2019, with significant variation in growth rates and magnitudes between cities. Compared to the nine cities in Guangdong province, Hong Kong and Macao exhibited significantly superior energy efficiency, with Foshan recording the highest growth rate of 14%. In 2020, most cities experienced a decline in energy efficiency due to the COVID-19 pandemic, with Macao experiencing the greatest decrease at 57%. Hong Kong and Macao are both in the "low consumption and high efficiency" target region, while Guangzhou, Shenzhen and Zhuhai are consistently in the "both high" region. Changes in the industrial upgrading index correspond significantly with changes in energy efficiency trajectories, with the transition from primary to secondary and tertiary industries playing a more substantial role. There is no significant association found between the strength of environmental regulation and changes in energy efficiency. The study's findings indicate that the most effective way to achieve economic transformation in the majority of China's regions is to combine adequate environmental legislation with industrial structural adjustment.

Deubiquitinating enzymes (DUBs) play a pivotal role in regulating the antiviral immune response by targeting members of the RLR signaling pathway. As a pivotal member of the RLR pathway, TRAF3 is essential for activating the MAVS/TBK-1/IRF3 signaling pathway in response to viral infection. Despite its importance, the function of DUBs in the TRAF3-mediated antiviral response is poorly understood. Ubiquitin-specific protease 26 (USP26) regulates the RLR signaling pathway to modulate the antiviral immune response. The results demonstrate that EV71 infection upregulates the expression of USP26. Knockdown of USP26 significantly enhances EV71-induced expression of IFN-β and downstream interferon-stimulated genes (ISGs). Deficiency of USP26 not only inhibits EV71 replication but also weakens the host's resistance to EV71 infection. USP26 physically interacts with TRAF3 and reduces the K63-linked polyubiquitination of TRAF3, thereby promoting pIRF3-mediated antiviral signaling. USP26 physically interacts with TRAF3 and reduces the K63-linked polyubiquitination of TRAF3, thereby promoting pIRF3-mediated antiviral signaling. Conversely, knockdown of USP26 leads to an increase in the K63-linked polyubiquitination of TRAF3. These findings unequivocally establish the essential role of USP26 in RLR signaling and significantly contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.

Abstract Water-induced strength deterioration of rock mass is a crucial factor for rock slope instability. To better show the degradation process of rock slope water–rock interaction, we used bentonite as a water-sensitive regulator to build a new rock-like material that matches the features of water-induced strength degradation based on the cement-gypsum bonded materials. Twenty-five schemes of the material mixture proportion were designed using the orthogonal design method considering four factors with five variable levels, and a variety of experiments were conducted to obtain physico-mechanical parameters. In addition, one group of rock-like material proportion was selected and applied to the large-scale physical model test. The experiment results reveal that: (1) The failure mode of this rock-like material is highly similar to that of natural rock masses, and the physico-mechanical parameters vary over a wide range; (2) The bentonite content has a significant influence on the density, elastic modulus, and tensile strength of rock-like materials; (3) It is feasible to obtain the regression equation based on the linear regression analysis to determine the proportion of rock-like material; (4) Through application, the new rock-like material can effectively simulate or reveal the startup mechanism and instability characteristics of rock slopes under water-induced degradation. These studies can serve as a guide for the fabrication of rock-like material in the other model tests.

Abstract Large-scale urban growth has modified the hydrological cycle of our cities, causing greater and faster runoff. Urban forests (UF), i.e. the stock of trees and shrubs, can substantially reduce runoff; still, how climate, tree functional types influence rainfall partitioning into uptake and runoff is mostly unknown. We analyzed 92 published studies to investigate: interception (I), transpiration (T), soil infiltration (IR) and the subsequent reduction in runoff. Trees showed the best runoff protection compared to other land uses. Within functional types, conifers provided better protection on an annual scale through higher I and T but broadleaved species provided better IR. Regarding tree traits, leaf area index (LAI) showed a positive influence for both I and T. For every unit of LAI increment, additional 5% rainfall partition through T (3%) and I (2%) can be predicted. Overall, runoff was significantly lower under mixed species stands. Increase of conifer stock to 30% in climate zones with significant winter precipitation and to 20% in areas of no dry season can reduce runoff to an additional 4%. The study presented an overview of UF potential to partition rainfall, which might help to select species and land uses in different climate zones for better storm-water management.

Abstract Genomic instability (GI) in cancer facilitates cancer evolution and is an exploitable target for therapy purposes. However, specific genes involved in cancer GI remain elusive. Causal genes for GI via expressions have not been comprehensively identified in colorectal cancers (CRCs). To fill the gap in knowledge, we developed a data mining strategy (Gene Expression to Copy Number Alterations; “GE-CNA”). Here we applied the GE-CNA approach to 592 TCGA CRC datasets, and identified 500 genes whose expression levels associate with CNA. Among these, 18 were survival-critical (i.e., expression levels correlate with significant differences in patients’ survival). Comparison with previous results indicated striking differences between lung adenocarcinoma and CRC: (a) less involvement of overexpression of mitotic genes in generating genomic instability in the colon and (b) the presence of CNA-suppressing pathways, including immune-surveillance, was only partly similar to those in the lung. Following 13 genes (TIGD6, TMED6, APOBEC3D, EP400NL, B3GNT4, ZNF683, FOXD4, FOXD4L1, PKIB, DDB2, MT1G, CLCN3, CAPS) were evaluated as potential drug development targets (hazard ratio [> 1.3 or

Abstract In atrial fibrillation (AF) patients, complex electrograms during sinus rhythm (C-EGMs) could be pathological or not. We aimed to demonstrate whether local pacing was helpful to discern pathological C-EGMs. 126 persistent AF patients and 27 patients with left-side accessory pathway (LAP) underwent left atrial mapping during sinus rhythm. If C-EGMs were detected, local pacing was performed. If the electrograms turned normal, we defined them as non-fixed C-EGMs, otherwise as fixed C-EGMs. No difference was detected in the incidence and proportion of non-fixed C-EGMs between AF patients and LAP patients (101/126 vs. 19/27, P = 0.26; 9.1 ± 6.0% vs. 7.7 ± 5.7%, P = 0.28). However, the incidence and proportion of fixed C-EGMs were higher in persistent AF patients (87/126 vs. 1/27, P

Abstract During influenza A virus (IAV) infection, it is unclear whether type I interferons (IFNs) have defensive antiviral effects or contribute to immunopathology in smokers. We treated nonsmoking (NS) and cigarette smoke (CS)-exposed mice intranasally with early (prophylactic) or late (therapeutic) IFN-β. We compared the mortality and innate immune responses of the treated mice following challenge with IAV. In NS mice, both early and late IFN-β administration decreased the survival rate in mice infected with IAV, with late IFN-β administration having the greatest effect on survival. In contrast, in CS-exposed mice, early IFN-β administration significantly increased survival during IAV infection while late IFN-β administration did not alter mortality. With regards to inflammation, in NS mice, IFN-β administration, especially late administration, significantly increased IAV-induced inflammation and lung injury. Early IFN-β administration to CS-exposed mice did not increase IAV-induced inflammation and lung injury as occurred in NS mice. Our results demonstrate, although IFN-β administration worsens the susceptibility of NS mice to influenza infection with increased immunopathology, early IFN-β administration to CS-exposed mice, which have suppression of the intrinsic IFN response, improved outcomes during influenza infection.

Abstract Bladder cancer (BLCA) is the most common malignancy whose early diagnosis can ensure a better prognosis. However, the predictive accuracy of commonly used predictors, including patients’ general condition, histological grade, and pathological stage, is insufficient to identify the patients who need invasive treatment. Autophagy is regarded as a vital factor in maintaining mitochondrial function and energy homeostasis in cancer cells. Whether autophagy-related genes (ARGs) can predict the prognosis of BLCA patients deserves to be investigated. Based on BLCA data retrieved from the Cancer Genome Atlas and ARGs list obtained from the Human Autophagy Database website, we identified prognosis-related differentially expressed ARGs (PDEARGs) through Wilcox text and constructed a PDEARGs-based prognostic model through multivariate Cox regression analysis. The predictive accuracy, independent forecasting capability, and the correlation between present model and clinical variables or tumor microenvironment were evaluated through R software. Enrichment analysis of PDEARGs was performed to explore the underlying mechanism, and a systematic prognostic signature with nomogram was constructed by integrating clinical variables and the aforementioned PDEARGs-based model. We found that the risk score generated by PDEARGs-based model could effectively reflect deteriorated clinical variables and tumor-promoting microenvironment. Additionally, several immune-related gene ontology terms were significantly enriched by PDEARGs, which might provide insights for present model and propose potential therapeutic targets for BLCA patients. Finally, a systematic prognostic signature with promoted clinical utility and predictive accuracy was constructed to assist clinician decision. PDEARGs are valuable prognostic predictors and potential therapeutic targets for BLCA patients.

Abstract Background Understanding dental students’ future career choice and motivation could provide beneficial references for both educators and students, but there were few studies on students in a Chinese dental school. The study aimed to investigate Chinese final year dental students’ the short-term and long-term plans, motivations, and identify the influence of gender on the future plans. Methods A total of 265 final year dental school students of the School of Stomatology, China Medical University from 2016 through 2020 were invited to complete an anonymous, 27-item questionnaire. Moreover, almost all of questions were in multiple-choice formats. Data were categorized and analysed using chi-square comparative analyses. Results 88.3% of respondents decided to pursue a graduate degree after graduating from dental school. Moreover, the single most important reason influencing their plans was “eligible for better jobs” (42.8%). More females than males studied dentistry (222 vs 111), and gender had an influence on the choice of specialty. Conclusions This study listed the selection tendency and influencing factors of students in a Chinese dental school for the reference of educators and students. And the results could raise some useful influence and feedback effect on current health and education policy, and on the career development of practicing dentists or dental students.

Abstract Acoustic emission (AE) characterization is an effective technique to indirectly capture the failure process of quasi brittle rock. In previous studies, both experiments and numerical simulations were adopted to investigate the AE characteristics of rocks. However, as the most popular numerical model, the moment tensor model (MTM) cannot be constrained by the experimental result because there is a gap between MTM and experiments in principle, signal processing and energy analysis. In this paper, we developed a particle-velocity-based model (PVBM) that enabled direct monitoring and analysis of the particle velocity in the numerical model and had good robustness. The PVBM imitated the actual experiment and could fill in gaps between the experiment and MTM. AE experiments of marine shale under uniaxial compression were carried out, and the results were simulated by MTM. In general, the variation trend of the experimental result could be presented by MTM. Nevertheless, the magnitudes of AE parameters by MTM presented notable differences of more than several orders of magnitude compared with those by the experiment. We sequentially used PVBM as a proxy to analyse these discrepancies and systematically evaluate the AE characterization of rocks from the experiment to numerical simulation, considering the influence of wave reflection, energy geometrical diffusion, viscous attenuation, particle size and progressive deterioration of rock material. The combination of MTM and PVBM could reasonably and accurately acquire AE characteristics of the actual AE experiment of rocks by making full use of their respective advantages.

The COVID-19 pandemic has led to significant global health and economic consequences. There is an unmet need to define a molecular fingerprint of severity of the disease that may guide an early, rational and directed intervention preventing severe illness. We collected plasma from patients with moderate (nine cases), severe (22 cases) and critical (five cases) COVID-19 within three days of hospitalization (approximately one week after symptom onset) and used a cytokine antibody array to screen the 105 cytokines included in the array. We found that I-TAC, IP-10, ST2 and IL-1ra were significantly upregulated in patients with critical disease as compared to the non-critical (moderate and severe combined). ELISA further quantified I-TAC levels as 590.24±410.89, 645.35±517.59 and 1613.53±1010.59 pg/ml in moderate, severe and critical groups, respectively. Statistical analysis showed that I-TAC levels were significantly higher in patients with critical disease when compared with moderate (p = 0.04), severe (p = 0.03) or the combined non-critical (p = 0.02) group. Although limited by the low sample numbers, this study may suggest a role of I-TAC as a potential early marker to discriminate between critical and non-critical COVID-19 cases. Such knowledge is urgently needed for appropriate allocation of resources and to serve as a platform for future research towards early interventions that could mitigate disease severity and save lives.

Objectives Optimal periprocedural blood pressure (BP) management during mechanical thrombectomy (MT) for acute ischaemic stroke is still controversial. The aim of this study was to investigate the association between intraprocedural BP variability (BPV) and outcomes in patients with large vessel occlusion (LVO) following MT with general anaesthesia.Design A prospective observational cohort study.Setting This study was conducted in a single tertiary hospital of Hangzhou in Zhejiang province.Participants A total of 141 patients with LVO treated with MT were finally included between January 2018 and September 2020.Main outcome measures Intraprocedural BP was recorded every 5 min throughout the procedure. BPV was measured as SD, coefficient of variation (CV), max-min (RANGE) and successive variation. Haemorrhagic transformation was assessed on 24-hour CT images according to European Cooperative Acute Stroke Study III trial. Poor functional outcome was defined as 90-day modified Rankin Scale score 3–6. Binary logistic regression analysis was used to investigate the association of BPV parameters with the incidence of parenchymal haemorrhage (PH) and poor functional outcome.Results After controlling for age, female, history of smoking, hypertension and atrial fibrillation, baseline National Institutes of Health Stroke Scale, baseline systolic BP (SBP), baseline Alberta Stroke Program Early CT Score, bridging thrombolysis and times of retrieval attempts, the results demonstrated that intraprocedural SBPRANGE (OR 1.029; 95% CI 1.003 to 1.055; p=0.027), SBPSD (OR 1.135; 95% CI 1.023 to 1.259; p=0.017) and SBPCV (OR 1.189; 95% CI 1.053 to 1.342; p=0.005) were independently associated with poor functional outcome. However, the independent association between intraprocedural BPV and PH at 24 hours has not been established in this study.Conclusions Increased intraprocedural BPV was more likely to have poor functional outcome in patients with LVO following MT with general anaesthesia. This finding indicates that special precautions should be taken to minimise BP fluctuation during procedure.

Abstract Background Dozens of genes are involved in 46, XY differences in sex development (DSD). Notably, about 3/4 of patients cannot make a clear etiology diagnosis and single gene variant identified cannot fully explain the clinical heterogeneity of 46, XY DSD. Materials and methods We conducted a systematic clinical analysis of a 46, XY DSD patient, and applied whole-exome sequencing for the genetic analysis of this pedigree. The identified variants were analyzed by bioinformatic analysis and in vitro studies were performed in human embryonic kidney 293T (HEK-293T) cells which were transiently transfected with wild type or variant NR5A1 and MAP3K1 plasmid. Furthermore, protein production of SRY-box transcription factor 9 (SOX9) was analyzed in cell lysates. Results A novel NR5A1 variant (c.929A > C, p. His310Pro) and a rare MAP3K1 variant (c.2282T > C, p. Ile761Thr) were identified in the proband, whereas the proband's mother and sister who only carry rare MAP3K1 variant have remained phenotypically healthy to the present. These two variants were predicted to be pathogenic by bioinformatic analysis. In vitro, NR5A1 variant decreased the SOX9 production by 82.11% compared to wild type NR5A1, while MAP3K1 variant had little effect on the SOX9 production compared to wild type MAP3K1. Compared to wild type NR5A1 transfection, the SOX9 production of cells transfected with both wild type plasmids decreased by about 17.40%. Compared to variant NR5A1 transfection, the SOX9 production of cells transfected with both variant plasmids increased by the 36.64%. Conclusions Our findings suggested the novel compound variants of NR5A1 and MAP3K1 can alter the expression of SOX9 and ultimately lead to abnormality of sex development.

More than 50 million people are affected by traumatic brain injury (TBI) each year around the world, and nearly half of the population worldwide will have one or more TBI(s) in their lifetime. And in 2017, more than 1.39 billion people in China suffered from TBI, representing nearly 18% of the world population; these were mainly caused by road traffic incidents. Salvianolic acid A is a compound obtained from Salvia miltiorrhiza Bunge, which is one of the active components of many traditional Chinese medicines for the treatment of cardiovascular and cerebrovascular disease, with the effect of inhibition of inflammatory response. ASC is a critical factor in the activation of inflammation response process via promoting the maturation of caspase-1, and activation of NLPR3 under bacterial infection promotes the necrosis of cells in an ASC-dependent manner. However, few studies focus on the effect of ASC in a TBI model. In this study, we found that inhibition of ASC reduced the expression of inflammatory cytokines, and the concentration of calcium and ROS, while it increased the expression of mitochondrial function-related proteins. We further noticed that these effects were regulated by DLK2/MLK3/JNK signalling pathway and might contribute to the treatment of TBI.

Abstract First principle calculations were performed to investigate the structural, mechanical, electronic properties, and thermodynamic properties of three binary Mg–B compounds under pressure, by using the first principle method. The results implied that the structural parameters and the mechanical properties of the Mg–B compounds without pressure are well matched with the obtainable theoretically simulated values and experimental data. The obtained pressure–volume and energy–volume revealed that the three Mg–B compounds were mechanically stable, and the volume variation decreases with an increase in the boron content. The shear and volume deformation resistance indicated that the elastic constant Cij and bulk modulus B increased when the pressure increased up to 40 GPa, and that MgB7 had the strongest capacity to resist shear and volume deformation at zero pressure, which indicated the highest hardness. Meanwhile, MgB4 exhibited a ductility transformation behaviour at 30 GPa, and MgB2 and MgB7 displayed a brittle nature under all the considered pressure conditions. The anisotropy of the three Mg–B compounds under pressure were arranged as follows: MgB4 > MgB2 > MgB7. Moreover, the total density of states varied slightly and decreased with an increase in the pressure. The Debye temperature ΘD of the Mg–B compounds gradually increased with an increase in the pressure and the boron content. The temperature and pressure dependence of the heat capacity and the thermal expansion coefficient α were both obtained on the basis of Debye model under increased pressure from 0 to 40 GPa and increased temperatures. This paper brings a convenient understanding of the magnesium–boron alloys.

Abstract Background The objective of this study was to ascertain the importance rankings of factors affecting the implementation of shared decision-making (SDM) in medical students in China and determine whether these factors were consistent across the respondents’ individual characteristics. Method Students studying clinical medicine were recruited from three medical universities in China. A cross-sectional online survey using best-worst object scaling with a balanced incomplete block design was adopted to investigate their preference towards implementing SDM in China. Count analysis, multinomial logit analysis and mixed logit analysis were used to estimate the preference heterogeneity of the SDM factors among respondents. Results A total of 574 medical students completed the online survey. The three most important factors for implementing SDM were trust and respect, (providing) high-quality medical information and multi-disciplinary collaboration. The mixed logit regression model identified significant heterogeneity in SDM preferences among respondents, and sub-group analysis showed that some heterogeneities varied in respondents by sex, study programs and their experience of visiting doctors. Conclusion The importance rankings provide rich information for implementing SDM and facilitate the reform of education in medical schools in China. However, the heterogeneities in SDM preference need further explorations.

Purpose To investigate the mechanism of miR-148a-3p regulating the proliferation and migration of bladder tumor cells. Materials and Methods We conducted a preliminary study to detect the relative expression of miR-148a-3p in bladder cancer and para-cancerous tissue samples. Three bladder tumor cell lines, T24, 5,637 and UM-UC-3, were selected. The expression levels of miR-148a-3p were artificially regulated with miR-148a-3p mimics and the miR-148a-3p inhibitor. The relative expression levels of miR-148a-3p in the samples of each cell line were determined. Cell Counting Kit-8 (CCK-8) was used to detect cell proliferation, while the effect of the miR-148a-3p mimics and inhibitor on tumor cell migration was detected by wound healing assay. Flow cytometry assay was carried out to explore the effect of miR-148a-3p on cell apoptosis. Dual-luciferase reporter assay was performed in order to verify miR-148a-3p’s target gene. The expressions of ROCK-1 and Bcl-2 were analyzed by western blot. Results The relative expression of miR-148a-3p in tumor and adjacent tissues was assessed with qRT-PCR (P < 0.05) and found to be significantly lower in the tumor tissues than the adjacent tissues. The data obtained from the CCK-8 and wound healing assay showed that intracellular transfection of miR-148a-3p mimics could inhibit cell proliferation and migration, while the miR-148a-3p inhibitor promoted them. Overexpression of miR-148a-3p promoted cell apoptosis in the T24 and 5,637 cell lines. The dual-luciferase reporter assay verified that ROCK-1 is a direct target of miR-148a-3p. Western blot showed that miR-148a-3p overexpression downregulated the expression of ROCK-1 and Bcl-2, while miR-148a-3p knockdown upregulated the expression of ROCK-1 and Bcl-2. Conclusions We confirmed that miR-148a-3p was significantly decreased in bladder cancer cells. miR-148a-3p overexpression inhibited bladder cancer cell proliferation and migration, whereas miR-148a-3p knockdown promoted bladder cancer cell proliferation and migration. Moreover, we found that ROCK-1 was a downstream target of miR-148a-3p. We also found that miR-148a-3p induced cell apoptosis by regulating the expression of Bcl-2. However, the deeper mechanism of this regulatory relationship needs further study.

Background: N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Methods: An integrated model named “m6Ascore” is constructed based on RNA-seq data of m6A regulators in PDAC. Association of m6Ascore and overall survival is validated across several different datasets. Overlaps of m6Ascore and established molecular classifications of PDAC is examined. Immune infiltration, enriched pathways, somatic copy number alterations (SCNAs), mutation profiles and response to immune checkpoint inhibitors are compared between m6Ascore-high and m6Ascore-low tumors. Findings: m6Ascore is associated with dismal overall survival and increased tumor recurrence in PDAC as well as several other solid tumors including colorectal cancer and breast cancer. Basal-like (Squamous) PDAC has higher m6Ascore than that in the classical PDAC. Mechanism study showed m6Ascore-high tumors are characterized with reduced immune infiltration and T cells exhaustion. Meanwhile, m6Ascore is associated with genes regulating cachexia and chemoresistance in PDAC. Furthermore, distinct SCNAs patterns and mutation profiles of KRAS and TP53 are present in m6Ascore-high tumors, indicating immune evasion. m6Ascore-low tumors have higher response rates to immune checkpoint inhibitors (ICIs). Interpretation: These findings indicate m6Ascore can predict aggressiveness and immune evasion in pancreatic cancer. This model has implications for pancreatic cancer prognosis and treatment response to ICIs. Funding: This work was supported in part by National Institutes of Health (NIH) grants to M. Li (R01 CA186338, R01 CA203108, R01 CA247234 and the William and Ella Owens Medical Research Foundation) and NIH/National Cancer Institute Q39 award P30CA225520 to Stephenson Cancer Center.

Background: The 47,XYY syndrome could result in fertility problems. However, seldom studies reported comprehensive researches on the embryonic development and pregnancy outcomes of these patients. This study aimed to evaluate the clinical outcomes of nonmosaic 47,XYY patients performed with fluorescent in situ hybridization (FISH) and preimplantation genetic diagnosis (PGD) treatment. Methods: This was a retrospective study. Between January 2012 and May 2017, 51 infertile males with nonmosaic 47,XYY syndrome underwent FISH-PGD were included in the study. According to sex chromosomal FISH results, embryos were classified as normal signal, no nuclei fixed, no signal in fixed nuclei, suspensive signal, and abnormal signal groups, respectively. The incidence of each group, the fixation rate, and hybridization rate were calculated. Embryonic development and pregnancy outcomes were also analyzed. The measurement data were analyzed with Student's t-test. The comparison of categorical data was analyzed with the Chi-square test and Fisher's exact test when expected cell count was 0.05), and were significantly lower than the normal signal group (66.4%, P < 0.001). The clinical pregnancy rates of fresh and frozen embryos transferred cycles were 70.6% and 85.7%, respectively. Conclusions: Among embryos with a clear diagnosis of sex chromosome, about one-fifth showed abnormal signals. Embryos with two sex chromosomal signals are more likely to develop into good-quality ones. The application of the PGD by FISH may help to improve the clinical outcomes.

SETD3 is a member of the SET (Su(var)3–9, Enhancer of zeste, and Trithorax) domain protein superfamily and plays important roles in hypoxic pulmonary hypertension, muscle differentiation, and carcinogenesis. Previously, we identified SETD3 as the actin-specific methyltransferase that methylates the N3 of His73 on β-actin (Kwiatkowski et al., 2018). Here, we present two structures of S-adenosyl-L-homocysteine-bound SETD3 in complex with either an unmodified β-actin peptide or its His-methylated variant. Structural analyses, supported by biochemical experiments and enzyme activity assays, indicate that the recognition and methylation of β-actin by SETD3 are highly sequence specific, and that both SETD3 and β-actin adopt pronounced conformational changes upon binding to each other. In conclusion, this study is the first to show a catalytic mechanism of SETD3-mediated histidine methylation on β-actin, which not only throws light on the protein histidine methylation phenomenon but also facilitates the design of small molecule inhibitors of SETD3.

Background: Cardiovascular diseases, including dilated cardiomyopathy (DCM) and hypertension, are the leading cause of death worldwide. The role of mitochondrial DNA (mtDNA) in the pathogenesis of these diseases has not been completely clarified. In this study, we evaluate whether A8701G mutation is associated with maternally inherited hypertension and DCM in a Chinese pedigree of a consanguineous marriage. Methods: Fourteen subjects in a three-generation Han Chinese family with hypertension and DCM, in which consanguineous marriage was present in the parental generation, were interviewed. We divided all the family members into case (7 maternal members) and control group (7 nonmaternal members) for comparison. Clinical evaluations and sequence analysis of mtDNA were obtained from all participants. Frequency differences between maternal and nonmaternal members were tested to locate the disease-associated mutations. Results: The majority of the family members presented with a maternal inheritance of hypertension and DCM. Sequence analysis of mtDNA in this pedigree identified eight mtDNA mutations. Among the mutations identified, there was only one significant mutation: A8701G (P = 0.005), which is a homoplasmic mitochondrial missense mutation in all the matrilineal relatives. There was no clear evidence for any synergistic effects between A8701G and other mutations. Conclusions: A8701G mutation may act as an inherited risk factor for the matrilineal transmission of hypertension and DCM in conjunction with genetic disorders caused by consanguineous marriage.

Previous studies have demonstrated the genetic correlations between type 2 diabetes, obesity and dyslipidemia, and indicated that many genes have pleiotropic effects on them. However, these pleiotropic genes have not been well-defined. It is essential to identify pleiotropic genes using systematic approaches because systematically analyzing correlated traits is an effective way to enhance their statistical power. To identify potential pleiotropic genes for these three disorders, we performed a systematic analysis by incorporating GWAS (genome-wide associated study) datasets of six correlated traits related to type 2 diabetes, obesity and dyslipidemia using Meta-CCA (meta-analysis using canonical correlation analysis). Meta-CCA is an emerging method to systematically identify potential pleiotropic genes using GWAS summary statistics of multiple correlated traits. 2,720 genes were identified as significant genes after multiple testing (Bonferroni corrected p value < 0.05). Further, to refine the identified genes, we tested their relationship to the six correlated traits using VEGAS-2 (versatile gene-based association study-2). Only the genes significantly associated (Bonferroni corrected p value < 0.05) with more than one trait were kept. Finally, 25 genes (including two confirmed pleiotropic genes and eleven novel pleiotropic genes) were identified as potential pleiotropic genes. They were enriched in 5 pathways including the statin pathway and the PPAR (peroxisome proliferator-activated receptor) Alpha pathway. In summary, our study identified potential pleiotropic genes and pathways of type 2 diabetes, obesity and dyslipidemia, which may shed light on the common biological etiology and pathogenesis of these three disorders and provide promising insights for new therapies.

Detection and monitoring are the first essential step for effective management of sheath blight (ShB), a major disease in rice worldwide. Unmanned aerial systems have a high potential of being utilized to improve this detection process since they can reduce the time needed for scouting for the disease at a field scale, and are affordable and user-friendly in operation. In this study, a commercialized quadrotor unmanned aerial vehicle (UAV), equipped with digital and multispectral cameras, was used to capture imagery data of research plots with 67 rice cultivars and elite lines. Collected imagery data were then processed and analyzed to characterize the development of ShB and quantify different levels of the disease in the field. Through color features extraction and color space transformation of images, it was found that the color transformation could qualitatively detect the infected areas of ShB in the field plots. However, it was less effective to detect different levels of the disease. Five vegetation indices were then calculated from the multispectral images, and ground truths of disease severity and GreenSeeker measured NDVI (Normalized Difference Vegetation Index) were collected. The results of relationship analyses indicate that there was a strong correlation between ground-measured NDVIs and image-extracted NDVIs with the R2 of 0.907 and the root mean square error (RMSE) of 0.0854, and a good correlation between image-extracted NDVIs and disease severity with the R2 of 0.627 and the RMSE of 0.0852. Use of image-based NDVIs extracted from multispectral images could quantify different levels of ShB in the field plots with an accuracy of 63%. These results demonstrate that a customer-grade UAV integrated with digital and multispectral cameras can be an effective tool to detect the ShB disease at a field scale.

This paper is the first public report that Streptomyces flavogriseus can produce both actinomycin D and holomycin. The actinomycete strain NJ-4 isolated from the soil of Nanjing Agricultural University was identified as S. flavogriseus. This S. flavogriseus strain was found for the first time to produce two antimicrobial compounds that were identified as actinomycin D and holomycin. GS medium, CS medium and GSS medium were used for the production experiments. All three media supported the production of actinomycin D, while holomycin was detected only in GS medium and was undetectable by HPLC in the CS and GSS media. The antimicrobial activity against B. pumilus, S. aureus, Escherichia coli, F. moniliforme, F. graminearum and A. niger was tested using the agar well diffusion method. Actinomycin D exhibited strong antagonistic activities against all the indicator strains. Holomycin exhibited strong antagonistic activities against B. pumilus, S. aureus and E. coli and had antifungal activity against F. moniliforme and F. graminearum but had no antifungal activity against A. niger. The cell viability was determined using an MTT assay. Holomycin exhibited cytotoxic activity against A549 lung cancer cells, BGC823 gastric cancer cells and HepG2 hepatocellular carcinoma cells. The yield of actinomycin D from S. flavogriseus NJ-4 was 960 mg/l. S. flavogriseus NJ-4 exhibits a distinct capability and has the industrial potential to produce considerable yields of actinomycin D under unoptimized conditions.

The heat-tolerance mechanisms of (hyper)thermophilic proteins provide a unique opportunity to investigate the unsolved protein folding problem. In an attempt to determine whether the interval between residues in sequence might play a role in determining thermostability, we constructed a sequence interval-dependent value function to calculate the residue pair frequency. Additionally, we identified a new sequence arrangement pattern, where like-charged residues tend to be adjacently assembled, while unlike-charged residues are distributed over longer intervals, using statistical analysis of a large sequence database. This finding indicated that increasing the intervals between unlike-charged residues can increase protein thermostability, with the arrangement patterns of these charged residues serving as thermodynamically favorable nucleation points for protein folding. Additionally, we identified that the residue pairs K-E, R-E, L-V and V-V involving long sequence intervals play important roles involving increased protein thermostability. This work demonstrated a novel approach for considering sequence intervals as keys to understanding protein folding. Our findings of novel relationships between residue arrangement and protein thermostability can be used in industry and academia to aid the design of thermostable proteins.

Multidrug resistance (MDR) against chemotherapeutic agents has become the major obstacle to successful cancer therapy and multidrug resistance-associated proteins (MRPs) mediated drug efflux is the key factor for MDR. Indomethacin (IND), one of the non-steroidal anti-inflammatory agents, has been demonstrated to increase cytotoxic effects of anti-tumor agents as MRP substrates. In this study, dextran-g-indomethacin (DEX-IND) polymeric micelles were designed to delivery paclitaxel (PTX) for the treatment of MDR tumors. The DEX-IND polymer could effectively encapsulate PTX with high loading content and DEX-IND/PTX micelles present a small size distribution. Compared with free PTX, the release of PTX from DEX-IND/PTX micelles could be prolonged to 48 h. Cellular uptake test showed that the internalization of DEX-IND/PTX micelles by drug-sensitive MCF-7/ADR cells was significantly higher than free PTX benefiting from the inhibitory effect of IND on MRPs. In vitro cytotoxicity test further demonstrated that DEX-IND/PTX micelles could enhance the cytotoxicity of PTX against MCF-7/ADR tumor cells. In vivo pharmacokinetic results showed that DEX-IND/PTX micelles had longer systemic circulation time and slower plasma elimination rate in comparison to PTX. The anti-tumor efficacy test showed that DEX-IND/PTX micelles exhibited greater tumor growth-inhibition effects on MDR tumor-bearing mice, with good correlation between in vitro and in vivo. Overall, the cumulative evidence indicates that DEX-IND/PTX micelles hold significant promise for the treatment of MDR tumors.

Few studies have examined the trajectories of symptom severity in first episode psychosis (FEP) and their impact on functioning. This study aimed to identify discrete trajectories of positive, negative and general psychopathological symptoms and functioning, determine predictors of the identified symptom trajectories and subsequently investigate the relationship between symptom and functioning trajectories over the 2-year follow-up period.Data were extracted from the Singapore Early Psychosis Intervention Programme clinical database. Trajectories of the Positive and Negative Syndrome Scale and Global Assessment of Functioning (GAF) scale over the two-year follow up were modelled using latent class growth curve modelling.Two distinct trajectories (early response and stable trajectory and delayed response trajectory) for positive symptoms, four distinct trajectories (early response and stable trajectory, early response and relapse trajectory, slower response and no response trajectory and delayed response trajectory) for negative and general psychopathology symptoms and three distinct trajectories for functioning (high functioning trajectory, moderately stable functioning trajectory and deterioration in functioning trajectory) were identified in our sample. Compared to individuals in the early response and stable trajectory, those in the delayed response trajectory for positive and negative symptoms, early response and relapse for negative and general psychopathology symptoms and slower response and no response trajectories for general psychopathology symptoms were significantly associated with higher odds of having deterioration in functioning over time. Poor symptom trajectories were also significantly predicted by younger age, male gender, unemployed and economically inactive status, lower education, longer duration of untreated psychosis and diagnosis of schizophrenia spectrum and delusional disorders.The results confirm that the symptoms trajectories among patients with FEP are heterogeneous and suggest that a small group of patients may be at higher risk of deterioration in symptom severity and functioning over the 2-year follow-up.

Deoxynivalenol (DON) is a class of mycotoxin produced in cereal crops infected with Fusarium graminearum species complex (FGSC). In China, FGSC mainly includes Fusarium asiaticum and F. graminearum. DON belongs to the trichothecenes and poses a serious threat to the safety and health of humans and animals. Succinate dehydrogenase inhibitors (SDHIs) are a class of fungicides that act on succinate dehydrogenase and inhibit the respiration of pathogenic fungi. In this study, the fungicidal activities of five SDHIs, including fluopyram, flutolanil, boscalid, benzovindiflupyr, and fluxapyroxad, against FGSC were determined based on mycelial growth and spore germination inhibition methods. The five SDHIs exhibited better inhibitory activities in spore germination than mycelial growth. Fluopyram exhibited a higher inhibitory effect in mycelial growth and spore germination in comparison to the other four SDHIs. In addition, the biological characteristics of F. asiaticum as affected by the five SDHIs were determined. We found that these five SDHIs decreased DON, pyruvic acid and acetyl-CoA production, isocitrate dehydrogenase mitochondrial (ICDHm) and SDH activities, and NADH and ATP content of F. asiaticum but increased the citric acid content. In addition, TRI5 gene expression was inhibited, and the formation of toxisomes was disrupted by the five SDHIs, further confirming that SDHIs can decrease DON biosynthesis of F. asiaticum. Thus, we concluded that SDHIs may decrease DON biosynthesis of F. asiaticum by inhibiting glycolysis and the tricarboxylic acid (TCA) cycle. Overall, the findings from the study will provide important references for managing Fusarium head blight (FHB) caused by FGSC and reducing DON contamination in F. asiaticum-infected wheat grains.

The Haloxylon genus belongs to the Amaranthaceae (formerly Chenopodiaceae) family. The small trees or shrubs in this genus are referred to as the King of psammophytic plants, and perform important functions in environmental protection, including wind control and sand fixation in deserts. To better understand these beneficial plants, we sequenced the chloroplast (cp) genomes of Haloxylon ammodendron (HA) and Haloxylon persicum (HP) and conducted comparative genomic analyses on these and two other representative Amaranthaceae species. Similar to other higher plants, we found that the Haloxylon cp genome is a quadripartite, double-stranded, circular DNA molecule of 151,570 bp in HA and 151,586 bp in HP. It contains a pair of inverted repeats (24,171 bp in HA and 24,177 bp in HP) that separate the genome into a large single copy region of 84,214 bp in HA and 84,217 bp in HP, and a small single copy region of 19,014 bp in HA and 19,015 bp in HP. Each Haloxylon cp genome contains 112 genes, including 78 coding, 30 tRNA, and four ribosomal RNA genes. We detected 59 different simple sequence repeat loci, including 44 mono-nucleotide, three di-nucleotide, one tri-nucleotide, and 11 tetra-nucleotide repeats. Comparative analysis revealed only 67 mutations between the two species, including 44 substitutions, 23 insertions/deletions, and two micro-inversions. The two inversions, with lengths of 14 and 3 bp, occur in the petA-psbJ intergenic region and rpl16 intron, respectively, and are predicted to form hairpin structures with repeat sequences of 27 and 19 bp, respectively, at the two ends. The ratio of transitions to transversions was 0.76. These results are valuable for future studies on Haloxylon genetic diversity and will enhance our understanding of the phylogenetic evolution of Amaranthaceae.

PHF13 is a chromatin affiliated protein with a functional role in differentiation, cell division, DNA damage response and higher chromatin order. To gain insight into PHF13's ability to modulate these processes, we elucidate the mechanisms targeting PHF13 to chromatin, its genome wide localization and its molecular chromatin context. Size exclusion chromatography, mass spectrometry, X-ray crystallography and ChIP sequencing demonstrate that PHF13 binds chromatin in a multivalent fashion via direct interactions with H3K4me2/3 and DNA, and indirectly via interactions with PRC2 and RNA PolII. Furthermore, PHF13 depletion disrupted the interactions between PRC2, RNA PolII S5P, H3K4me3 and H3K27me3 and resulted in the up and down regulation of genes functionally enriched in transcriptional regulation, DNA binding, cell cycle, differentiation and chromatin organization. Together our findings argue that PHF13 is an H3K4me2/3 molecular reader and transcriptional co-regulator, affording it the ability to impact different chromatin processes.

Three-dimensional (3D) nanometal scaffolds have gained considerable attention recently because of their promising application in high-performance supercapacitors compared with plain metal foils. Here, a highly oriented nickel (Ni) nanowire array (NNA) film was prepared via a simple magnetic-field-driven aqueous solution deposition process and then used as the electrode scaffold for the vapor-phase polymerization of 3,4-ethylenedioxythiophene (EDOT). Benefiting from the unique 3D open porous structure of the NNA that provided a highly conductive and oriented backbone for facile electron transfer and fast ion diffusion, the as-obtained poly(3,4-ethylenedioxythiophene) (PEDOT) exhibited an ultra-long cycle life (95.7% retention of specific capacitance after 20 000 charge/discharge cycles at 5 A/g) and superior capacitive performance. Furthermore, two electrodes were fabricated into an aqueous symmetric supercapacitor, which delivered a high energy density (30.38 Wh/kg at 529.49 W/kg) and superior long-term cycle ability (13.8% loss of capacity after 20 000 cycles). Based on these results, the vapor-phase polymerization of EDOT on metal nanowire array current collectors has great potential for use in supercapacitors with enhanced performance.

As cortical bone has a hierarchical structure, the macroscopic bone strength may be affected by the alterations of mineral crystal and collagen, which are main components of cortical bone. Limited studies focused on the time related alterations of these two components in osteoporosis, and their contributions to bone mechanics at tissue level and whole-bone level. Therefore, the purpose of this study was to elucidate the time related changes of mineral and collagen in cortical bone of ovariectomized (OVX) rabbits, and to relate these changes to cortical bone nanomechanics and macromechanics. 40 Rabbits (7-month-old) were randomly allocated into two groups (OVX and sham). OVX group received bilateral ovariectomy operation. Sham group received sham-OVX operation. Cortical bone quality of five rabbits in each group were assessed by DXA, μCT, nanoindentation, Fourier transform infrared (FTIR) spectroscopy and biomechanical tests (3-point bending of femoral midshaft) at pre-OVX, 4, 6, and 8 weeks after OVX. As time increased from pre-OVX to 8 weeks, the mineral to matrix ratio decreased with time, while both collagen crosslink ratio and crystallinity increased with time in OVX group. Elastic modulus and hardness measured by nanoindentation, whole-bone strength measured by biomechanical tests all decreased in OVX group with time. Bone material properties measured by FTIR correlated well with nano or whole-bone level mechanics. However, bone mineral density (BMD), structure, tissue-level and whole-bone mechanical properties did not change with age in sham group. Our study demonstrated that OVX could affect the tissue-level mechanics and bone strength of cortical bone. And this influence was attributed to the time related alterations of mineral and collagen properties, which may help us to design earlier interventions and more effective treatment strategies on osteoporosis.

Integration of multiple profiling data and construction of functional gene networks may provide additional insights into the molecular mechanisms of complex diseases. Osteoporosis is a worldwide public health problem, but the complex gene-gene interactions, post-transcriptional modifications and regulation of functional networks are still unclear. To gain a comprehensive understanding of osteoporosis etiology, transcriptome gene expression microarray, epigenomic miRNA microarray and methylome sequencing were performed simultaneously in 5 high hip BMD (Bone Mineral Density) subjects and 5 low hip BMD subjects. SPIA (Signaling Pathway Impact Analysis) and PCST (Prize Collecting Steiner Tree) algorithm were used to perform pathway-enrichment analysis and construct the interaction networks. Through integrating the transcriptomic and epigenomic data, firstly we identified 3 genes (FAM50A, ZNF473 and TMEM55B) and one miRNA (hsa-mir-4291) which showed the consistent association evidence from both gene expression and methylation data; secondly in network analysis we identified an interaction network module with 12 genes and 11 miRNAs including AKT1, STAT3, STAT5A, FLT3, hsa-mir-141 and hsa-mir-34a which have been associated with BMD in previous studies. This module revealed the crosstalk among miRNAs, mRNAs and DNA methylation and showed four potential regulatory patterns of gene expression to influence the BMD status. In conclusion, the integration of multiple layers of omics can yield in-depth results than analysis of individual omics data respectively. Integrative analysis from transcriptomics and epigenomic data improves our ability to identify causal genetic factors, and more importantly uncover functional regulation pattern of multi-omics for osteoporosis etiology.

Thyroid-stimulating hormone (TSH) has been shown to play an important role in the regulation of triglyceride (TG) metabolism in adipose tissue. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme controlling the hydrolysis of TG. Thus far, it is unclear whether TSH has a direct effect on the expression of ATGL. Because TSH function is mediated through the TSH receptor (TSHR), TSHR knockout mice (Tshr-/- mice) (supplemented with thyroxine) were used in this study to determine the effects of TSHR deletion on ATGL expression. These effects were verified in 3T3-L1 adipocytes and potential underlying mechanisms were explored. In the Tshr-/- mice, ATGL expression in epididymal adipose tissue was significantly increased compared with that in Tshr+/+ mice. ATGL expression was observed to increase with the differentiation process of 3T3-L1 preadipocytes. In mature 3T3-L1 adipocytes, TSH significantly suppressed ATGL expression at both the protein and mRNA levels in a dose-dependent manner. Forskolin, which is an activator of adenylate cyclase, suppressed the expression of ATGL in 3T3-L1 adipocytes. The inhibitory effects of TSH on ATGL expression were abolished by H89, which is a protein kinase A (PKA) inhibitor. These results indicate that TSH has an inhibitory effect on ATGL expression in mature adipocytes. The associated mechanism is related to PKA activation.

Osteoprotegerin (OPG) is known to inhibit differentiation and activation of osteoclasts (OCs) by functioning as a decoy receptor blocking interactions between RANK and RANKL. However, the exact role of OPG in the survival/apoptosis of OCs remains unclear. OPG caused increased rates of apoptosis of both OCs and osteoclast precursor cells (OPCs). The expression of Fas and activated caspase-8 was increased by both 20 ng/mL and 40 ng/mL of OPG, but was markedly decreased at 80 ng/mL. Interestingly, we noted that while levels of Fas ligand (FasL) increased with increasing doses of OPG, the soluble form of FasL in the supernatant decreased. The results of a co-immunoprecipitation assay suggested that the decrease of sFasL might be caused by the binding of OPG. This would block the inhibition of the apoptosis of OCs and OPCs. Furthermore, changes in expression levels of Bax/Bcl-2, cleaved-caspase-9, cleaved-caspased-3 and the translocation of cytochrome c, illustrated that OPG induced apoptosis of OCs and OPCs via the classic Fas/FasL apoptosis pathway, and was mediated by mitochondria. Altogether, our results demonstrate that OPG induces OCs and OPCs apoptosis partly by the Fas/FasL signaling pathway.

Ship detection in static UAV aerial images is a fundamental challenge in sea target detection and precise positioning. In this paper, an improved universal background model based on Grabcut algorithm is proposed to segment foreground objects from sea automatically. First, a sea template library including images in different natural conditions is built to provide an initial template to the model. Then the background trimap is obtained by combing some templates matching with region growing algorithm. The output trimap initializes Grabcut background instead of manual intervention and the process of segmentation without iteration. The effectiveness of our proposed model is demonstrated by extensive experiments on a certain area of real UAV aerial images by an airborne Canon 5D Mark. The proposed algorithm is not only adaptive but also with good segmentation. Furthermore, the model in this paper can be well applied in the automated processing of industrial images for related researches.