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Abstract Background This study aimed to quantitatively evaluate the left ventricular global and regional myocardial work of patients in Fabry disease (FD) by echocardiographic pressure–strain loop (PSL) analysis. Results The study included 48 patients with FD and 48 healthy controls matched for age and sex. According to the presence/absence of left ventricular hypertrophy (LVH), the patients with FD were divided into an LVH + group and an LVH– group. Left ventricular blood pressure was estimated noninvasively according to echocardiographic valvular events and systolic pressure in the brachial artery. Left ventricular myocardial work parameters were acquired by echocardiographic pressure–strain loop analysis. The FD groups had a significantly lower global longitudinal strain (GLS), global work index, global work efficiency (GWE), global constructive work and higher global waste work than the control group (P

Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1–CaMKK2–AMPKα was decreased when compared to normal-weight individuals. Under high-fat diet condition, the Piezo1iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2–AMPKα and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity.

Abstract Maritime objects frequently exhibit low-quality and insufficient feature information, particularly in complex maritime environments characterized by challenges such as small objects, waves, and reflections. This situation poses significant challenges to the development of reliable object detection including the strategies of loss function and the feature understanding capabilities in common YOLOv8 (You Only Look Once) detectors. Furthermore, the widespread adoption and unmanned operation of intelligent ships have generated increasing demands on the computational efficiency and cost of object detection hardware, necessitating the development of more lightweight network architectures. This study proposes the EL-YOLO (Efficient Lightweight You Only Look Once) algorithm based on YOLOv8, designed specifically for intelligent ship object detection. EL-YOLO incorporates novel features, including adequate wise IoU (AWIoU) for improved bounding box regression, shortcut multi-fuse neck (SMFN) for a comprehensive analysis of features, and greedy-driven filter pruning (GDFP) to achieve a streamlined and lightweight network design. The findings of this study demonstrate notable advancements in both detection accuracy and lightweight characteristics across diverse maritime scenarios. EL-YOLO exhibits superior performance in intelligent ship object detection using RGB cameras, showcasing a significant improvement compared to standard YOLOv8 models.

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Molecular biology techniques revealed the expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (Piezo1 IntL-CKO) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high-fat diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These experimental results suggest a previously unknown regulatory mechanism for GLP-1 production in L cells, which could offer new insights into diabetes treatments.

ObjectiveWe aimed to explore the efficacy and safety of efgartigimod in patients with refractory immune-mediated necrotizing myopathy (IMNM).MethodsThis open-label pilot observational study included seven patients with refractory IMNM, all of whom received intravenous efgartigimod treatment. The clinical response was assessed after 4 weeks of efgartigimod treatment according to the 2016 American College of Rheumatology–European League Against Rheumatism response criteria for adult idiopathic inflammatory myopathy. Serum levels of immunoglobulin as well as anti–signal recognition particle (SRP) and anti–3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies were measured using enzyme-linked immunosorbent assays and commercial line immunoblot assays. Safety assessments included evaluations of adverse events and severe adverse events.ResultsThe seven patients with refractory IMNM included five cases with anti-HMGCR antibodies and two cases within anti-SRP antibodies. Four of the seven patients achieved clinical responses. The total improvement score for the responders at 4 weeks were 32.5, 40.0, 47.5, and 70.0, and those at 8 weeks were 27.5, 47.5, 57.5, and 70.0. In comparison to the responsive patients, the non-responsive patients had longer durations [8 (-) versus 2 (1–5) years, P = 0.03], and more chronic myopathic features by muscle biopsy (67% versus 0%, P = 0.046). Serum immunoglobulin G levels (11.2 ± 2.5 versus 5.7 ± 2.5, P = 0.007) and anti-HMGCR/SRP antibody levels (97.2 ± 6.9 versus 41.8 ± 16.8, P = 0.002) were decreased after treatment compared with baseline levels. Adverse events were reported in one of the seven patients, who showed mild headache.ConclusionsDespite its small size, our study demonstrated that promoting the degradation of endogenous immunoglobulin G may be effective for patients with IMNM. Efgartigimod may be a promising option for cases of refractory IMNM to shorten duration and minimize chronic myopathic features.

Abstract Geminiviruses are an important group of viruses that infect a variety of plants and result in heavy agricultural losses worldwide. The homologs of C4 (or L4) in monopartite geminiviruses and AC4 (or AL4) in bipartite geminiviruses are critical viral proteins. The C4 proteins from several geminiviruses are the substrates of S-acylation, a dynamic post-translational modification, for the maintenance of their membrane localization and function in virus infection. Here we initiated a screening and identified a plant protein ABAPT3 (Alpha/Beta Hydrolase Domain-containing Protein 17-like Acyl Protein Thioesterase 3) as the de-S-acylation enzyme of C4 encoded by BSCTV (Beet severe curly top virus). Overexpression of ABAPT3 reduced the S-acylation of BSCTV C4, disrupted its plasma membrane localization, inhibited its function in pathogenesis, and suppressed BSCTV infection. Because the S-acylation motifs are conserved among C4 from different geminiviruses, we tested the effect of ABAPT3 on the C4 protein of ToLCGdV (Tomato leaf curl Guangdong virus) from another geminivirus genus. Consistently, ABAPT3 overexpression also disrupted the S-acylation, subcellular localization, and function of ToLCGdV C4, and inhibited ToLCGdV infection. In summary, we provided a new approach to globally improve the resistance to different types of geminiviruses in plants via de-S-acylation of the viral C4 proteins and it can be extendedly used for suppression of geminivirus infection in crops.

Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G > C, c.4977C > G, and c.5444A > G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants.

ObjectivesThe aim of this study is to explore the expression of inflammatory cytokines (ICs) in Fabry disease (FD), the correlation between ICs and FD phenotypes, and the impact of enzyme replacement therapy (ERT) on IC expression.MethodsWe recruited 67 FD patients and 44 healthy controls (HCs) and detected concentrations of the following ICs: interferon-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12P70, IL-17A, IL-17F, IL-22, tumor necrosis factor (TNF)-α, and TNF-β. We also analyzed the impact of ERT on IC expression in FD patients and the relationship between IC expression and sex, genotype, phenotype, disease burden, and biomarkers.ResultsMost ICs were significantly higher in FD patients than in HCs. A number of ICs were positively correlated with clinical aspects, including disease burden (Mainz Severity Score Index [MSSI]) and cardiac and renal markers. IL-8 was higher in the high MSSI (P-adj=0.026*) than in the low MSSI.ConclusionsICs were upregulated in FD patients, indicating the role of the innate immune process in FD etiology. ERT ameliorated FD-related inflammatory activation, at least to some extent. IC expression was positively correlated with disease burden and clinical markers in FD. Our findings indicated that the inflammatory pathway may be a promising therapeutic target for FD.

Abstract The article presents a comprehensive summary of Intelligent Ship Marine Object Detection (ISMOD) based on the RGB Camera. Marine object detection plays a pivotal role in enabling intelligent ships to acquire crucial data and security assurances for autonomous navigation. Among the various detection sensors, the RGB Camera is an informative and cost‐effective tool with a wide range of civil applications. In the beginning, the ISMOD metrics based on the RGB camera is analyzed from three significant aspects, namely accuracy, speed, and robustness. Subsequently, the latest research status and comparative overview are presented, encompassing three mainstream detection methods: traditional detection, deep learning detection, and sensor fusion detection. Finally, the existing challenges of ISMOD are discussed and future development trends are recommended. The results demonstrate that forthcoming development will predominantly concentrate on deep learning approaches, complemented by other techniques. It is imperative to advance detection performance in domains such as deep fusion, multi‐feature extraction, multi‐fusion technology, and lightweight detection architecture.

Tunnel squeezing is a time-dependent significant deformation problem often occurring in weak rock masses and areas with high horizontal in situ stress. This phenomenon can cause construction delays, increased budgets, tunnel collapse, and additional problems. Therefore, accurately predicting tunnel squeezing is crucial. The surrounding rock of the tunnel is uneven in hardness and softness, and changes frequently due to the influence of geological structure, thereby rendering the prediction of extrusion deformation highly uncertain. The belief rule base (BRB) is a rule-based modeling approach capable of handling uncertain information. However, the performance of the BRB model is not only affected by the combinatorial rule explosion caused by too many input attributes but also by the limitations of expert knowledge. First, to solve the problem of the combinatorial rule explosion, a novel tunnel squeezing prediction model using a hierarchical BRB structure based on the Random Forest (RF) attribute selection method (H-RF-BRB) is proposed. Second, to avoid the limitations of expert knowledge, parameters of the tunnel squeezing prediction model are determined by combining the expert knowledge and the information gain ratio (IGR). The model effectively integrates qualitative knowledge with quantitative information, addressing the issue of limitations in expert knowledge. Additionally, it overcomes the challenge of limited datasets due to the difficulties in collecting tunnel squeezing samples, which enhances the accuracy of the model’s predictions. Finally, the model’s effectiveness and superiority are validated through five-fold cross-validation and several comparative experiments.

ObjectiveObservational studies have reported that mental disorders are comorbid with temporomandibular joint disorder (TMD). However, the causal relationship remains uncertain. To clarify the causal relationship between three common mental illnesses and TMD, we conduct this Mendelian Randomization (MR) study.MethodsThe large-scale genome-wide association studies data of major depression, bipolar disorder and schizophrenia were retrieved from the Psychiatric Genomics Consortium. The summary data of TMD was obtained from the Finn-Gen consortium, including 211,023 subjects of European descent (5,668 cases and 205,355 controls). The main approach utilized was inverse variance weighting (IVW) to evaluate the causal association between the three mental disorders and TMD. Five sensitivity analyses including MR-Egger, Maximum Likelihood, Weighted median, MR. RAPS and MR-PRESSO were used as supplements. We conducted heterogeneity tests and pleiotropic tests to ensure the robustness.ResultsAs shown by the IVW method, genetically determined major depression was associated with a 1.65-fold risk of TMD (95% CI = 1.10–2.47, p < 0.05). The direction and effect size remained consistent with sensitivity analyses. The odds ratios (ORs) were 1.51 (95% CI = 0.24–9.41, p > 0.05) for MR-Egger, 1.60 (95% CI = 0.98–2.61, p > 0.05) for Weighted median, 1.68 (95% CI = 1.19–2.38, p < 0.05) for Maximum likelihood, 1.56 (95% CI = 1.05–2.33, p < 0.05) for MR. RAPS, and 1.65 (95% CI = 1.10–2.47, p < 0.05) for MR-PRESSO, respectively. No pleiotropy was observed (both P for MR-Egger intercept and Global test >0.05). In addition, the IVW method identified no significant correlation between bipolar disorder, schizophrenia and TMD.ConclusionGenetic evidence supports a causal relationship between major depression and TMD, instead of bipolar disorder and schizophrenia. These findings emphasize the importance of assessing a patient’s depressive status in clinical settings.

Introduction: With global warming, the disaster losses caused by extreme precipitation events are increasing. The poor natural conditions and climate change make the arid and semi-arid mountainous grassland area a sensitive region of climate change. The study on the spatio-temporal variation characteristics of extreme precipitation events in this region is helpful to improve the ability of climate prediction and disaster prevention and reduction in grassland.Methods: Based on the daily precipitation data of four meteorological monitoring stations in the Yinshanbeilu from 1970 to 2020, the trend analysis, M-K test and wavelet analysis were used to select seven typical extreme precipitation indicators to analyze the temporal and spatial characteristics of extreme precipitation.Results and Discussion: The results showed that the precipitation in the Yinshanbeilu increased in the past 51a, and the number of heavy rain days increased significantly. The significance test of CDD and CWD showed that the number of continuous dry days and continuous wet days decreased abruptly. The spatial analysis showed that the high value areas of R95p, R95d and PRCRTOT were all located in Siziwang Banner, and it could be concluded that the extreme precipitation risk was the highest in Siziwang Banner, while the low value areas of SDII, Rx1day, R95p and PRCRTOT were all located in Sonid Right Banner, which could be inferred that the Sonid Right Banner was relatively dry. The first main cycle of the seven indexes of extreme precipitation almost runs through the whole time series, and the starting point of the minimum main cycle changes inconsistent. In addition to the number of consecutive dry days, the other indices have a good correlation with annual precipitation, flood season and monthly precipitation from June to September, and July is the peak period of extreme precipitation events.

Most pathogenic DMD variants are detectable and interpretable by standard genetic testing for dystrophinopthies. However, approximately 1∼3% of dystrophinopthies patients still do not have a detectable DMD variant after standard genetic testing, most likely due to structural chromosome rearrangements and/or deep intronic pseudoexon-activating variants. Here, we report on a boy with a suspected diagnosis of Becker muscular dystrophy (BMD) who remained without a detectable DMD variant after exonic DNA-based standard genetic testing. Dystrophin mRNA studies and genomic Sanger sequencing were performed in the boy, followed by in silico splicing analyses. We successfully detected a novel deep intronic disease-causing variant in the DMD gene (c.2380 + 3317A > T), which consequently resulting in a new dystrophin pseudoexon activation through the enhancement of a cryptic donor splice site. The patient was therefore genetically diagnosed with BMD. Our case report further emphasizes the significant role of disease-causing splicing variants within deep intronic regions in genetically undiagnosed dystrophinopathies.

Abstract Objective Anti‐mitochondrial antibodies (AMAs) are associated with idiopathic inflammatory myopathies (IIMs). We aimed to summarize the clinicopathological characteristics, assess circulating cell‐free mitochondrial DNA (ccf‐mtDNA), and circulating cell‐free nuclear DNA (ccf‐nDNA) in AMA‐associated IIMs. Methods Medical records of 37 IIMs patients with AMAs were reviewed. Circulating cell‐free mtDNA and ccf‐nDNA levels in sera from IIMs patients with AMAs (n = 21), disease controls (n = 66) and healthy controls (HCs) (n = 23) were measured and compared. Twenty‐eight immune‐mediated necrotizing myopathy (IMNM) patients, 23 dermatomyositis (DM) patients, and 15 anti‐synthetase syndrome (ASS) patients were enrolled as disease controls. Correlations between variables were analyzed. Results Limb weakness was observed in 75.7% and neck weakness in 56.8% of patients. Cardiac involvement occurred in 51.4% of patients. Muscle pathology revealed 81.1% of IMNM, 5.4% polymyositis, and 13.5% nonspecific myositis. Microinfarction was observed in 8.1% of patients. Serum ccf‐mtDNA levels in AMA‐associated IIMs were significantly higher than those in HCs (p

Abstract Background The coexistence of two myositis-specific autoantibodies (MSA) is considered extremely rare. We describe three patients with both anti-signal recognition particle (SRP) antibodies and another MSA in serum. Methods We performed a retrospective clinical data collection and follow-up studies of the clinical manifestations and treatment outcome of three patients positive with anti-SRP antibodies and other MSAs. IgG antibodies against MSAs were detected using commercial line immunoblot assay. Results The tests of MSA showed positive result of anti-SRP antibodies and another one MSA including anti-TIF1-γ, anti-Jo1, or anti-EJ antibodies, respectively. The proximal muscle weakness appeared in 2 patients; interstitial lung disease presented in 2 patients. The serum CK level was elevated in 1 patient. The muscle biopsy showed necrotizing myopathy in 1 patient and deposition of membrane attack complex on scattered myofibers in the other one patient. One of the two patients with interstitial lung disease died because of respiratory failure. One patient had completely improved and the other one showed partial remission after immunosuppressive therapy. Conclusions The patients with anti-SRP antibodies co-occurred with the other MSA may have various clinical characteristics. The clinicopathological phenotypes of these patients seem to be mainly caused by one of the MSAs, namely the responsible antibody.

The residual soil on a slope can slowly move downward under the influence of gravity, forming a creep landslide. These types of landslides are known for their extensive coverage, significant magnitude, and prolonged duration of hazard. A systematic study of the creep properties of creep landslide geotechnical bodies is essential for the analysis of the deformation process and long-term safety evaluation of landslides. This paper focuses on studying a creep landslide involving residual soil in western Henan Province. The creep characteristics of residual soil with different stone content are investigated through direct shear creep experiments. The findings reveal that stone content has a profound impact on the creep behavior of residual soil. As the stone content of the soil increased, the structure of the test soil changed significantly, resulting in a gradual decrease in its shear creep. The Burgers model can effectively fit the deceleration creep and steady-state creep stages of the residual soil. With the increase in stone content, the four parameters of the Burgers model show a significant increase, with the instantaneous elasticity coefficient G1 and the viscosity coefficient η1 experiencing more noticeable changes. The average long-term strength of specimens with different stone content is only 54% of their instantaneous strength. Additionally, as the stone content increases, the ratio of long-term strength to instantaneous strength also increases. Notably, the long-term strength of specimens with 10–30% stone content is significantly lower than that of specimens with 50–70% stone content.

AbstractPurpose To investigate ocular abnormalities in Fabry disease (FD).Methods Forty-five patients with FD diagnosed by genetic analysis were enrolled in a single medical centre. The following ocular examinations were performed: slit-lamp examination, ophthalmic fundus imaging, in vivo confocal microscopy (IVCM) and optical coherence tomography (OCT). The prevalences of typical abnormalities in the cornea, conjunctiva and retina were recorded; their differences between hemizygote and heterozygote were compared.Results In this study, the prevalence of corneal verticillata was 97.8% (44/45). Corneal examination with IVCM demonstrated hyper-reflective intracellular inclusions located within basal epithelial cells. Conjunctival vessel malformations were observed in 64.4% (29/45) of patients, and retinal vessel tortuosity was observed in 62.2% (28/45) of patients. OCT revealed many strong hyper-reflective foci (HRF) in the inner retinal layer (in 66.7% [30/45] of patients); these foci may represent retinal vascular plexi. The prevalences of conjunctival vessel malformation, retinal vessel tortuosity and HRF were higher in hemizygote than in heterozygote.Conclusions Corneal verticillata, HRF on OCT, conjunctival vessel malformation and retinal vessel tortuosity exhibit high prevalence in patients with FD. These ocular manifestations are characteristic and easily accessible; thus, they should be considered diagnostic criteria for FD.

With the development of agricultural information technology, the Internet of Things and blockchain have become important in the traceability of agricultural products. Sensors collect real-time data in agricultural production and a blockchain provides a secure and transparent storage medium for these data, which improves the transparency and credibility of agricultural product traceability. However, existing agricultural product traceability solutions are limited by the immutability of the blockchain, making it difficult to delete erroneous data and modify the scope of data sharing. This damages the credibility of traceability data and is not conducive to the exchange and sharing of information among enterprises. In this article, we propose an agricultural product traceability data management scheme based on a redactable blockchain. This scheme allows agricultural enterprises to encrypt data to protect privacy. In order to facilitate the maintenance and sharing of data, we introduce a chameleon hash function to provide data modification capabilities. Enterprises can fix erroneous data and update the access permissions of the data. To improve the efficiency of block editing, our scheme adopts a distributed block editing method. This method supports threshold editing operations, avoiding single-point-of-failure issues. We save records of data modifications on the blockchain and establish accountability mechanisms to identify malicious entities. Finally, in this paper we provide a security analysis of our proposed solution and verify its effectiveness through experiments. Compared with the existing scheme, the block generating speed is improved by 42% and the block editing speed is improved by 29.3% at 125 nodes.

Summary: In this paper, the municipal solid waste incineration bottom ash (MSW-IBA) is used as the fine aggregate and firming agent component of the premixed fluid stabilized soil (PFSS). Through the mechanical strength test, and the hydration products and microstructure characterization, the effects of the NaOH content for MSW-IBA pre-aging treatment and activator content on the mechanical properties of the PFSS are studied. The results show that the mechanical strength of the prepared PFSS is closely related to the amount of NaOH and the activator. The increase in the amount of NaOH and activator can affect the formation of early hydration product Aft, and reduce the early strength. However, it can promote the depolymerization of glass phase in MSW-IBA and slag to form C-(A)-S-H and Mg-(A)-S-H gel, increase the microstructure density, and thus improve the late strength. The application of MSW-IBA in PFSS can achieve the recycling of solid waste.

Abstract Background Metastasis of breast cancer grows from the local invasion to the distant colonization. Blocking the local invasion step would be promising for breast cancer treatment. Our present study demonstrated AQP1 was a crucial target in breast cancer local invasion. Methods Mass spectrometry combined with bioinformatics analysis was used to identify AQP1 associated proteins ANXA2 and Rab1b. Co-immunoprecipitation, immunofluorescence assays and cell functional experiments were carried out to define the relationship among AQP1, ANXA2 and Rab1b and their re-localization in breast cancer cells. The Cox proportional hazards regression model was performed toward the identification of relevant prognostic factors. Survival curves were plotted by the Kaplan–Meier method and compared by the log-rank test. Results Here, we show that the cytoplasmic water channel protein AQP1, a crucial target in breast cancer local invasion, recruited ANXA2 from the cellular membrane to the Golgi apparatus, promoted Golgi apparatus extension, and induced breast cancer cell migration and invasion. In addition, cytoplasmic AQP1 recruited cytosolic free Rab1b to the Golgi apparatus to form a ternary complex containing AQP1, ANXA2, and Rab1b, which induced cellular secretion of the pro-metastatic proteins ICAM1 and CTSS. Cellular secretion of ICAM1 and CTSS led to the migration and invasion of breast cancer cells. Both in vivo assay and clinical analysis data confirmed above results. Conclusions Our findings suggested a novel mechanism for AQP1-induced breast cancer local invasion. Therefore, targeting AQP1 offers promises in breast cancer treatment.

Abstract Intersectin 1 (ITSN1) contains two isoforms: ITSN1-S and ITSN1-L, which are highly regulated by alternative splicing. Our previous results showed that the two isoforms of ITSN1 displayed opposite functions: ITSN1-S promoted glioma development, while ITSN1-L exerted an inhibitory role in glioma progression. In this study, our transcriptome analysis using a large glioma cohort indicated that the ratio of ITSN1-S/ITSN1-L was positively correlated with glioma grading and poor prognosis. We identified the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) as an ITSN1 pre-mRNA interaction protein through RNA pull-down assay and RNA immunoprecipitation assay. Knockdown of PTBP1 decreased the ratio of ITSN1-S/ITSN1-L. Minigene reporter assay and mutation analyses further confirmed PTBP1 targeted polypyrimidine sequences on ITSN1 exon 30 (TTGCACTTCAGTATTTT) and promoted the inclusion of ITSN1 exon 30. Subsequently, silencing PTBP1 inhibited glioma cell proliferation, migration, and invasion by down-regulating the ratio of ITSN1-S/ITSN1-L. Taken together, our study provides a novel mechanism that PTBP1 modulates the alternative splicing of ITSN1 and promotes glioma proliferation and motility by up-regulating the ratio of ITSN1-S/ITSN1-L, thereby highlighting that PTBP1 may be an attractive therapeutic target for gliomas.

Abstract Objective The objective of this research was to study the clinical features, genetic characteristics, muscle imaging, and muscle pathological changes of a cohort of Chinese patients with mutations in the valosin‐containing protein (VCP) gene. Methods Nine patients from seven Chinese pedigrees were recruited. Variants were detected by next‐generation sequencing and confirmed by Sanger sequencing. Thigh muscle MRIs were performed in five patients. All the patients received muscle biopsies. Results Seven variants in VCP were identified, and two were novel. All the patients presented with adult‐onset muscle weakness. The appearance of “isolated island sign” or “contra‐isolated island sign” was observed in four of the five the patients on muscle MRIs. Muscle biopsies demonstrated the combination of neuropathic and myopathic changes in seven patients and muscle dystrophic changes in two patients. Notably, rimmed vacuoles and cytoplasmic VCP and p62‐positive protein aggregates were observed in all the patients. Conclusion Our finding of novel variants expanded the mutational spectrum of the VCP gene. This cohort of Chinese patients with VCP mutations mainly present with inclusion body myopathy with predominant limb–girdle distribution. The characteristic pattern of fatty infiltration, especially the “isolated island” and “contra‐isolated island” on muscle MRI, along with rimmed vacuoles in muscle biopsy, provides valuable clues for guiding genetic diagnostic workup.

Background: This study aimed to provide a detailed analysis of the temporal trends of cancer incidence rates for individuals aged 0–19 years in selected regions globally from 1978 to 2012. Methods: Data were obtained from Volumes V-XI of Cancer Incidence in Five Continents (CI5), published by the International Agency for Research on Cancer. A total of 53 registries in 23 regions from the Americas, Asia, Europe, and Oceania that contained information on cancer incidence throughout 1978-2012 (35 years) were included in this study. Joinpoint regression was used for the analysis of trends. Results: Most regions showed increasing trends in overall childhood cancer among children (aged 0-14 years) and adolescents (aged 15-19 years). Nearly all regions showed rising trends in childhood and adolescent leukemia incidence rates, whereas the incidence of lymphoma among children generally decreased. Only France, Australia, and New Zealand showed decreasing trends for malignant central nervous system (CNS) tumors among adolescents. Kidney cancer and bone cancer incidence rates remained stable for most regions. The incidence of thyroid cancer among adolescents increased in most regions and that of testicular cancer decreased in approximately one-half of the regions studied. Conclusion: The international temporal trends of cancer incidents among children and adolescents are varied by region, cancer type, age group, and gender, and have changed over time.

Background/purpose: The scanning accuracy of intraoral scanners’ data collection plays a key role in the success of the final treatment. However, few studies start from scanning technology itself to directly evaluate it. The aim of this study was to evaluate the scanning accuracy of three intraoral scanners, to provide a reference for relevant research and clinical applications. Materials and methods: Six types of resin models containing different numbers of crown-prepared abutments were three-dimensionally printed, and a model scanner, as well as three intraoral scanners, were used to digitally scan the six models. The obtained data were uploaded to three-dimensional reverse software for registration and comparison, and the accuracy of the models were analyzed. Results: When scanning the six groups of models, the Omnicam outperformed both the TRIOS and iTero in terms of accuracy in all groups except the second molar group. The TRIOS and iTero scanners also exhibited decreased degrees of accuracy when scanning the long dental arch. The accuracy decreased as the scanning scope increased; however, the Omnicam scanner exhibited a relatively high degree of accuracy when scanning the three-unit fixed bridge and anterior areas. All scanners exhibited the lowest degree of accuracy when scanning the full-arch model. Certain deviations were observed, and the scanning areas at the incisal edges of the anterior teeth and end of the dental arch exhibited relatively large deviations. Conclusion: With the model scanner data as reference, the scanning accuracy of the three scanners exhibited differences and certain deviations, which were within clinical tolerance.

ObjectivesDermatomyositis (DM) and anti-synthetase syndrome (ASS) are autoimmune diseases with multisystem involvement. Despite sharing some clinical and myopathological features, these are two diseases with different pathogeneses and prognoses. We aimed to clarify and compare cytokine/chemokine profiles in both disorders, which may help in the differential diagnosis.Materials and methodsWe collected clinical data and serum samples of consecutive patients with DM and ASS. Quantibody® Human Inflammation Array 3 for cytokines/chemokines was performed in the serum of all participants. Receiver operating characteristic analysis with the area under the curve and Youden's index were performed.ResultsEight newly diagnosed and treatment-naïve patients with DM, nine newly diagnosed and treatment-naïve patients with ASS, and 14 healthy controls were enrolled. Serum C-C motif chemokine ligand (CCL) 2, CCL4, C-X-C motif chemokine ligand (CXCL) 13, and tumor necrosis factor receptor 2 (TNFR2) were increased in patients with both DM and ASS. Serum interleukin (IL)-1 receptor type 1 (IL-1ra), IL-1b, CCL1, CXCL11, and CCL3 were modulated in patients with DM only, and IL-8, CXCL9, and tissue inhibitors of metalloproteinases-1 (TIMP-1) in patients with ASS only. Serum CCL2, CXCL13, and TNFR2 accurately distinguished patients with DM and ASS from healthy controls, as shown by the area under the curve >0.80. Moreover, receiver operating characteristic analysis showed that, as biomarkers for discrimination between DM and ASS, the combination of IL-1ra and TIMP-1, had an area under the curve of 0.944, a sensitivity of 87.5%, and a specificity of 88.9%.ConclusionOur study demonstrated that serum levels of cytokines/chemokines showed a different pattern in newly diagnosed patients with DM and ASS, in which serum IL-1ra and TIMP-1 could be used to distinguish between the two diseases.

Abstract Breast cancer is the most common type of cancer worldwide. However, the well-known molecular biomarkers are not enough to meet the needs of precision medicine. In search for novel targets in this regard, we reported ITSN1 (intersectin1) as one of the candidates through mRNA microarray analysis. In the present study, we reported that endocytic protein ITSN1-S exists not only in the cytoplasm but also in nuclei of breast cancer cells. ITSN1-S′ functional nuclear localization signal is within its residues 306–312. Its nuclear export signal (NES) resides within its SH3 domains. We also found, the interaction between the CC domain of nuclear ITSN1-S and the NT domain of nuclear DNA helicase II (NDH II) directly suppressed the DNA replication and nascent DNA synthesis by inhibiting the R-loops resolution in breast cancer cells. Furthermore, the interaction between the EH domains of cytoplasmic ITSN1-S and PI3KC2α inhibit cell migration and invasion by inactivating the PI3KC2α-AKT pathway. Our results were confirmed in both ITSN1 gene knockout cells and in vivo assays. Finally, our clinical data showed a potential application of the combined consideration of the cytoplasmic and nuclear ITSN1-S as an independent prognosis factor. In conclusion, our study revealed ITSN1-S′ novel positioning in the nuclei of breast cancer cells, its function in suppressing DNA replication, and its potential application in improved breast cancer prognosis.

ObjectiveTo present the global research features and hotspots, and forecast the emerging trends by conducting a bibliometric analysis based on literature related to autophagy of pancreatic cancer from 2011 to 2022.MethodsThe literature data regarding autophagy of pancreatic cancer were retrieved and downloaded from the Web of Science Core Collection (WOSCC) from Clarivate Analytics on June 10th, 2022. VOSviewer (version 1.6.18) was used to perform the bibliometric analysis.ResultsA total of 616 studies written by 3993 authors, covered 45 countries and 871 organizations, published in 263 journals and co-cited 28152 references from 2719 journals. China (n=260, 42.2%) and the United States (n=211, 34.3%) were the most frequent publishers and collaborated closely. However, publications from China had a low average number of citations (25.35 times per paper). The output of University of Texas MD Anderson Cancer Center ranked the first with 26 papers (accounting for 4.2% of the total publications). Cancers (n=23, 3.7%; Impact Factor = 6.639) published most papers in this field and was very pleasure to accept related researches. Daolin Tang and Rui Kang published the most papers (n=18, respectively). The research hotspots mainly focused on the mechanisms of autophagy in tumor onset and progression, the role of autophagy in tumor apoptosis, and autophagy-related drugs in treating pancreatic cancer (especially combined therapy). The emerging topics were chemotherapy resistance mediated by autophagy, tumor microenvironment related to autophagy, autophagy-depended epithelial-mesenchymal transition (EMT), mitophagy, and the role of autophagy in tumor invasion.ConclusionAttention has been increasing in autophagy of pancreatic cancer over the past 12 years. Our results undoubtedly provide scholars with new clues and ideas in this field.

The creep characteristics of sliding zones strongly influence slope deformation and long-term stability, as well as the occurrence of landslide catastrophes. In this paper, large-scale triaxial creep tests were performed on the strongly weathered argillaceous sandstone sliding zone of the Huaipa landslide in the Henan Province, China, to study its creep characteristics and long-term strength in natural and saturated states. Three-dimensional numerical simulations were conducted to analyze the deformation creep law and catastrophic evolution mechanism of the slope after excavation and rainfall. The results show that the sliding zone underwent appreciable creep deformation prior to failure, and that the progression of specimen damage with an increasing stress level followed decay creep → steady creep → accelerated creep. The stress level played a decisive role in the creep deformation, with higher stress levels resulting in higher instantaneous displacement, creep displacement, and longer times required to reach steady creep. The stress level also determined the specimen’s creep stage. When the stress level was low, the adjustment of the specimen’s internal structure was dominated by air space compression and particle movement, whereas particle fragmentation mostly occurred at high stress levels. The long-term rock strength was approximately 62–66% of the instantaneous strength, the internal friction angle decreased by approximately 8° relative to the instantaneous strength, and the cohesion decreased by approximately 30%. The slope foot unloaded and deformed owing to the excavation of a bauxite mine at its front edge, after which the slope deformed via creep. The landslide disaster occurred when the deformation was significantly accelerated and the slope started to slide as a whole once the sliding zone became water saturated owing to continuous rainfall. The simulation results indicate that the landslide can be divided into a front edge bulging zone, central sliding zone, and trailing edge tension zone, which provides valuable insight on the creep deformation evolution process and the disaster mechanism of the landslide under the action of front edge excavation and rainfall.

To improve the comprehensive performance of pervious concrete, the properties of pervious concrete in different paste–aggregate ratios were subjected to both early CO2 curing and uncarbonated curing conditions. The mechanical properties, water permeability, porosity, and chemical composition of pervious concrete under two curing conditions were investigated and compared. The effects of CO2 curing on the properties of pervious concrete with different paste–aggregate ratios were derived. Through mechanical experiments, it was revealed that early CO2 curing can enhance the mechanical strength of pervious concrete by about 15–18%. Meanwhile, with the increase in the paste–aggregate ratio, the improvement effect induced by early CO2 curing became more significant. The water resistance of carbonated concrete was not significantly reduced. And with the increase in the paste–aggregate ratio, the carbonation degree of pervious concrete was reduced; the differences in porosity and water resistance became less significant when the paste–aggregate ratio exceeded 0.39. Micro-structural analysis shows that the early CO2 curing reduced both total porosity and the volume of micropores with a pore diameter of less than 40 nm, while it increased the volume of pores with a diameter of more than 40 nm. This is also the main reason that the strength of pervious concrete under early CO2 curing is higher than that without CO2 curing. The effect of varying paste–aggregate ratio and curing methods adds to the limited knowledge of the performance of pervious concrete.

Abstract Objective We aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes. Methods The clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up. Results Thirty‐five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb‐girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha‐dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long‐term use in patients with COLQ or AGRN mutations. Interpretation The genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb‐girdle myasthenic syndrome, tubular aggregates, and decreased alpha‐dystroglycan were indicative of the specific subtypes. Based on the follow‐up findings, we suggest cautious evaluation of the long‐term efficacy of therapeutic agents in congenital myasthenic syndrome.

Abstract Objective This study aimed to investigate mitochondrial changes and the mitochondrial antiviral‐signaling protein (MAVS)‐type I interferon (IFN1) signaling pathway in the muscles of anti‐melanoma differentiation gene 5(MDA5) dermatomyositis (DM) patients. Methods Eleven anti‐MDA5 DM and ten antibody‐negative DM patients were included. Muscle biopsies were performed in all patients. Muscle pathology and mitochondrial morphology in particular were compared between two groups. The expression of MDA5, MAVS, interferon (IFN) regulatory factor 7, and IFN‐stimulated gene 15, which are components of the MAVS‐IFN1 signaling pathway, was measured in muscle specimen. The correlation between MAVS expression in muscles and disease phenotypes and muscle pathology were analyzed. Results Anti‐MDA5 DM showed a significantly lower incidence of the characteristic DM pathology (P

Litchi florescence has large flower spikes and volume; reasonable control of the ratio of male to female litchi flowers is the key operational aspect of litchi orchards for preserving quality and increasing production. To achieve the rapid detection of male and female litchi flowers, reduce manual statistical errors, and meet the demand for accurate fertilizer regulation, an intelligent detection method for male and female litchi flowers suitable for deployment to low-power embedded platforms is proposed. The method uses multi-teacher pre-activation feature distillation (MPFD) and chooses the relatively complex YOLOv4 and YOLOv5-l as the teacher models and the relatively simple YOLOv4-Tiny as the student model. By dynamically learning the intermediate feature knowledge of the different teacher models, the student model can improve its detection performance by meeting the embedded platform application requirements such as low power consumption and real-time performance. The main objectives of this study are as follows: optimize the distillation position before the activation function (pre-activation) to reduce the feature distillation loss; use the LogCosh-Squared function as the distillation distance loss function to improve distillation performance; adopt the margin-activation method to improve the features of the teacher model passed to the student model; and propose to adopt the Convolution and Group Normalization (Conv-GN) structure for the feature transformation of the student model to prevent effective information loss. Moreover, the distilled student model is quantified and ported for deployment to a field-programmable gate array (FPGA)-embedded platform to design and implement a fast, intelligent detection system for male and female litchi flowers. The experimental results show that compared with an undistilled student model, the mAP of the student model obtained after MPFD feature distillation is improved by 4.42 to 94.21%; the size of the detection model ported and deployed to the FPGA-embedded platform is 5.91 MB, and the power consumption is only 10 W, which is 73.85% and 94.54% lower than that of the detection models on the server and PC platforms, respectively, and it can better meet the application requirements of rapid detection and accurate statistics of male and female litchi flowers.

The largest carbonate condensate field in China has been found in the central Tarim Basin. Ordovician carbonate reservoirs are generally attributed to reef-shoal microfacies along a platform margin. However, recent production success has been achieved along the NE-trending strike-slip fault zones that intersect at the platform margin. For this contribution, we analyzed the strike-slip fault effects on the reef-shoal reservoirs by using new geological, geophysical, and production data. Seismic data shows that some NE-trending strike-slip faults intersected the NW-trending platform margin in multiple segments. The research indicated that the development of strike-slip faults has affected prepositional landforms and the subsequent segmentation of varied microfacies along the platform margin. In addition, the strike-slip fault compartmentalized the reef-shoal reservoirs into multiple segments along the extent of the platform margin. We show that fractured reef-shoal complexes are favorable for the development of dissolution porosity along strike-slip fault damage zones. In the tight matrix reservoirs (porosity < 6%, permeability < 0.5 mD), the porosity and permeability could be increased by more than 2–5 times and to 1–2 orders of magnitude in the fault damage zone, respectively. This suggests that high production wells are correlated with “sweet spots” of fractured reservoirs along the strike-slip fault damage zones, and that the fractured reservoirs in the proximity of strike-slip fault activity might be a major target for commercial exploitation of the deep Ordovician tight carbonates.

Aim: Increasing studies have demonstrated lymph node ratio (LNR) to be an accurate prognostic indicator in breast cancer and an alternative to pN staging; however, the AJCC-TNM staging system classified apical or infraclavicular/ipsilateral supraclavicular lymph node-positive (APN(+)) patients with a worse prognosis as the pN3 stage. Until now, different reports on LNR in breast cancer have ignored this possibility. Consequently, it is necessary to discuss the role of APN(+) patients in the LNR system to obtain a precise LNR that predicts the prognosis accurately.Materials and Methods: We collected data on 10,120 breast cancer patients, including 3,936 lymph node-positive patients (3,283 APN(−) and 653 APN(+) patients), who visited our hospital from 2007 to 2012. Then we applied X-tile analysis to calculate cut-off values and conduct survival analysis and multivariate analysis to evaluate patients’ prognosis.Results: We confirmed that some APN(+) patients were mis-subgrouped according to previously reported LNR, indicating that APN(+) patients should be excluded in the application of LNR to predict prognosis. Then we applied X-tile analysis to calculate two cut-off values (0.15 and 0.34) for LNR-APN(−) patients and conducted survival analysis and found that LNR-APN(−) staging was superior to pN staging in predicting the prognosis of APN(−) breast cancer patients.Conclusion: From this study, we conclude that excluding APN(+) patients is the most necessary condition for effective implementation of the LNR system. LNR-APN(−) staging could be a more comprehensive approach in predicting prognosis and guiding clinicians to provide accurate and appropriate treatment.

Background and PurposePrevious studies have found tacrolimus to be a favorable drug for treating different types of myasthenia gravis (MG), but few have focused on very-late-onset MG (VLOMG). This study evaluated the efficacy and safety of tacrolimus for VLOMG therapy.MethodsThis was a retrospective single-center cohort study of 70 patients with VLOMG (onset ≥65 years) who visited Peking University First Hospital in 2019. Participants were divided into the tacrolimus (Tac) group and the control group based on tacrolimus usage. We further divided the Tac group into patients treated without corticosteroids and with corticosteroids. Sociodemographic features, clinical profiles, and outcomes were compared between different therapies and further analyzed by multivariate regression. Details of tacrolimus treatment, comorbidities, and adverse drug reactions (ADRs) were described.ResultsAmong 70 patients, the median (interquartile range) age at onset was 71 (68–77) years, and the follow-up duration was 27 (27-29) months. Most patients were types I (28%) and III (40%) according to the MG Foundation of America (MGFA) classification. In the Tac group, tacrolimus treatment was maintained for 36 (27-38) months. The dosage at the final evaluation was 1.0 (1.0–1.75) mg/day, and the last blood concentration test was 4.25 (2.85–5.7) ng/ml. A total of 43% reached remission, and 37% improved based on MGFA postintervention status (MGFA-PIS). For the 9 patients, newly diagnosed at enrollment within this group, MG activities of daily living (MG-ADL) decreased significantly from 3 (2-5) to 2 (1-2) (p = 0.041). Regarding the 13 patients, coadministering Wuzhi capsules the tacrolimus concentration increased from 2.75 (1.4–3.8) ng/ml to 5.95 (5.1–7.0) ng/ml (p = 0.012). No significant differences in outcomes were observed between tacrolimus treatment without and with corticosteroids or between the Tac group and the control group. A total of 93% had at least one comorbidity. ADRs related to tacrolimus emerged in 25% (9/36) of patients, most of which were not serious and reversible.ConclusionsTacrolimus is effective and safe in treating VLOMG. Tacrolimus monotherapy without corticosteroids can be used as an initial and maintenance treatment for VLOMG. Wuzhi capsules work well in elevating tacrolimus concentrations in this population.

Abstract Background Autoimmune necrotizing myopathy with anti-signal recognition particle antibodies (ANM-SRP) is regarded as refractory myositis, whereby some patients respond poorly to conventional immunosuppression and require B cell depletion treatment. This study aimed to evaluate factors associated with refractory ANM-SRP. Results Clinical and pathological data from 48 patients with ANM-SRP were collected. We followed up clinical symptoms and image changes over 12 months. Univariate and multivariate analyses were undertaken to determine the associations between variables of interest and poor response to therapy. Refractory ANM-SRP appeared in 32.5% of patients who showed no or minimal improvement after 12 months of steroid therapy. The clinical risk factors for refractory patients were being male (OR, 19.57; P

Montmorillonite-loaded solid lipid nanoparticles with good biocompatibility, using Betaxolol hydrochloride as model drug, were prepared by the melt-emulsion sonication and low temperature-solidification methods and drug bioavailability was significantly improved in this paper for the first time to application to the eye. The appropriate physical characteristics were showed, such as the mean particle size, Zeta potential, osmotic pressure, pH values, entrapping efficiency (EE%) and drug content (DC%), all showed well suited for possible ocular application. In vitro release experiment indicated that this novel system could continuously release 57.83% drugs within 12 h owing to the dual drug controlled-release effect that was achieved by ion-exchange feature of montmorillonite and structure of solid lipid nanoparticles. Low irritability and good compatibility of nanoparticles were proved by both CAM-TBS test and cytotoxicity experiment. We first discovered from the results of Rose Bengal experiment that the hydrophilicity of the drug-loaded nanoparticles surface was increased during the loading and releasing of the hydrophilic drug, which could contribute to prolong the ocular surface retention time of drug in the biological interface membrane of tear-film/cornea. The results of in vivo pharmacokinetic and pharmacodynamics studies further confirmed that increased hydrophilicity of nanoparticles surface help to improve the bioavailability of the drug and reduce intraocular pressure during administration. The results suggested this novel drug delivery system could be potentially used as an in situ drug controlled-release system for ophthalmic delivery to enhance the bioavailability and efficacy.

To better understand the effect of the size of hole defects on the mechanical properties of a rock mass, the two-dimensional particle flow discrete element code (PFC2D) is applied to establish rock mass models with single circular hole defects of different diameters. Uniaxial compressive strength (UCS) tests are conducted on each model by only taking the defect size (area) as a variable. This study analyzes each model's stress-strain, contact force chain, crack evolution, meso-damage and failure, and mechanical properties. The results showed that with the size enlargement of the circular hole defects, each model's UCS and elastic modulus gradually decrease, and the defect size is negatively correlated with the mechanical strength of the rock samples. The size of the hole defects affects the entire process of contact force chain and crack evolution. The larger the aperture dimension of the circular hole defects in each model, the greater the concentration degree of the contact force chain, the earlier the crack initiation, and the higher the degree of crack coalescence in the post-peak stage. The number of cracks decreases as the hole size increases, and the model is more prone to failure. Rock models' strength and failure characteristics with different numbers and arrangements of hole defects are discussed under the same defect area condition.

This research offers a new perceptive of the dynamic connection between CO2 and globalization, technological innovation (TI), economic growth, and renewable energy (REN) consumption in Spain. The current research applied the wavelet tools to assess these interconnection utilizing data stretching from 1980 to 2018. The outcomes of these analyses disclose that the association among the series evolves over frequency and time. The current analysis uncovers notable wavelet coherence and strong lead and lag connections in the frequency domain, whereas the time domain indicates inconsistent correlations among the variables of interest. The outcomes of the wavelet analysis from the economic perspective affirm that in the short and medium term, globalization, economic growth, and TI contribute to environmental degradation; however, in the long term, globalization, economic growth, and TI do not contribute to the degradation of the environment. Moreover, at different frequencies, REN consumption helps mitigate environmental degradation in Spain. Furthermore, the spectral causality test unveiled that in the long term, REN utilization, globalization, TI, and economic growth can predict CO2 emissions in Spain.

BackgroundBreast cancer is the most commonly diagnosed cancer worldwide. However, the well-known biomarkers are not enough to meet the needs of precision medicine. Novel targets are desirable and highly valuable for improved patient survival. In this regard, we identified complement component C7 as one of the candidates based on data from the OCOMINE database.MethodsC7 expression was examined by immunohistochemistry in 331 cases of invasive ductal carcinoma (IDC), 45 cases of ductal carcinoma in situ (DCIS), and 52 cases of non-neoplastic tissues adjacent to tumor. Then, C7 expression was further confirmed by Western blot analysis based on IDC specimens and non-neoplastic breast specimens. The relationship between the C7 expression and prognosis of breast cancer patients was analyzed in order to investigate the function of C7 in breast cancer patients. Meanwhile, we also analyzed the relationship between the C7 expression and prognosis of 149 patients treated with conventional TE (taxane and anthracycline)-based chemotherapy. Then, a cohort of patients (22 cases) treated with TE neoadjuvant chemotherapy was used to further confirm the relationship between the C7 expression and TE-based chemosensitivity.ResultsIn our present study, we reported for the first time that C7 was an independent prognostic factor of breast cancer and C7 expression of IDC tissues was higher than non-neoplastic tissues adjacent to tumor and DCIS. In a cohort of 331 IDC patients, high expression of C7 indicated poor prognosis especially in the triple negative subtype and luminal B subtype. Furthermore, C7 was also a promoting factor for triple negative subtype patients to develop bone metastasis. Meanwhile, we provided the first evidence that patients with high C7 expression were insensitive to TE (taxane and anthracycline)-based chemotherapy by analyzing a cohort of 149 patients treated with TE-based chemotherapy and another cohort of 22 patients treated with TE neoadjuvant chemotherapy.ConclusionsIn summary, high expression of C7 may promote breast cancer development and might be insensitive to TE-based chemotherapy. Our present study laid a foundation to help clinicians improve the identification of patients for TE-based chemotherapy by C7 in the era of precision medicine.

Abstract Background Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare and treatable inherited lipid storage myopathy. Here, we report an elderly patient with MADD mimicking myositis. Case presentation An 80-year-old woman had progressive weakness in her limbs, exercise intolerance, and no muscle pain for 3 months. The patient’s serum creatine kinase level was slightly elevated. The initial diagnosis was myositis. However, muscle biopsy showed many cytoplasmic vacuoles stained with oil red O, indicating the presence of lipid storage myopathy. The plasma acylcarnitine profile showed increased medium-chain and long-chain acylcarnitine species, consistent with the diagnosis of MADD. Riboflavin treatment dramatically improved muscle weakness. Conclusions MADD should be considered when evaluating elderly patients with subacute muscle weakness.

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease characterized by progressive fibro-fatty replacement of cardiac myocytes. Up to now, the existing therapeutic modalities for ACM are mostly palliative. About 50% of ACM is caused by mutations in genes encoding desmosomal proteins including Desmoglein-2 (Dsg2). In the current study, the cardiac fibrosis of ACM and its underlying mechanism were investigated by using a cardiac-specific knockout of Dsg2 mouse model. Methods: Cardiac-specific Dsg2 knockout (CS-Dsg2−/−) mice and wild-type (WT) mice were respectively used as the animal model of ACM and controls. The myocardial collagen volume fraction was determined by histological analysis. The expression levels of fibrotic markers such as α-SMA and Collagen I as well as signal transducers such as STAT3, SMAD3, and PPARα were measured by Western blot and quantitative real-time PCR. Results: Increased cardiac fibrosis was observed in CS-Dsg2−/− mice according to Masson staining. PPARα deficiency and hyperactivation of STAT3 and SMAD3 were observed in the myocardium of CS-Dsg2−/− mice. The biomarkers of fibrosis such as α-SMA and Collagen I were upregulated after gene silencing of Dsg2 in HL-1 cells. Furthermore, STAT3 gene silencing by Stat3 siRNA inhibited the expression of fibrotic markers. The activation of PPARα by fenofibrate or AAV9-Pparα improved the cardiac fibrosis and decreased the phosphorylation of STAT3, SMAD3, and AKT in CS-Dsg2−/− mice. Conclusions: Activation of PPARα alleviates the cardiac fibrosis in ACM.

The largest ultra-deep (>6000 m) strike-slip fault-controlled oilfield in the world is found in the Tarim Basin of Northwestern China. The localized fractured reservoirs are the major production targets along the strike-slip fault zones. Different from its use in the primary porous-type reservoirs, however, the conventional technology is not favorable for use in oil/gas development in Ordovician carbonate reservoirs. For this reason, high-density seismic acquisition and high-resolution seismic processing were carried out to provide high-precision data for fault and fractured reservoir identification. In addition, the multi-filtering process and the maximum likelihood method are typically used to identify small faults and fault segments along a strike-slip fault zone. Further, seismic facies-constrained inversion and amplitude attributes are favorable for large fracture-cave reservoir description. With the advancements in seismic technology, the high and stable production well ratio has been doubled in the “sweet spots” of fractured reservoir optimization, and the first ultra-deep strike-slip fault-controlled oilfield with an annual oil production of over 1 million tons has been realized, achieving economic development in the ultra-deep fractured reservoirs. However, unstable production and high rates of production decline are still significant challenges in the economic exploitation of the ultra-deep fractured reservoirs. Seismic technology requires further improvement for the description of small fractured reservoirs and matrix reservoirs, as well as reservoir connectivity prediction and hydrocarbon detection in the deep subsurface.

Abstract Background Neutral lipid storage disease with myopathy (NLSDM) is a rare clinical heterogeneous disorder caused by mutations in the patatin-like phospholipase domain-containing 2 (PNPLA2) gene. NLSDM usually presents skeletal myopathy, cardiomyopathy and the multiple organs dysfunction. Around 50 cases of NLSDM have been described worldwide, whereas the comprehensive understanding of this disease are still limited. We therefore recruit NLSDM patients from 10 centers across China, summarize the clinical, muscle imaging, pathological and genetic features, and analyze the genotype-phenotype relationship. Results A total of 45 NLSDM patients (18 men and 27 women) were recruited from 40 unrelated families. Thirteen patients were born from consanguineous parents. The phenotypes were classified as asymptomatic hyperCKemia (2/45), pure skeletal myopathy (18/45), pure cardiomyopathy (4/45), and the combination of skeletal myopathy and cardiomyopathy (21/45). Right upper limb weakness was the early and prominent feature in 61.5% of patients. On muscle MRI, the long head of the biceps femoris, semimembranosus and adductor magnus on thighs, the soleus and medial head of the gastrocnemius on lower legs showed the most severe fatty infiltration. Thirty-three families were carrying homozygous mutations, while seven families were carrying compound heterozygous mutations. A total of 23 mutations were identified including 11 (47.8%) point mutations, eight (34.8%) deletions and four (17.4%) insertions. c.757 + 1G > T, c.245G > A and c.187 + 1G > A were the three most frequent mutations. Among four groups of phenotypes, significant differences were shown in disease onset (

Florescence information monitoring is essential for strengthening orchard management activities, such as flower thinning, fruit protection, and pest control. A lightweight object recognition model using cascade fusion YOLOv4-CF is proposed, which recognizes multi-type objects in their natural environments, such as citrus buds, citrus flowers, and gray mold. The proposed model has an excellent representation capability with an improved cascade fusion network and a multi-scale feature fusion block. Moreover, separable deep convolution blocks were employed to enhance object feature information and reduce model computation. Further, channel shuffling was used to address missing recognition in the dense distribution of object groups. Finally, an embedded sensing system for recognizing citrus flowers was designed by quantitatively applying the proposed YOLOv4-CF model to an FPGA platform. The mAP@.5 of citrus buds, citrus flowers, and gray mold obtained on the server using the proposed YOLOv4-CF model was 95.03%, and the model size of YOLOv4-CF + FPGA was 5.96 MB, which was 74.57% less than the YOLOv4-CF model. The FPGA side had a frame rate of 30 FPS; thus, the embedded sensing system could meet the demands of florescence information in real-time monitoring.

Green citrus detection in citrus orchards provides reliable support for production management chains, such as fruit thinning, sunburn prevention and yield estimation. In this paper, we proposed a lightweight object detection YOLOv5-CS (Citrus Sort) model to realize object detection and the accurate counting of green citrus in the natural environment. First, we employ image rotation codes to improve the generalization ability of the model. Second, in the backbone, a convolutional layer is replaced by a convolutional block attention module, and a detection layer is embedded to improve the detection accuracy of the little citrus. Third, both the loss function CIoU (Complete Intersection over Union) and cosine annealing algorithm are used to get the better training effect of the model. Finally, our model is migrated and deployed to the AI (Artificial Intelligence) edge system. Furthermore, we apply the scene segmentation method using the “virtual region” to achieve accurate counting of the green citrus, thereby forming an embedded system of green citrus counting by edge computing. The results show that the mAP@.5 of the YOLOv5-CS model for green citrus was 98.23%, and the recall is 97.66%. The inference speed of YOLOv5-CS detecting a picture on the server is 0.017 s, and the inference speed on Nvidia Jetson Xavier NX is 0.037 s. The detection and counting frame rate of the AI edge system-side counting system is 28 FPS, which meets the counting requirements of green citrus.