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Objective: Monitoring the disease status of Epstein–Barr virus (EBV)–related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA. Method: A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis. Results: Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with re-elevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse. Conclusion: The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient's immune function.

Abstract Nipah virus (NiV) is a zoonotic emergent paramyxovirus that can cause severe encephalitis and respiratory infections in humans, with a high fatality rate ranging from 40% to 75%. Currently, there are no approved human vaccines or antiviral drugs against NiV. Here, we designed a ferritin-based self-assembling nanoparticle displaying the NiV G head domain on the surface (NiV G-ferritin) and assessed immune responses elicited by the soluble NiV G head domain (NiV sG) or NiV G-ferritin. Immunization with NiV G-ferritin or NiV sG conferred complete protection against lethal NiV challenge without detection of viral RNA in Syrian golden hamsters. Compared to NiV sG, NiV G-ferritin induced significantly faster, broader, and higher serum neutralizing responses against three pathogenic henipaviruses (NiV-Malaysia, NiV-Bangladesh, and Hendra virus). Moreover, NiV G-ferritin induced a durable neutralizing immunity in mice as antisera potently inhibited NiV infection even after six months of the third immunization. Additionally, we isolated a panel of 27 NiV G-binding monoclonal antibodies (mAbs) from NiV G-ferritin immunized mice and found that these mAbs targeted four distinct antigenic sites on NiV G head domain with two sites that have not been defined previously. Notably, 25 isolated mAbs have potent neutralizing activity with 50% inhibitory concentrations less than 10 ng/mL against NiV pseudovirus. Collectively, these findings provide new insights into the immunogenicity of NiV G protein and reveal that NiV G-ferritin is a safe and highly effective vaccine candidate against Nipah virus infection.

Abstract The global epidemic of Mpox virus (MPXV) continues, and a local outbreak has occurred in Shenzhen city since June 2023. Herein, the evolutionary trajectory and characteristics of MPXV in 2023 were analyzed using 92 MPXV sequences from the Shenzhen outbreak and the available genomes from GISAID and GenBank databases. Phylogenetic tracing of the 92 MPXVs suggests that MPXVs in Shenzhen may have multiple sources of importation, and two main transmission chains have been established. The combination of phylogenetic relationships, epidemiological features, and mutation characteristics supports the emergence of a new lineage C.1.1. Together with the B.1 lineage diverging from the A.1 lineage, C.1.1 lineage diverging from the C.1 lineage may serve as another significant evolutionary events of MPXV. Moreover, increasing apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (APOBEC3) related mutations, higher rate of missense mutations, and less mutations in the non-coding regions have been shown during MPXV evolution. Host regulation proteins of MPXV have accumulated considerable amino acid mutations since the B.1 lineage, and a lineage-defining APOBEC3-related mutation that disrupts the N2L gene encoding a viral innate immune modulator has been identified in the C.1.1 lineage. In summary, our study provides compelling evidence for the ongoing evolution of MPXV with specific features.

In the wake of the largest-ever recorded outbreak of mpox in terms of magnitude and geographical spread in human history since May 2022, we innovatively developed an automated online sewage virus enrichment and concentration robot for disease tracking. Coupled with an artificial intelligence (AI) model, our research aims to estimate mpox cases based on the concentration of the monkeypox virus (MPXV) in wastewater. Our research has revealed a compelling link between the levels of MPXV in wastewater and the number of clinically confirmed mpox infections, a finding that is reinforced by the ability of our AI prediction model to forecast cases with remarkable precision, capturing 87 % of the data’s variability. However, it is worth noting that this high precision in predictions may be related to the relatively high frequency of data acquisition and the relatively non-mobile isolated environment of the hospital itself. In conclusion, this study represents a significant step forward in our ability to track and respond to mpox outbreaks. It has the potential to revolutionize public health surveillance by utilizing innovative technologies for disease surveillance and prediction.

Abstract Nonthrombotic iliac vein lesions (NIVLs) are significant causes of chronic venous insufficiency (CVI) in the left lower limb and symptom recurrence following left lower limb varicose vein treatment. The goal of this study was to explore the haemodynamic and morphological characteristics of iliac veins in patients with NIVLs. Pressure at the caudal end of the stenotic left common iliac vein (LCIV) segment, local blood flow velocity, and time-averaged wall shear stress in the stenotic segment exhibited positive correlations with the clinical CVI classification (R = 0.92, p

Abstract Background Epstein-Barr virus DNA (EBV-DNA) is closely related to the pathogenesis and prognosis of EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The quantitative measurement of blood EBV-DNA is widely used in EBV-HLH, but there remains a lack of evidence to guide clinicians. Methods A retrospective analysis was conducted on clinical manifestations, laboratory tests, 310 blood EBV-DNA loads, and prognosis of 51 pediatric patients diagnosed with EBV-HLH. Receiver operating characteristic (ROC) curves were utilized to determine the optimal cutoff values of EBV-DNA for predicting mortality and evaluating the active status of EBV-HLH. Results EBV-positive- lymphoma-HLH had higher initial plasma EBV-DNA load(1.10 × 106copies/ml) compared to the EBV-HLH group (1.98 × 104 copies/ml) (P = 0.006), and experienced recurrently elevated plasma EBV-DNA levels during treatment. The optimal cut-off value of initial plasma EBV-DNA load in predicting mortality was 2.68 × 105 copies/ml, with a sensitivity of 88.57% and a specificity of 56.25%. For determining the active status of HLH, the optimal cutoff value of PBMC EBV-DNA load during treatment was 2.95 × 105 copies/ml, with a sensitivity of 69.14% and a specificity of 64.71%. The cut-off value of plasma EBV-DNA for determining active status was 1.32 × 103 copies/ml, with a sensitivity of 84.34%, and a specificity of 87.67%. Patients with higher PBMC and plasma EBV-DNA at initial and those with repeated elevated plasma EBV-DNA during treatment had worse prognoses (P

Abstract Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver’s balance of redox buffering and triglyceride production.

Abstract Background Airway epithelial cell (AEC) necroptosis contributes to airway allergic inflammation and asthma exacerbation. Targeting the tumor necrosis factor-like ligand 1 A (TL1A)/death receptor 3 (DR3) axis has a therapeutic effect on asthmatic airway inflammation. The role of TL1A in mediating necroptosis of AECs challenged with ovalbumin (OVA) and its contribution to airway inflammation remains unclear. Methods We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma. Results High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway. Conclusions TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy.

Abstract Purpose This study aimed to investigate the feasibility of using computed tomography (CT) attenuation values to differentiate hypodense brain lesions, specifically acute ischemic stroke (AIS) from asymmetric leukoaraiosis (LA) and old cerebral infarction (OCI). Materials and methods This retrospective study included patients with indeterminate hypodense lesions identified via brain CT scans conducted between June 2019 and June 2021. All lesions were confirmed through head MRI/diffusion-weighted imaging within 48 h after CT. CT attenuation values of hypodense lesions and symmetrical control regions were measured. Additionally, CT attenuation value difference (ΔHU) and ratio (RatioHU) were calculated. One-way analysis of variance (ANOVA) was used to compare age and CT parameters (CT attenuation values, ΔHU and RatioHU) across the groups. Finally, receiver operating characteristic (ROC) analysis was performed to determine the cutoff values for distinguishing hypodense lesions. Results A total of 167 lesions from 146 patients were examined. The CT attenuation values for AIS(n = 39), LA(n = 53), and OCI(n = 75) were 18.90 ± 6.40 HU, 17.53 ± 4.67 HU, and 11.90 ± 5.92 HU, respectively. The time interval between symptom onset and CT scans for AIS group was 32.21 ± 26.85 h. ANOVA revealed significant differences among the CT parameters of the hypodense lesion groups (all P

Abstract Tobacco smoking (TS) is implicated in lung cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to TS-mediated LC progression remains to be established. Our findings demonstrate that 4-(methylnitrosamino)−1-(3-pyridyl)−1-butanone and benzo[a]pyrene (NNK and BaP; NB), components of tobacco smoke, induce metabolic syndrome characteristics, particularly hyperglycemia, promoting lung cancer progression in male C57BL/6 J mice. NB enhances glucose uptake in tumor-associated macrophages by increasing the expression and surface localization of glucose transporter (GLUT) 1 and 3, thereby leading to transcriptional upregulation of insulin-like growth factor 2 (IGF2), which subsequently activates insulin receptor (IR) in LC cells in a paracrine manner, promoting its nuclear import. Nuclear IR binds to nucleophosmin (NPM1), resulting in IR/NPM1-mediated activation of the CD274 promoter and expression of programmed death ligand-1 (PD-L1). Restricting glycolysis, depleting macrophages, or blocking PD-L1 inhibits NB-mediated LC progression. Analysis of patient tissues and public databases reveals elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, as well as tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR) expression, suggesting potential poor prognostic biomarkers for LC patients. Our data indicate that paracrine IGF2/IR/NPM1/PD-L1 signaling, facilitated by NB-induced dysregulation of glucose levels and metabolic reprogramming of macrophages, contributes to TS-mediated LC progression.

Abstract Background Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma. Methods The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor. Results Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-β1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression. Conclusions Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.

Abstract Understanding of infection dynamics is important for public health measures against monkeypox virus (MPXV) infection. Herein, samples from multiple body sites and environmental fomites of 77 acute MPXV infections (HIV co-infection: N = 42) were collected every two to three days and used for detection of MPXV DNA, surface protein specific antibodies and neutralizing titers. Skin lesions show 100% positivity rate of MPXV DNA, followed by rectum (88.16%), saliva (83.78%) and oropharynx (78.95%). Positivity rate of oropharynx decreases rapidly after 7 days post symptom onset (d.p.o), while the rectum and saliva maintain a positivity rate similar to skin lesions. Viral dynamics are similar among skin lesions, saliva and oropharynx, with a peak at about 6 d.p.o. In contrast, viral levels in the rectum peak at the beginning of symptom onset and decrease rapidly thereafter. 52.66% of environmental fomite swabs are positive for MPXV DNA, with highest positivity rate (69.89%) from air-conditioning air outlets. High seropositivity against A29L (100%) and H3L (94.74%) are detected, while a correlation between IgG endpoint titers and neutralizing titers is only found for A29L. Most indexes are similar between HIV and Non-HIV participants, while HIV and rectitis are associated with higher viral loads in rectum.

Aplastic anemia (AA), is a rare but potentially life-threatening disease characterized by pancytopenia and a hypocellular bone marrow. Pulmonary mucormycosis (PM) is a rare but life-threatening fungal infection observed in immunocompromised patients, particularly those with neutropenia and those using corticosteroids, with a high mortality rate from 40 to 80%. However, PM diagnosis and treatment remain challenging. This study reports a case of very severe aplastic anemia (VSAA) in a male child with PM. The innovation of this article lies in the following aspects: the patient exhibited typical clinical manifestations, the reverse halo sign (RHS) on chest computed tomography (CT), and a positive metagenomic next-generation sequencing (mNGS) analysis; despite aggressive anti-infective treatment and left lower lobectomy, he experienced a poor clinical outcome. Reflecting on cases with poor prognosis can indeed offer valuable insights and opportunities for learning. This study underlines the diagnostic challenges in mucormycosis, which should be considered in persistent fever that is unresponsive to standard antibiotic and antifungal therapies, and conduct a comprehensive examination to achieve early detection, diagnosis and treatment. It was concluded that, in addition to antifungal treatment, early surgery is essential for treating mucormycosis.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

BackgroundRadiogenomics is an emerging technology that integrates genomics and medical image–based radiomics, which is considered a promising approach toward achieving precision medicine. ObjectiveThe aim of this study was to quantitatively analyze the research status, dynamic trends, and evolutionary trajectory in the radiogenomics field using bibliometric methods. MethodsThe relevant literature published up to 2023 was retrieved from the Web of Science Core Collection. Excel was used to analyze the annual publication trend. VOSviewer was used for constructing the keywords co-occurrence network and the collaboration networks among countries and institutions. CiteSpace was used for citation keywords burst analysis and visualizing the references timeline. ResultsA total of 3237 papers were included and exported in plain-text format. The annual number of publications showed an increasing annual trend. China and the United States have published the most papers in this field, with the highest number of citations in the United States and the highest average number per item in the Netherlands. Keywords burst analysis revealed that several keywords, including “big data,” “magnetic resonance spectroscopy,” “renal cell carcinoma,” “stage,” and “temozolomide,” experienced a citation burst in recent years. The timeline views demonstrated that the references can be categorized into 8 clusters: lower-grade glioma, lung cancer histology, lung adenocarcinoma, breast cancer, radiation-induced lung injury, epidermal growth factor receptor mutation, late radiotherapy toxicity, and artificial intelligence. ConclusionsThe field of radiogenomics is attracting increasing attention from researchers worldwide, with the United States and the Netherlands being the most influential countries. Exploration of artificial intelligence methods based on big data to predict the response of tumors to various treatment methods represents a hot spot research topic in this field at present.

Immune checkpoint inhibitors (ICIs) are essential for urothelial carcinoma (UC) treatment. Fibroblast growth factor receptor (FGFR) alterations, as common oncogenic drivers in UC, have been reported to drive T cell depletion of UC immune microenvironment via up-regulating FGFR signaling, which indicated FGFR alterations potentially result in reduced response to ICIs. In addition, the selective pan-FGFR inhibitor showed better clinical benefit in clinical trials, indicating FGFR has emerged as critical therapeutic target via inhibiting FGFR signaling. The present study aims to evaluate prognosis and response to ICIs between FGFR-altered UC patients and FGFR-wildtype UC patients via 1963 UC patients and offers new insights into personalized precision therapy and combination therapy for UC.

Abstract In this study we aimed to investigate the prevalence of SARS-CoV-2 infection in psoriasis patients, and outcomes of SARS-CoV-2 infection and associated risk factors. A cross-sectional survey was conducted from February 2023 to March 2023. Information was obtained with online questionnaire about psoriasis patients on demographic characteristics, clinical characteristics, SARS-CoV-2 infection and outcomes, vaccination, and routine protection against COVID-19. Logistic regression analysis was used to explore risk factors with SARS-CoV-2 infection and exacerbation of psoriasis. A total of 613 participants were recruited. 516 (84.2%) were infected, and associated factors were sex, working status, routine protection against COVID-19, COVID-19 vaccination, impaired nail, infection exacerbate psoriasis, and severity of psoriasis. Among the patients infected with SARS-CoV-2, 30 (5.8%) required hospitalization, 122 (23.6%) had psoriasis exacerbation due to SARS-CoV-2 infection, and associated factors were subtype of psoriasis, discontinuation of psoriasis treatment during SARS-CoV-2 infection, response following COVID-19 vaccination, and severity of psoriasis. Booster dose vaccination contributed a low probability of COVID-19 sequelae. COVID-19 vaccine’s effectiveness was unsatisfactory, while booster dose vaccination reduced the occurrence of COVID-19 sequelae in psoriasis patients of Southwest China. Patients treated with psoriasis shown to be safe, without a higher incidence of SARS-CoV-2 infection or COVID-19hospitalization compared to untreated patients. Stopping treatment during SARS-CoV-2 infection led to psoriasis exacerbation, so psoriasis treatment could be continued except severe adverse reaction.

Abstract Microdamage and its related inflammation contribute to the development of radiographic axial spondyloarthritis (r-axSpA). Inflammation and cell death in damaged tissues are associated with cell-free DNA (cfDNA) release. Here we investigated whether circulating cfDNA could be a potential biomarker for evaluating disease activity and treatment response in r-axSpA. Circulating cfDNA was detected in the discovery and validation cohort with 79 and 60 newly diagnosed r-axSpA patients respectively and 42 healthy controls using the Quant-iT PicoGreen dsDNA reagent and kit. As a result, cfDNA levels were significantly higher in r-axSpA patients compared with healthy controls in the discovery and validation cohort. Moreover, cfDNA levels were positively correlated with CRP, ASDAS-CRP and neutrophil counts. Additionally, non-steroid anti-inflammatory drugs (NSAIDs) combined with disease-modifying anti-rheumatic drugs or tumor necrosis factor inhibitors but not NSAIDs alone could reduce cfDNA levels. Moreover, a decrease of cfDNA levels after treatment was associated with an effective therapeutic response. Intriguingly, patients with higher levels of cfDNA at diagnosis responded better to combination therapy rather than NSAIDs. However, patients with lower levels of cfDNA displayed similar responses to combination or mono-NSAID treatment. In conclusion, circulating cfDNA levels showed a significant correlation with disease activity as well as treatment efficacy in patients with r-axSpA. Moreover, cfDNA at diagnosis might predict the response to different therapy. Consequently, cfDNA may serve as a useful biomarker of inflammation in r-axSpA.

Interferometry synthetic aperture radar (InSAR) technology has emerged as a powerful tool for the early identification and monitoring of geological hazards in the Loess Plateau. Since the SAR satellite adopts the range-azimuth two-dimensional side-looking imaging mode, the corresponding field area of the pixel will change with slope, aspect, and incident angle, especially in areas with severe changes in terrain and landforms, which causes serious area distortion, leading to abnormal deformation rate mapping. Considering the SAR imaging geometry, terrain slope and aspect conditions, this article proposes a quantitative analysis method for accurate geometric distortion (GD) based on pixel area and corresponding field area and constructs a weighted fusion method based on distortion values for InSAR deformation rate maps in overlapping regions of adjacent tracks. Taking Lingtai County, Gansu Province as the research area and sentinel-1 data as the research data, we utilize the SBAS method to process the sentinel-1 data and estimate the deformation rate, and then use the GD value as a weight factor to estimate the fusion rate of the overlapping area of adjacent tracks. The results demonstrate that the weighted fusion method based on distortion values can achieve a high-quality mosaic effect of deformation rate maps of adjacent tracks, effectively improve the GD influence in deformation rate mapping, and the identification of geological hazards.

Abstract Background Pediatric myelodysplastic syndromes (MDS) are rare disorders with an unrevealed pathogenesis. Our aim is to explore the role of genetic factors in the pathogenesis of MDS in children with different outcomes and to discover the correlation between genetic features and clinical outcomes as well as disease characteristics. Methods We conducted an analysis of archived genetic data from 26 patients diagnosed with pediatric MDS at our institution between 2015 and 2021, examining the association between different genetic characteristics and clinical manifestations as well as prognosis. Additionally, We presented three cases with distinct genetic background and outcomes as examples to elaborate the role of genetic factors in pediatric MDS with different prognoses. Results Genetic variations were detected in 13 out of the 26 patients, including 8 patients with co-occurrence of somatic and germline mutations (CSGMs) and 5 patients with somatic mutations alone. Our analysis revealed that advanced MDS (4/8, 50% vs. 1/5, 20% and 4/11, 36.4%), PD (3/8, 37.5% vs. 1/5, 20% and 1/11 9.1%), and TD (6/8, 75% vs. 2/5, 40% and 2/11, 18.2%) were more common in patients with CSGMs than those with somatic mutations alone or without any mutations. We also found out in our study that 8 patients with CSGMs had evidently different clinical outcomes, and we presented 3 of them as examples for elaboration. Case 1 with germline and somatic mutations of unknown significance had a relatively slow disease course and a good prognosis. Case 2 with compound heterozygous germline SBDS variants and somatic mutations like del20q had a stable disease course and a reversed outcome. Case 3 with a germline GATA2 variant and somatic mutations including − 7 had a rapidly progressive disease course and a worst prognosis. Conclusion Our findings indicate that genetic background of pediatric MDS is closely linked with disease characteristics as well as outcomes and that CSGMs may lead to disease progression. It should be emphasized that the interaction between certain germline variants and somatic mutations, such as SBDS and del20q, may result in hematopoietic stem cell adaptation (improved hematopoiesis) and reversed clinical outcomes, which can facilitate the development of targeted therapy.

Image restoration is a crucial task in computer vision, aiming to fill in missing areas within an image to restore its integrity. Traditional methods fall short when dealing with intricate facial image restoration, often failing to produce high-quality results. Denoising Diffusion Probabilistic Models(DDPM), characterized by its diversity and stability, plays a significant role in the domain of facial image restoration. This study aims to explore a facial image restoration method based on DDPM, utilizing a pre-trained unconditional DDPM model to achieve more flexible facial image restoration. At the same time, this study found that when the total number of iterations in the resampling process is relatively low, the quality of the restored image is poor. Therefore, we propose a method to optimize the inversion process by combining progressive sampling with sample scheduling to improve the quality of the restored images, and conduct extensive experiments on the CelebA-HQ and FFHQ datasets. Comparisons with other methods demonstrate that our approach yields higher-quality results in facial image restoration. Our method achieved the best results in terms of PSNR and LPIPS metrics. For random masks, the accuracy of face recognition increased by 15.7% after the restoration of facial images. For central masks, the accuracy improved by 26%.

High-resolution land cover mapping (LCM) is pivotal in numerous disciplines but still challenging to be acquired because traditional supervised methods require a substantial number of high-resolution labels that is labouring and expensive. To this issue, abundantly available low-resolution land-cover maps are regarded as alternative label sources, but the mismatch of spatial resolution and the misidentification of different land-cover categories introduced an amount of noisy labeled samples. This study introduces a novel cross-resolution deep learning framework, termed CRNN, to generate high-resolution LCM by leveraging low-resolution mapping products. First, a high-resolution backbone is proposed to safeguard the preservation of output resolution while simultaneously retaining the deep feature extraction capability of the network. Furthermore, an attention module is incorporated into the CRNN framework to alleviate the adverse impact of imbalanced samples. More importantly, to address the label noise issue, a weakly supervised loss based on feature similarity is proposed and calculated for obtaining dependable supervision information from low-resolution LCM products. The qualitative and quantitative results demonstrate that the CRNN framework surpasses several state-of-the-art methods. Moreover, based on the CRNN, the 10-m resolution land-cover maps of Beijing and Shanghai for 2020 are produced using 30-m resolution LCM products as reference data. As a further application, CRNN provides a viable and promising approach for reusing existing data products, contributing to some extent toward achieving sustainability goals.

Hydrogen production by wind power is a full-cycle, zero-carbon emission hydrogen production method. However, the random and intermittent nature of wind energy leads to instability in the grid-connected power of wind power. Hence, this paper proposes an intraday energy management strategy for wind-hydrogen coupled systems to achieve flexible operation. Firstly, the AHP and EWM were used to optimise the capacity ratios of the hybrid electrolyzer to improve the objectivity of the hybrid electrolyser selection. Then, a wind-hydrogen coupled system model including a wind power system, hybrid electrolyser hydrogen generation system, and hydrogen fuel cell power system is constructed. Energy management strategies for six operating conditions are proposed to combine the operating characteristics of each system, which solves the problem of poor wind power consumption due to the fluctuation of wind power effectively. Finally, the effectiveness and feasibility of the proposed control strategy are verified based on actual wind farm data.

ABSTRACTPaediatric Mycoplasma pneumoniae pneumonia (MPP) is a heterogeneous disease with a diverse spectrum of clinical phenotypes. No studies have demonstrated the relationship between underlying endotypes and clinical phenotypes as well as prognosis about this disease. Thus, we conducted a multicentre prospective longitudinal study on children hospitalized for MPP between June 2021 and March 2023, with the end of follow-up in August 2023. Blood samples were collected and processed at multiple time points. Multiplex cytokine assay was performed to characterize serum cytokine profiles and their dynamic changes after admission. Cluster analysis based on different clinical phenotypes was conducted. Among the included 196 patients, the levels of serum IL-17A and IL-6 showed remarkable variabilities. Four cytokine clusters based on the two cytokines and four clinical groups were identified. Significant elevation of IL-17A mainly correlated with diffuse bronchiolitis and lobar lesion by airway mucus hypersecretions, while that of IL-6 was largely associated with lobar lesion which later developed into lung necrosis. Besides, glucocorticoid therapy failed to inhibit IL-17A, and markedly elevated IL-17A and IL-6 levels may correlate with lower airway obliterans. Our study provides critical relationship between molecular signatures (endotypes) and clustered clinical phenotypes in paediatric patients with MPP.

ABSTRACTThe South-to-North Water Diversion Project Middle Route (SNWD-MR) annually diverts hundreds of millions of cubic meters of water from the Danjiangkou Reservoir to Beijing, significantly impacting the regional groundwater cycle. To conserve water resources, the government has implemented ecological water replenishment (EWR) in some water systems. This study aimed to study the coupled process of groundwater dynamics and land subsidence (LS) in Yongding River (YDR) basin (Beijing section) following the implementation of the SNWD-MR and EWR. First, an Interferometric Synthetic Aperture Radar (InSAR) time series technique was used to detect spatial and temporal distributions of surface displacement between 2015 and 2020 based on satellite images from Sentinel-1A/B. The results indicated a predominant LS deceleration trend during the InSAR observation period. The area with subsidence velocity below 20 mm/yr decreased significantly by 18.6% after SNWD-MR and EWR (from 2016 to 2020). Then, groundwater level fluctuations during the InSAR observation period were analyzed using groundwater measurement well data. Over 60% of these wells showed a rebound in groundwater levels after the implementation of SNWD-MR and EWR. The polynomial distribution lag model (PDL) revealed the association between LS and groundwater level changes, depicting both short- and long-term lag effect. The results showed significant spatial and temporal heterogeneity on the short- and long-term response between groundwater level change and regional subsidence. In addition, we calculated the differential subsidence slope based on the InSAR-derived LS and analyzed its impact on the river slope after SNWD-MR and EWR. The results show that two sections with significant severe differential subsidence slope occur between 0 and 14,000 m and between 54,000 and 78,000 m along the YDR. The slope change caused by LS may reduce the conveyance capacity of surface canals, and more attention should be paid in those two sections. These findings have an important scientific significance for management strategy for LS control against the background of SNWD-MR and EWR.

Purpose: Conduct a bibliometric analysis to review the knowledge structure and research trends regarding the association between periodontal disease and cardiovascular disease (CVD). Methods: The Web of Science Core collection database was searched for retrieving publications related to periodontitis and CVD between January 1, 2003 and December 31, 2022. The VOSviewer, CiteSpace, and R software package “bibliometrix” were employed for the bibliometric analysis. Results: In total, 3447 articles were collected from 98 countries over the past 20 years, with the United States (1,003), Japan (377), and China (321) contributing the most publications. The literature in this field exhibited exponential growth. The University of Helsinki (n = 125, 1.37 %) holds the distinction of being the research institution with the highest number of publications, with a predominant representation from institutions in the United States. Notably, the Journal of Periodontology emerges as the most popular journal in the field, whereas the Journal of Clinical Periodontology takes the lead in terms of citations. These publications originated from 15,236 authors, with Pussinen (n = 40) having the highest number of published papers and Tonetti (n = 976) garnering the most citations. The visualization analysis of keywords identified “oral microbiome,” “inflammation,” and “porphyromonas gingivalis” as emerging research hotspots in exploring the relationship between periodontitis and CVDs. Conclusion: Through a comprehensive bibliometric analysis, this study posits that periodontitis may heighten the risk of cardiovascular events, offering valuable academic references for scholars investigating the link between periodontitis and CVDs.

BackgroundTuberculosis (TB) persists as a global health challenge, with its treatment hampered by the side effects of long-term combination drug therapies and the growing issue of drug resistance. Therefore, the development of novel therapeutic strategies is critical. This study focuses on the role of immune checkpoint molecules (ICs) and functions of CD8+ T cells in the search for new potential targets against TB.MethodsWe conducted differential expression genes analysis and CD8+ T cell functional gene analysis on 92 TB samples and 61 healthy individual (HI) samples from TB database GSE83456, which contains data on 34,603 genes. The GSE54992 dataset was used to validated the findings. Additionally, a cluster analysis on single-cell data from primates infected with mycobacterium tuberculosis and those vaccinated with BCG was performed.ResultsThe overexpression of LAG-3 gene was found as a potentially important characteristic of both pulmonary TB (PTB) and extrapulmonary TB (EPTB). Further correlation analysis showed that LAG-3 gene was correlated with GZMB, perforin, IL-2 and IL-12. A significant temporal and spatial variation in LAG-3 expression was observed in T cells and macrophages during TB infection and after BCG vaccination.ConclusionLAG-3 was overexpressed in TB samples. Targeting LAG-3 may represent a potential therapeutic target for tuberculosis.

Abstract The ongoing mutations of the SARS‐CoV‐2 pose serious challenges to the efficacy of the available antiviral drugs, and new drugs with fantastic efficacy are always deserved investigation. Here, a nanobody called IBT‐CoV144 is reported, which exhibits broad neutralizing activity against SARS‐CoV‐2 by inducing the conformation of spike trimer dimers. IBT‐CoV144 was isolated from an immunized alpaca using the RBD of wild‐type SARS‐CoV‐2, and it showed strong cross‐reactive binding and neutralizing potency against diverse SARS‐CoV‐2 variants, including Omicron subvariants. Moreover, the prophylactically and therapeutically intranasal administration of IBT‐CoV144 confers fantastic protective efficacy against the challenge of Omicron BA.1 variant in BALB/c mice model. The structure analysis of the complex between spike (S) protein, conducted using Cryo‐EM, revealed a special conformation known as the trimer dimers. This conformation is formed by two trimers, with six RBDs in the “up” state and bound by six VHHs. IBT‐CoV144 binds to the lateral region of the RBD on the S protein, facilitating the aggregation of S proteins. This aggregation results in steric hindrance, which disrupts the recognition of the virus by ACE2 on host cells. The discovery of IBT‐CoV144 will provide valuable insights for the development of advanced therapeutics and the design of next‐generation vaccines.

The Nipah virus (NiV), a highly deadly bat-borne paramyxovirus, poses a substantial threat due to recurrent outbreaks in specific regions, causing severe respiratory and neurological diseases with high morbidity. Two distinct strains, NiV-Malaysia (NiV-M) and NiV-Bangladesh (NiV-B), contribute to outbreaks in different geographical areas. Currently, there are no commercially licensed vaccines or drugs available for prevention or treatment. In response to this urgent need for protection against NiV and related henipaviruses infections, we developed a novel homotypic virus-like nanoparticle (VLP) vaccine co-displaying NiV attachment glycoproteins (G) from both strains, utilizing the self-assembling properties of ferritin protein. In comparison to the NiV G subunit vaccine, our nanoparticle vaccine elicited significantly higher levels of neutralizing antibodies and provided complete protection against a lethal challenge with NiV infection in Syrian hamsters. Remarkably, the nanoparticle vaccine stimulated the production of antibodies that exhibited superior cross-reactivity to homologous or heterologous henipavirus. These findings underscore the potential utility of ferritin-based nanoparticle vaccines in providing both broad-spectrum and long-term protection against NiV and emerging zoonotic henipaviruses challenges.

This study presents a groundbreaking approach to modeling the Hall-Héroult cathode used in aluminum production. Our innovative model is grounded in a sophisticated porous electrode methodology coupled with state-of-the-art numerical simulations. This enables us to capture the intricate physicochemical processes within the system precisely, encompassing the migration, diffusion, and convection of ionic species. A key feature of our model is the integration of detailed electrochemical reaction kinetics at the microscale, providing a nuanced understanding of the internal dynamics of the cathode. Furthermore, we have incorporated a unique penalization method that rigorously enforces the principles of electroneutrality and ionic thermodynamic equilibrium, ensuring the model's fidelity to real-world phenomena. Computational simulation using the finite element method (FEM) serves as the backbone of our model, offering unparalleled accuracy and robustness. This has been confirmed through validation against empirical data, underlining the model's potential to significantly enhance both the efficiency and sustainability of aluminum production processes. • Development of an advanced porous electrode model for the Hall-Héroult process, utilizing numerical simulations42 to unravel complex physicochemical dynamics. • Incorporation of a novel penalization method for ensuring electroneutrality and thermodynamic equilibrium, enhancing 44 model accuracy. • Validation of the model against empirical data using FEM, demonstrating potential improvements in aluminum 46 production efficiency and sustainability.

Psoriasis is a chronic inflammatory skin disease. It is associated with many autoimmune diseases such as rheumatoid arthritis, Crohn’s disease and thyroid diseases. Graves’ disease (GD) is a common organ-specific autoimmune disease characterized by diffuse goitre and thyrotoxicosis. Management of psoriasis patients with GD is challenging. This current report presents the case of a 34-year-old female patient with refractory psoriasis with GD who was hospitalized for drug eruption and then experienced new-onset erythema and scaling following treatment with adalimumab and secukinumab. Despite the sequential move to phototherapy, tofacitinib and ustekinumab, the erythema and scaling continued unabated and exacerbated. Finally, switching to guselkumab resulted in the psoriasis lesions significantly improving. These findings suggest that guselkumab might be an effective treatment option for refractory psoriasis combined with GD.

This study addresses the challenge of simulating fluid flow around flexible net panels, which are critical components in aquaculture systems. Traditional grid-based Eulerian methods struggle with the complex deformations and interactions of such panels. To fill this gap, a numerical approach leveraging the Smoothed Particle Hydrodynamics (SPH) method is introduced. The proposed approach employs a knot-spring model to represent the flexible net panels. The nets are idealized as a structure of physical net-knots linked by virtual elastic springs. The SPH method is used to simulate the fluid flow, capturing the movement of the knots and the resulting deformation of the nets. The model's parameters and numerical schemes are detailed, along with the implementation process. The accuracy of the model is validated through comparisons with existing experimental and simulation data. The results indicate that the SPH-based approach accurately simulates the flow past flexible net panels, providing a detailed velocity distribution and deformation analysis. The study's findings demonstrate the potential of the SPH method for aquaculture engineering applications. The proposed approach offers a promising alternative to traditional methods, particularly in scenarios involving significant net deformation or interaction with other objects. The implications for the design and operation of aquaculture facilities are discussed, along with suggestions for future research directions.

Stability analysis and benefit estimation have substantial implications for lane-change decision-making to reduce delay and variation. Connected platoons drive with minor headway to increase capacity, whereas dividing or reforming platoons significantly impacts traveling efficiency. Therefore, this article focuses on the instability of the platoon caused by an en-route lane-change. Construction of platoon forming, combination rules, and car-following models for various vehicle types are presented to describe driving behaviours. Then, a velocity adjustment and a model for lane-change preparation and recovery are proposed. In addition, a group of stability recognition indexes and related stability evaluation factors are presented. Experiments involving numerical comparisons of the proposed factors are conducted to demonstrate the propagation properties of the instability and reveal the fluctuation degree. The variation duration, velocity variation range, and total delay are the primary indicators for evaluating lane-change feasibility. The models and findings can be applied effectively in practice to determine the optimal time and location for en-route lane-change and to assist with traffic management and lane selection at the entrance.

The perinuclear theca (PT) is a dense cytoplasmic web encapsulating the sperm nucleus. The physiological roles of PT in sperm biology and the clinical relevance of variants of PT proteins to male infertility are still largely unknown. We reveal that cylicin-1, a major constituent of the PT, is vital for male fertility in both mice and humans. Loss of cylicin-1 in mice leads to a high incidence of malformed sperm heads with acrosome detachment from the nucleus. Cylicin-1 interacts with itself, several other PT proteins, the inner acrosomal membrane (IAM) protein SPACA1, and the nuclear envelope (NE) protein FAM209 to form an ‘IAM–cylicins–NE’ sandwich structure, anchoring the acrosome to the nucleus. WES (whole exome sequencing) of more than 500 Chinese infertile men with sperm head deformities was performed and a CYLC1 variant was identified in 19 patients. Cylc1-mutant mice carrying this variant also exhibited sperm acrosome/head deformities and reduced fertility, indicating that this CYLC1 variant most likely affects human male reproduction. Furthermore, the outcomes of assisted reproduction were reported for patients harbouring the CYLC1 variant. Our findings demonstrate a critical role of cylicin-1 in the sperm acrosome–nucleus connection and suggest CYLC1 variants as potential risk factors for human male fertility.

In recent years, radiomics has emerged as a novel research methodology that plays a crucial role in the diagnosis and treatment of ischemic stroke. By integrating multimodal medical imaging techniques such as computed tomography and magnetic resonance imaging, radiomics offers in-depth insights into aspects such as the extent of brain tissue damage and hemodynamics. These data help physicians to accurately assess patient condition, select optimal treatment strategies, and predict recovery trajectories and long-term prognoses, thereby enhancing treatment efficacy and reducing the risk of complications. With the anticipated further advancements in radiomic technology, this methodology has great potential for expanded applications in the early detection, treatment, and prognosis of ischemic stroke. The present narrative review explores the burgeoning field of radiomics and its transformative impact on ischemic stroke.

Epidemiological evidence on the health effects of pesticide exposure among greenhouse workers is limited, and the mechanisms are lacking. Building upon our team’s previous population study, we selected two pesticides, CPF and EB, with high detection rates, based on the theoretical foundation that the liver serves as a detoxifying organ, we constructed a toxicity model using HepG2 cells to investigate the impact of individual or combined pesticide exposure on the hepatic metabolism profile, attempting to identify targeted biomarkers. Our results showed that CPF and EB could significantly affect the survival rate of HepG2 cells and disrupt their metabolic profile. There were 117 metabolites interfered by CPF exposure, which mainly affected ABC transporter, biosynthesis of amino acids, center carbon metabolism in cancer, fatty acid biosynthesis and other pathways, 95 metabolites interfered by EB exposure, which mainly affected center carbon metabolism in cancer, HIF-1 signaling pathway, valine, leucine and isoleucine biosynthesis, fatty acid biosynthesis and other pathways. The cross analysis and further biological experiments confirmed that CPF and EB pesticide exposure may affect the HIF-1 signaling pathway and valine, leucine and isoleucine biosynthesis in HepG2 cells, providing reliable experimental evidence for the prevention and treatment of liver damage in greenhouse workers.

Abstract Progress in immunotherapy for prostate cancer (PCa) lags that for other cancers, mainly because of limited immune infiltration in PCa. This study aimed to assess the feasibility of NSD2 as an immunotherapeutic target in PCa. Immunohistochemistry was performed to evaluate the expression pattern of NSD2 in 34 cases of benign prostatic hyperplasia (BPH), 36 cases of prostatic intraepithelial neoplasia (PIN), and 57 cases of PCa, including 19 cases of metastatic castration-resistant prostatic cancer (mCRPC). Single-cell RNA sequencing and gene set enrichment analysis (GSEA) were used to correlate NSD2 with certain downstream pathways. Furthermore, the Immuno-Oncology-Biological-Research (IOBR) software package was used to analyze the potential roles of NSD2 in the tumor microenvironment. We found that the positive expression rate of NSD2 increased progressively in BPH, PIN and PCa. mCRPC had the highest staining intensity for NSD2. High NSD2 expression was positively correlated with the infiltration level of CD4+ tumor-infiltrating lymphocytes (TILs) and negatively correlated with that of CD8+ TILs. Importantly, a new immune classification based on NSD2 expression and CD4+ TILs and CD8+ TILs was successfully used to stratify PCa patients based on OS.PSA and CD4+ TILs are independent risk factors for PCa bone metastasis. This study demonstrates a novel role for NSD2 in defining immune infiltrate on in PCa and highlights the great potential for its application in immunotherapy response evaluation for prostate malignancies.

AbstractContext Luteolin can affect multiple biological functions, such as anti-inflammatory, antioxidant and immune enhancement processes. Luteolin can inhibit inflammation of T2-high asthma, but its role in neutrophilic asthma has been insufficently studied.Objective This study determines the effect of luteolin on IL-36γ secretion-mediated MAPK pathway signalling in neutrophilic asthma.Materials and methods The asthma model was established by using ovalbumin/lipopolysaccharide (OVA/LPS). Female 6–8-week-old C57BL/6 mice were divided into control, asthma, luteolin (20 mg/kg) and asthma + luteolin (20 mg/kg) groups. To explore the mechanism of anti-inflammatory effects of luteolin in neutrophilic asthma, Beas-2B cells were treated with luteolin (20 µmol/L), LPS (100 ng/mL), recombinant human IL-36γ protein (rhIL-36γ; 100 ng/mL) or IL-36γ siRNA.Results IL-36γ secretion and MAPK/IL-1β signalling were significantly increased in the asthma mouse model compared with the control (p

Abstract Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus that poses a severe threat to humans due to its high morbidity and the lack of viable countermeasures. Vaccines are the most crucial defense against NiV infections. Here, a recombinant chimpanzee adenovirus-based vaccine (AdC68-G) and a DNA vaccine (DNA-G) were developed by expressing the codon-optimized full-length glycoprotein (G) of NiV. Strong and sustained neutralizing antibody production, accompanied by an effective T-cell response, was induced in BALB/c mice by intranasal or intramuscular administration of one or two doses of AdC68-G, as well as by priming with DNA-G and boosting with intramuscularly administered AdC68-G. Importantly, the neutralizing antibody titers were maintained for up to 68 weeks in the mice that received intramuscularly administered AdC68-G and the prime DNA-G/boost AdC68-G regimen, without a significant decline. Additionally, Syrian golden hamsters immunized with AdC68-G and DNA-G via homologous or heterologous prime/boost immunization were completely protected against a lethal NiV virus challenge, without any apparent weight loss, clinical signs, or pathological tissue damage. There was a significant reduction in but not a complete absence of the viral load and number of infectious particles in the lungs and spleen tissue following NiV challenge. These findings suggest that the AdC68-G and DNA-G vaccines against NiV infection are promising candidates for further development.

Abstract Background Infection is the most common adverse event of acute lymphoblastic leukemia (ALL) treatment and is also one of the main causes of death. Methods To investigate the clinical characteristics and risk factors of severe infections during the maintenance phase of ALL treatment, we conducted a retrospective study. Results A total of 181 children were eligible and 46 patients (25.4%) suffered from 51 events of severe infection, most of which occurred in the first half year of the maintenance phase (52.9%). The most common infection was pulmonary infection (86.3%) followed by bloodstream infection (19.6%). The main symptoms of ALL patients with pulmonary infection were fever, cough, and shortness of breath. The main manifestations of computer tomography (CT) were ground glass shadow (56.8%), consolidation shadow (27.3%), and streak shadow (25%). Multivariate binary logistic regression analysis showed that agranulocytosis, agranulocytosis ≥7 days, anemia, and low globulin level were independent risk factors for severe infection during the maintenance phase (all p

Abstract Purpose To develop and evaluate the performance of radiomics-based computed tomography (CT) combined with machine learning algorithms in detecting occult vertebral fractures (OVFs). Materials and methods 128 vertebrae including 64 with OVF confirmed by magnetic resonance imaging and 64 corresponding control vertebrae from 57 patients who underwent chest/abdominal CT scans, were included. The CT radiomics features on mid-axial and mid-sagittal plane of each vertebra were extracted. The fractured and normal vertebrae were randomly divided into training set and validation set at a ratio of 8:2. Pearson correlation analyses and least absolute shrinkage and selection operator were used for selecting sagittal and axial features, respectively. Three machine-learning algorithms were used to construct the radiomics models based on the residual features. Receiver operating characteristic (ROC) analysis was used to verify the performance of model. Results For mid-axial CT imaging, 6 radiomics parameters were obtained and used for building the models. The logistic regression (LR) algorithm showed the best performance with area under the ROC curves (AUC) of training and validation sets of 0.682 and 0.775. For mid-sagittal CT imaging, 5 parameters were selected, and LR algorithms showed the best performance with AUC of training and validation sets of 0.832 and 0.882. The LR model based on sagittal CT yielded the best performance, with an accuracy of 0.846, sensitivity of 0.846, and specificity of 0.846. Conclusion Machine learning based on CT radiomics features allows for the detection of OVFs, especially the LR model based on the radiomics of sagittal imaging, which indicates it is promising to further combine with deep learning to achieve automatic recognition of OVFs to reduce the associated secondary injury.

Abstract Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein we report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in 36 NAFLD patients (NCT04140123). There were three cohorts. Each cohort included twelve patients, nine of whom received ZSP1601 50 mg once daily, 50 mg twice daily, or 100 mg twice daily, and three of whom received matching placebos for 28 days. The primary outcomes were the safety and tolerability of ZSP1601. A total of 27 (27/36, 75%) patients experienced at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild to moderate. There was no Serious Adverse Event. Diarrhea, transiently elevated creatinine and adaptive headache were frequently reported adverse drug reaction. We conclude that ZSP1601 is well-tolerated and safe, showing effective improvement in liver chemistries, liver fat content and fibrosis in patients with NAFLD.

As important nodes of the global coal supply chain, coal export terminals bear the tasks of coal storage, processing, and handling, whose efficiency and stability are of great importance with the growing coal shipping market in recent years. However, poor working conditions of the handling equipment in the coal export terminal, together with its relatively fixed layout and poor flexibility, allow frequent equipment failures to seriously affect the ship-loading operations. To solve the problem, this paper constructs a scheduling optimization model for ship-loading operation systems considering equipment maintenance and proposes an opportunity-maintenance-based two-layer algorithm to solve the model. The upper layer aims to optimize the scheduling scheme of the ship-loading operation system under a certain maintenance plan. The lower layer of the algorithm, an opportunity-maintenance-based “equipment-level–flow-level” maintenance optimization method, determines the best equipment maintenance plan. A coal export terminal in China is employed as the case study to verify the effectiveness of the proposed method. The results show that the proposed method can reduce the average dwell time of ships at the terminal by 15.8% and save total scheduling and maintenance costs by 10.3%. This paper shows how to make full use of equipment failure historical data and integrate equipment maintenance schemes into the scheduling problem of the ship-loading operation system, which can effectively reduce the impact of equipment failures on ship-loading operations and provide decision support for coal export terminal management.

IntroductionPostmenopausal osteoporosis (PMOP) is a common chronic disease, and the loss of bone density and bone strength after menopause are its main symptoms. Effective treatments for PMOP are still uncertain, but Chinese medicine has some advantages in slowing down bone loss. Shengu granules are often used clinically to treat PMOP. It has been shown to be an effective prescription for the treatment of PMOP, and there is evidence that gut flora may play an important role. However, whether Shengu granules attenuate PMOP by modulating gut flora and related mechanisms remains unclear.MethodsIn this study, we mainly examined the bone strength of the femur, the structure of the intestinal microbiota, SCFAs in the feces and the level of FOXP3 cells in the colon. To further learn about the inflammation response, the condition of the mucosa and the level of cytokines in the serum also included in the testing. In addition, to get the information of the protein expression, the protein expression of OPG and RANKL in the femur and the protein expression of ZO-1 and Occludin in the colon were taken into account.ResultsThe osteoporosis was significantly improved in the SG group compared with the OVX group, and the diversity of intestinal flora, the secretion level of SCFAs and the expression level of FOXP3 were significantly increased compared with the OVX group. In terms of inflammatory indicators, the intestinal inflammation scores of the SG group was significantly lower than those in the OVX group. Additionally, the serum expression levels of IL-10 and TGF-β in the SG group were significantly increased compared with the OVX group, and the expression levels of IL-17 and TNF-α were significantly decreased compared with the OVX group. In terms of protein expression, the expression levels of ZO-1, Occluding and OPG were significantly increased in the SG group compared with the OVX group, and the expression level of RANKL was significantly decreased compared with the OVX group.DiscussionShengu granules treatment can improve the imbalance of intestinal flora, increase the secretion of SCFAs and the expression of FOXP3, which reduces the inflammatory response and repairs the intestinal barrier, as well as regulates the expression of OPG/RANKL signaling axis. Overall, Shengu granules ameliorate ovariectomy-induced osteoporosis by the gut-bone-immune axis.

Groupitizing is a well-established strategy in numerosity perception that enhances speed and sensory precision. Building on the ATOM theory, Anobile proposed the sensorimotor numerosity system, which posits a strong link between number and action. Previous studies using motor adaptation technology have shown that high-frequency motor adaptation leads to underestimation of numerosity perception, while low-frequency adaptation leads to overestimation. However, the impact of motor adaptation on groupitizing, and whether visual motion adaptation produces similar effects, remain unclear. In this study, we investigate the persistence of the advantage of groupitizing after motor adaptation and explore the effects of visual motion adaptation. Surprisingly, our findings reveal that proprioceptive motor adaptation weakens the advantage of groupitizing, indicating a robust effect of motor adaptation even when groupitizing is employed. Moreover, we observe a bidirectional relationship, as groupitizing also weakens the adaptation effect. These results highlight the complex interplay between motor adaptation and groupitizing in numerosity perception. Furthermore, our study provides evidence that visual motion adaptation also has an adaptation effect, but does not fully replicate the effects of proprioceptive motor adaptation on groupitizing. In conclusion, our research underscores the importance of groupitizing as a valuable strategy in numerosity perception, and sheds light on the influence of motion adaptation on this strategy.

Pediatric hepatoblastoma (HB) is the most common primary liver malignancy in infants and children. With great diversity and plasticity, tumor-infiltrating neutrophils were one of the most determining factors for poor prognosis in many malignant tumors. In this study, through bulk RNA sequencing for sorted blood and tumor-infiltrated neutrophils and comparison of neutrophils in tumor and para-tumor tissue by single-cell sequencing, we found that intratumoral neutrophils were composed of heterogenous functional populations at different development stages. Our study showed that terminally differentiated neutrophils with active ferroptosis prevailed in tumor tissue, whereas, in para-tumor, pre-fate naïve neutrophils were dominant and ferroptotic neutrophils dispersed in a broad spectrum of cell maturation. Gene profiling and in vitro T-cell coculture experiment confirmed that one of main functional intratumoral neutrophils was mainly immunosuppressive, which relied on the activation of ferroptosis. Combining the bulk RNA-seq, scRNA-seq data, and immunochemistry staining of tumor samples, CXCL12/CXCR4 chemotaxis pathway was suggested to mediate the migration of neutrophils in tumors as CXCR4 highly expressed by intratumoral neutrophils and its ligand CXCL12 expressed much higher level in tumor than that in para-tumor. Moreover, our study pinpointed that infiltrated CXCR4hi neutrophils, regardless of their differential distribution of cell maturation status in HB tumor and para-tumor regions, were the genuine perpetrators for immune suppression. Our data characterized the ferroptosis-dependent immunosuppression energized by intratumoral CXCR4 expression neutrophils and suggest a potential cell target for cancer immunotherapies.

The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) is rapidly increasing, revealing a strong association between these two diseases. Currently, there are no curative medication available for the comorbidity of T2DM and AD. Ceramides are structural components of cell membrane lipids and act as signal molecules regulating cell homeostasis. Their synthesis and degradation play crucial roles in maintaining metabolic balance in vivo, serving as important mediators in the development of neurodegenerative and metabolic disorders. Abnormal ceramide metabolism disrupts intracellular signaling, induces oxidative stress, activates inflammatory factors, and impacts glucose and lipid homeostasis in metabolism-related tissues like the liver, skeletal muscle, and adipose tissue, driving the occurrence and progression of T2DM. The connection between changes in ceramide levels in the brain, amyloid β accumulation, and tau hyper-phosphorylation is evident. Additionally, ceramide regulates cell survival and apoptosis through related signaling pathways, actively participating in the occurrence and progression of AD. Regulatory enzymes, their metabolites, and signaling pathways impact core pathological molecular mechanisms shared by T2DM and AD, such as insulin resistance and inflammatory response. Consequently, regulating ceramide metabolism may become a potential therapeutic target and intervention for the comorbidity of T2DM and AD. The paper comprehensively summarizes and discusses the role of ceramide and its metabolites in the pathogenesis of T2DM and AD, as well as the latest progress in the treatment of T2DM with AD.

Background: High-flow nasal cannula (HFNC) and conventional oxygen therapy (COT) are important respiratory support strategies for acute hypoxemic respiratory failure (AHRF) in coronavirus disease 2019 (COVID-19) patients. However, the results are conflicting for the risk of intubation with HFNC as compared to COT. Objectives: We systematically synthesized the outcomes of HFNC relative to COT in COVID-19 patients with AHRF and evaluated these outcomes in relevant subpopulations. Design: This study was designed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data sources and methods: We searched PubMed, EMBASE, Web of Science, Scopus, ClinicalTrials.gov, medRxiv, BioRxiv, and the Cochrane Central Register of Controlled Trials for randomized controlled trials and observational studies that compared the efficacy of HFNC with COT in patients with COVID-19-related AHRF. Primary outcomes were intubation rate and mortality rate. Secondary outcomes were the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO 2 /FiO 2 ), respiratory rate, hospital length of stay, intensive care unit (ICU) length of stay, and days free from invasive mechanical ventilation. Results: In total, 20 studies with 5732 patients were included. We found a decreased risk of requiring intubation in HFNC compared to COT [odds ratio (OR) = 0.61, 95% confidence interval (CI): 0.46–0.82, p = 0.0009, I 2 = 75%]. Similarly, we found HFNC was associated with lower risk of intubation rate compared to COT in the subgroup of patients with baseline PaO 2 /FiO 2

Abstract Background Researches and practice of traditional Chinese medicine indicated that Agrimonia pilosa Ledeb could improve insulin resistance (IR) and treat type 2 diabetes (T2DM). To reveal its underling mechanisms, we isolated Flavonoid component (FC) from Agrimonia pilosa Ledeb and elucidated its effects on glucose metabolism to improve IR by suppressing oxidative stress and inflammation. Methods Adipocytes or mice IR model was established with overdosed glucose and insulin or high-fat diet. The uptake of 2-NBDG and glucose consumption were measured to verify insulin sensitivity in vitro and vivo. Reactive oxidative species (ROS) were detected by flow cytometry, and superoxide dismutase (SOD) activity as well as the malondialdehyde (MDA) content were also measured. Meanwhile, factors associated with insulin signal pathway including PPARγ, insulin receptor substrate-1 (IRS-1), GLUT4, and oxidative stress including NF-E2-related factor 2 (Nrf2), as well as the related inflammatory cytokines such as NF-κB, IL-1β, IL-6 and TNF-α were tested. Furthermore, the JNK/PI3K/Akt signal pathway was also explored. Results FC extracted from Agrimonia pilosa Ledeb ameliorated the impaired glucose metabolism significantly. Further study indicated that FC could regulate the insulin signal pathway to improve insulin resistance. Moreover, it could upregulate PPARγ with the similar efficacy as pioglitazone (Piog) straightway. FC also decreased the endogenous ROS and MDA content, increased SOD activity and Nrf2 expression to facilitate oxidative homeostasis. It attenuated expression and secretion of inflammatory cytokines obviously. At last, our results indicated JNK/PI3K/Akt pathway was regulated by FC in adipocytes and adipose tissue. Conclusion FC could ameliorate glucose metabolism and improve IR. It exerted these effects by suppressing oxidative stress and inflammation. FC from Agrimonia pilosa Ledeb has a good prospect to be drugs or functional foods for IR and T2DM.