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Abstract Background Anesthetic drugs may alter exosomal microRNA (miRNA) contents and mediate cancer progression and tumor microenvironment remodeling. Our study aims to explore how the anesthetics (sevoflurane and propofol) impact the miRNA makeup within exosomes in hepatocellular carcinoma (HCC), alongside the interconnected signaling pathways linked to the tumor immune microenvironment. Methods In this prospective study, we collected plasma exosomes from two groups of HCC patients (n = 5 each) treated with either propofol or sevoflurane, both before anesthesia and after hepatectomy. Exosomal miRNA profiles were assessed using next-generation sequencing (NGS). Furthermore, the expression data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) was used to pinpoint the differentially expressed exosomal miRNAs (DEmiRNAs) attributed to the influence of propofol or sevoflurane in the context of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to dissect the signaling pathways and biological activities associated with the identified DEmiRNAs and their corresponding target genes. Results A total of 35 distinct DEmiRNAs were exclusively regulated by either propofol (n = 9) or sevoflurane (n = 26). Through TCGA-LIHC database analysis, 8 DEmiRNAs were associated with HCC. These included propofol-triggered miR-452-5p and let-7c-5p, as well as sevoflurane-induced miR-24-1-5p, miR-122-5p, miR-200a-3p, miR-4686, miR-214-3p, and miR-511-5p. Analyses revealed that among these 8 DEmiRNAs, the upregulation of miR-24-1-5p consistently demonstrated a significant association with lower histological grades (p

AimsThis study aims to systematically analyze the global trends in glioma methylation research using bibliometric methodologies. We focus on identifying the scholarly trajectory and key research interests, and we utilize these insights to predict future research directions within the epigenetic context of glioma.MethodsWe performed a comprehensive literature search of the Web of Science Core Collection (WoSCC) to identify articles related to glioma methylation published from January 1, 2004, to December 31, 2023. The analysis included full-text publications in the English language and excluded non-research publications. Analysis and visualization were performed using GraphPad Prism, CiteSpace, and VOSviewer software.ResultsThe search identified 3,744 publications within the WoSCC database, including 3,124 original research articles and 620 review articles. The research output gradually increased from 2004 to 2007, followed by a significant increase after 2008, which peaked in 2022. A minor decline in publication output was noted during 2020–2021, potentially linked to the coronavirus disease 2019 pandemic. The United States and China were the leading contributors, collectively accounting for 57.85% of the total research output. The Helmholtz Association of Germany, the German Cancer Research Center (DKFZ), and the Ruprecht Karls University of Heidelberg were the most productive institutions. The Journal of Neuro-Oncology led in terms of publication volume, while Neuro-Oncology had the highest Impact Factor. The analysis of publishing authors revealed Michael Weller as the most prolific contributor. The co-citation network analysis identified David N. Louis's article as the most frequently cited. The keyword analysis revealed “temozolomide,” “expression,” “survival,” and “DNA methylation” as the most prominent keywords, while “heterogeneity,” “overall survival,” and “tumor microenvironment” showed the strongest citation bursts.ConclusionsThe findings of this study illustrate the increasing scholarly interest in glioma methylation, with a notable increase in research output over the past two decades. This study provides a comprehensive overview of the research landscape, highlighting the importance of temozolomide, DNA methylation, and the tumor microenvironment in glioma research. Despite its limitations, this study offers valuable insights into the current research trends and potential future directions, particularly in the realm of immunotherapy and epigenetic editing techniques.

The MS6.8 earthquake occurred in Luding County, Ganzi Prefecture, Sichuan Province, China at 12:52 p.m. on Sept. 5, 2022, is preliminarily analyzed in terms of regional tectonics, historical earthquakes, sequence characteristics and focal mechanism solutions. The results show that: 1) The magnitude difference ΔM between the main shock and the maximum aftershock, the energy ratio ER of the main shock to the aftershocks, the p-value and the estimated Mmax-value indicate that the MS6.8 Luding earthquake sequence can be divided into the main shock-aftershock type (MAT). 2) The spatial distribution of the aftershocks, their corresponding b-value and expected maximum magnitude are obviously segmented, which reflect the complexity of the seismogenic tectonics. 3) According to the focal mechanisms obtained from the HASH program, the geometry distribution of the sequence, and the relationship between the sequence and the nearby faults, it can be inferred that the Moxi fault segment of the Xianshuihe fault zone is the seismogenic tectonics of the MS6.8 Luding earthquake sequence.

On June 10, 2022, the MS6.0 Ma'erkang earthquake sequence occurred in the Bayan Har block. In this paper, the temporal and spatial distribution and attenuation characteristics of earthquake sequence is analyzed based on the regional structure, the temporal and spatial distribution of earthquake sequence, the focal mechanism solution, and the parameters of earthquake sequence, using the data of Sichuan Seismic Network and the temporary stations incorporated into the network. The results show that: (1) The MS6.0 Ma'erkang earthquake sequence is generally distributed in NW-SE direction, and the long axis of this series is basically consistent with the nearby Songgang fault. (2) As the earthquake sequence is formed by three large events with MS ≥5.0, the frequency of small earthquakes in the earthquake sequence area generally attenuates relatively slowly, while the activity level (magnitude) of aftershocks attenuates rapidly. (3) After the MS5.2 earthquake, the sequence parameters obtained show that the h-value is 1.09 and the p-value is stable at 1.02, indicating that the intensity and frequency attenuation of the earthquake sequence are gradually stable and tend to be normal. The b-value is 0.95, indicating that the maximum aftershock magnitude of the series is estimated to be ML5.1, and the b-value gradually tended to be stable, indicating that the stress in the region gradually tended to be balanced after the MS5.2 earthquake. The MS4.4 (ML5.0) earthquake that occurred at 4:37 on June 10 (local time) is the largest aftershock after the MS5.2 earthquake in the sequence. (4) The Songgang fault with NW-SE trend is presumed to be the main seismogenic tectonics, but the migration of three earthquakes with MS≥5.0 may also indicate that the Songgang fault is not a single seismogenic tectonics, which requires further field scientific investigation and analysis.

Abstract Syringa oblata is an important garden plant whose leaf colour turns from green to red in autumn when air temperature and daylength decrease. This study explored the reasons for leaf reddening by detecting phenotypic characteristics and pigment types and contents. With leaf reddening, luminance L* increased and chrominance a* decreased significantly. Chlorophyll and carotenoid contents significantly decreased in accordance with the distribution change of green pigment in leaf cells. Conversely, the red pigment distribution increased and the total polyphenol, total flavonoid and total anthocyanin contents evidently increased. Anthocyanin accumulation was the important reason for leaf reddening. Of the anthocyanins detected in leaves, cyanidin and delphinidin-3-O-rutinoside contents gradually increased with leaf reddening and were negatively correlated with L*. They were considered key anthocyanins influencing leaf colour. Apigenin and syringic acid were correlated with delphinidin-3-O-rutinoside and cyanidin, and they could be the anthocyanin co-pigments. Cyanidin-3-O-arabinoside and taxifolin were more abundant polyphenols in leaves. In summary, anthocyanin accumulation and chlorophyll degradation occurred along with leaf reddening. Temperature, light, and other co-pigments influenced the anthocyanin and chlorophyll contents. This study provides evidence for applications of S. oblata as a coloured-leaf plant in gardens and as a source of active ingredients in the commercial market.

The detection and traceability research of massive log information has always been a focal point in Advanced Persistent Threats (APT) studies. Causality relationship technology analyzes attack paths and simplifies graph scale by mapping attack behaviors, but rule-based detection methods often introduce numerous false alarms. To address this issue, this paper proposes a multi-feature provenance graph for the Accurate Alert System (FPGAA). It constructs trace graphs by selecting feature graphs based on the attack types, effectively improving the compression ratio of trace graphs. The FPGAA system utilizes graph neural network technology to efficiently filter out erroneous attack paths generated by false alarm information. We evaluated the system‘s performance using widely recognized classic datasets, including the DARPA TC dataset and the ATLAS dataset, as well as a self-constructed dataset to ensure comprehensiveness and reliability. The results demonstrate that the FPGAA system shows significant improvements in trace graph optimization compared to similar systems, successfully reducing the provenance graph size by over 300 times. Additionally, the FPGAA system effectively overcomes the interference caused by false alarm alerts, successfully filtering out approximately 94% of false alarms. In summary, our system can accurately identify a variety of attack paths, expedite event investigation efficiency through concise contextual alarms, and enhance identification accuracy by increasing features.

Abstract Chronic stress and elevated levels of glucocorticoids (GCs), the main stress hormones, accelerate Alzheimer’s disease (AD) onset and progression. A major driver of AD progression is the spreading of pathogenic Tau protein between brain regions, precipitated by neuronal Tau secretion. While stress and high GC levels are known to induce intraneuronal Tau pathology (i.e. hyperphosphorylation, oligomerization) in animal models, their role in trans-neuronal Tau spreading is unexplored. Here, we find that GCs promote secretion of full-length, primarily vesicle-free, phosphorylated Tau from murine hippocampal neurons and ex vivo brain slices. This process requires neuronal activity and the kinase GSK3β. GCs also dramatically enhance trans-neuronal Tau spreading in vivo, and this effect is blocked by an inhibitor of Tau oligomerization and type 1 unconventional protein secretion. These findings uncover a potential mechanism by which stress/GCs stimulate Tau propagation in AD.

IntroductionWhen doctors’ work stress increases, their joy in work decreases, severely affecting the quality of care and threatening patient safety. Analysis of the latent categories of joy in work of doctors in public hospitals and the differences in the characteristics of each category can help uncover hidden messages that enhance doctors’ joy in work.MethodsQuestionnaires were administered to 426 doctors working in public hospitals using the general information questionnaire and the public hospital doctor’s joy in work evaluation scale. Upon identifying their potential categories using latent profile analysis, chi-square test, and multinomial logistic regression were performed to analyze the differences in the characteristics of each category.ResultsThe 426 public hospital doctors could be divided into three potential categories: “low joy in work” (11.27%), “medium joy in work” (59.86%), and “high joy in work” (28.87%). Most of the doctors did not have much joy in work, with 71.13% of them having “low to medium joy in work.” Doctors who work in secondary or tertiary hospitals, have a personnel agency or contract, and are older than 45 years are more likely to belong to the “low joy in work” category. Some of the protective factors are having an average monthly income (RMB) of 10,001–15,000 yuan and having a fair or good self-rated health status.ConclusionThere are obvious classification characteristics of doctors’ level of joy in work. Hospital managers can take commensurate actions to improve their joy in work, thereby improving patient safety and the quality of medical services.

Abstract Background Patients who possess various histological subtypes of early‐stage lung adenocarcinoma (LUAD) have considerably diverse prognoses. The simultaneous existence of several histological subtypes reduces the clinical accuracy of the diagnosis and prognosis of early‐stage LUAD due to intratumour intricacy. Methods We included 11 postoperative LUAD patients pathologically confirmed to be stage IA. Single‐cell RNA sequencing (scRNA‐seq) was carried out on matched tumour and normal tissue. Three formalin‐fixed and paraffin‐embedded cases were randomly selected for 10× Genomics Visium analysis, one of which was analysed by digital spatial profiler (DSP). Results Using DSP and 10× Genomics Visium analysis, signature gene profiles for lepidic and acinar histological subtypes were acquired. The percentage of histological subtypes predicted for the patients from samples of 11 LUAD fresh tissues by scRNA‐seq showed a degree of concordance with the clinicopathologic findings assessed by visual examination. DSP proteomics and 10× Genomics Visium transcriptomics analyses revealed that a negative correlation (Spearman correlation analysis: r = –.886; p = .033) between the expression levels of CD8 and the expression trend of programmed cell death 1(PD‐L1) on tumour endothelial cells. The percentage of CD8+ T cells in the acinar region was lower than in the lepidic region. Conclusions These findings illustrate that assessing patient histological subtypes at the single‐cell level is feasible. Additionally, tumour endothelial cells that express PD‐L1 in stage IA LUAD suppress immune‐responsive CD8+ T cells.

Genome-wide association studies (GWAS) have identified thousands of variants in the human genome with autoimmune diseases. However, identifying functional regulatory variants associated with autoimmune diseases remains challenging, largely because of insufficient experimental validation data. We adopt the concept of semi-supervised learning by combining labeled and unlabeled data to develop a deep learning-based algorithm framework, sscNOVA, to predict functional regulatory variants in autoimmune diseases and analyze the functional characteristics of these regulatory variants. Compared to traditional supervised learning methods, our approach leverages more variants’ data to explore the relationship between functional regulatory variants and autoimmune diseases. Based on the experimentally curated testing dataset and evaluation metrics, we find that sscNOVA outperforms other state-of-the-art methods. Furthermore, we illustrate that sscNOVA can help to improve the prioritization of functional regulatory variants from lead single-nucleotide polymorphisms and the proxy variants in autoimmune GWAS data.

A facile method, refluxing with hydrothermal process, was used to synthesize the fluorinated graphene sheets (FGS) with high F/C ratio. Then, the surface of aluminum hydride (AlH3) was coated with FGS by means of liquid self-assembly process. The structure and performance of FGS were characterized through fourier transform infrared spectra (FTIR), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscope (TEM) and elemental analyzer. FTIR spectra show that the FGS have obvious absorption peak of CF bond. Raman spectra display many defects on FGS. XPS spectra and elemental analysis also prove the existence of CF bond, and the content of fluorine is more than 25%. From SEM photos we can see that FGS have thin layers with some curled wrinkles. TEM photos demonstrate intuitively the FGS has a few layers. At last, the aluminum hydride (AlH3) was coated with FGS by means of liquid self-assembly process, and AlH3 samples before and after treated were characterized through hydrogen content (H%) analysis, X-ray diffraction (XRD), FTIR, SEM and differential thermal analysis (DTA), ect. The results demonstrate that there is only a little FGS on the surface of AlH3, which won't affect the effective H% and release efficiency of hydrogen. AlH3@FGS also reduces the mechanical sensitivity of solid propellant with AlH3, which will remarkably promote the application of AlH3 in the novel high-energy solid propellant.

Abstract Background Immunosuppressive medication reduces the immunogenicity of the coronavirus disease 2019 (COVID‐19) vaccines in patients with rheumatic and musculoskeletal diseases (RMDs). However, the underlying mechanism remains unclear. The primary aim of our study was to dissect the impact of immunosuppressive medication on cellular and humoral immune responses in RMD patients receiving the inactivated COVID‐19 vaccine. Methods A total of 28 RMD patients and five healthy controls (HCs) receiving two doses of the inactivated COVID‐19 vaccine (Sinovac‐CoronaVac) were prospectively enrolled. Blood samples were collected before the primary vaccination (Week 0) and one week after the second vaccination (Week 5). Neutralizing antibody (nAb) titers and autoantibody titers were measured by a pseudovirus‐based neutralization assay and enzyme‐linked immunosorbent assay, respectively. CD4+ T‐cell and CD19+ B‐cell subsets and serum cytokines were analyzed by flow cytometry. Results The inactivated COVID‐19 vaccine was immunogenic in RMD patients and HCs after the second vaccination, but the nAb titers were lower in RMD patients than those in HCs. Only patients with systemic lupus erythematosus (SLE) had notably increased nAb titers. Remarkably, IgG+CD27+, IgG+IgG1+, and IgG+IgG1− B cells were reduced, whereas IgG−IgG1+ B cells, and total IgA and IgG titers were markedly increased. However, Tfh cell and Tfr cell subsets and cytokines produced by Tfh cells were not increased. The flare rate was low in RMD patients with comparable autoantibody titers, unchanged CD4+ T cell subsets and serum pro‐inflammatory cytokines (interleukin [IL]‐6, IL‐17, interferon‐γ, and tumor necrosis factor‐α) after the second vaccination. Conclusions Immunosuppressive therapy decreased the immunogenicity of the vaccine and maintained a low flare rate by selectively modulating B cell but not CD4+ T cell responses in RMD patients receiving the inactivated COVID‐19 vaccine. Optimization of the treatment regimen might ensure a durable and robust COVID‐19 vaccination response.

Background: Postoperative analgesia is an essential component of enhanced recovery after surgery following abdominal surgery. Studies comparing the effectiveness of epidural analgesia with that of other analgesic modalities after liver surgery have reported inconsistent results. Consequently, the use of epidural analgesia for open hepatectomy is controversial. Objective: The present single-center retrospective study aimed to compare the efficacy and safety of patient-controlled epidural analgesia (PCEA) and patient-controlled intravenous analgesia (PCIA) in adults undergoing open hepatectomy. Methods: Patients who underwent open hepatectomy between January 2018 to December 2019 at Zhongshan Hospital, Fudan University were retrospectively analyzed. Propensity score matching was used to adjust baseline information between the PCEA and PCIA groups. The primary outcome measure was scores of the numeric rating scales (NRSs) for resting, exercise, and nocturnal pain at postoperative 24 h (postoperative day 1 [POD1]) and 48 h (POD2). The secondary outcome indicators included postoperative nausea and vomiting (PONV), hypotension, pruritus, respiratory depression, functional activity score (FAS), effective analgesic pump compression ratio, analgesic relief rate, discontinuation of the analgesic pump, reasons for discontinuation of the analgesic pump, and patient satisfaction with postoperative analgesia. Results: The NRS scores of the PCEA group on POD1 were significantly lower than those of the PCIA group (P

Abstract Systemic Lupus Erythematosus (SLE) etiopathogenesis highlights the contributions of overproduction of CD4+ T cells and loss of immune tolerance. However, the involvement of CD8+ T cells in SLE pathology and disease progression remains unclear. Here, the comprehensive immune cell dysregulation in total 263 clinical peripheral blood samples composed of active SLE (aSLE), remission SLE (rSLE) and healthy controls (HCs) is investigated via mass cytometry, flow cytometry and single‐cell RNA sequencing. This is observed that CD8+CD27+CXCR3− T cells are increased in rSLE compare to aSLE. Meanwhile, the effector function of CD8+CD27+CXCR3− T cells are overactive in aSLE compare to HCs and rSLE, and are positively associated with clinical SLE activity. In addition, the response of peripheral blood mononuclear cells (PBMCs) is monitored to interleukin‐2 stimulation in aSLE and rSLE to construct dynamic network biomarker (DNB) model. It is demonstrated that DNB score‐related parameters can faithfully predict the remission of aSLE and the flares of rSLE. The abundance and functional dysregulation of CD8+CD27+CXCR3− T cells can be potential biomarkers for SLE prognosis and concomitant diagnosis. The DNB score with accurate prediction to SLE disease progression can provide clinical treatment suggestions especially for drug dosage determination.

Background An important factor contributing to the development and occurrence of post-traumatic epilepsy (PTE) is neuroinflammation and oxidative stress. The effects of celecoxib include inhibiting inflammatory reactions and antioxidant stress and reducing seizures, making it a potential epilepsy treatment solution. Objective To observe the effect of celecoxib on early epilepsy in post-traumatic epilepsy rats. Methods: Twenty-four adult healthy male Sprague-Dawley rats were randomly assigned to three groups: sham-operated, PTE, and celecoxib. A rat model of PTE was established by injecting ferrous chloride into the right frontal cortex. Afterward, the behavior of rats was observed and recorded. 3.0T superconducting magnetic resonance imaging (MRI) was used to describe the changes in ADC values of the brain. HE and Nissl staining were also used to detect the damage to frontal lobe neurons. Furthermore, the expression of COX-2 protein in the right frontal lobe was detected by Western blot. Moreover, the contents of IL-1 and TNF-α in the right frontal lobe were detected by enzyme-linked immunosorbent assay. Results Compared with the PTE group, the degree of seizures in rats treated with celecoxib declined dramatically (P < 0.05). Celecoxib-treated rats had significant decreases in tissue structural damage and cell death in the brain. The results of the MRI showed that celecoxib reduced the peripheral edema zone and ADC value of the cortex around the damaged area of the right frontal lobe in the celecoxib-treatment group, which was significantly decreased compared with the PTE group (P < 0.05). Furthermore, celecoxib decreased the expression of COX-2, IL-1β, and TNF-α in brain tissue (P < 0.05). Conclusions In PTE rats, celecoxib significantly reduced brain damage and effectively reduced seizures. As a result of celecoxib’s ability to inhibit inflammation, it can reduce the edema caused by injury in rat brain tissue.

ABSTRACTThe two most common systemic amyloidosis types are immunoglobulin light chain (AL) and amyloid transthyretin (ATTR) amyloidosis, in which the precursor proteins responsible for amyloidosis are light chain and transthyretin, respectively. Identification of precursor proteins is paramount to determine the type of amyloidosis, given that both amyloidosis types lack specificity in clinical presentation. Congo red staining followed by immunohistochemistry or immunofluorescence using fibril protein-specific antibodies is crucial for the diagnosis of amyloidosis. Here we describe a patient who was initially diagnosed with AL amyloidosis due to strong positive kappa light chain staining results. However, the diagnosis was corrected to hereditary ATTR amyloidosis using mass spectrometry and gene sequencing, confirming the important role of mass spectrometry in identifying the amyloid precursor protein and ruling out false-positive result from immunohistochemistry.

Key Clinical Message Acute thrombus formation on the delivery sheath is rare condition during percutaneous left atrial appendage occlusion. We presented two cases that transesophageal echocardiography (TEE) showed a floating thrombus attached to the tip of delivery sheath during the procedure. Cerebral embolic protection devices were used to prevent neurological events after thrombus was detected. The neurological function was not impaired post‐procedure.

Abstract. Background:. Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, is characterized by synovitis and progressive damage to the bone and cartilage of the joints, leading to disability and reduced quality of life. This study was a randomized clinical trial comparing the outcomes between withdrawal and dose reduction of tofacitinib in patients with RA who achieved sustained disease control. Methods:. The study was designed as a multicenter, open-label, randomized controlled trial. Eligible patients who were taking tofacitinib (5 mg twice daily) and had achieved sustained RA remission or low disease activity (disease activity score in 28 joints [DAS28] ≤3.2) for at least 3 months were enrolled at six centers in Shanghai, China. Patients were randomly assigned (1:1:1) to one of three treatment groups: continuation of tofacitinib (5 mg twice daily); reduction in tofacitinib dose (5 mg daily); and withdrawal of tofacitinib. Efficacy and safety were assessed up to 6 months. Results:. Overall, 122 eligible patients were enrolled, with 41 in the continuation group, 42 in the dose-reduction group, and 39 in the withdrawal group. After 6 months, the percentage of patients with a DAS28-erythrocyte sedimentation rate (ESR) of

Landslides pose a serious threat to human life, safety, and natural resources. Remote sensing images can be used to effectively monitor landslides at a large scale, which is of great significance for pre-disaster warning and post-disaster assistance. In recent years, deep learning-based methods have made great progress in the field of remote sensing image landslide detection. In remote sensing images, landslides display a variety of scales and shapes. In this article, to better extract and keep the multiscale shape information of landslides, a shape-enhanced vision transformer (ShapeFormer) model is proposed. For the feature extraction, a pyramid vision transformer (PVT) model is introduced, which directly models the global information of local elements at different scales. To learn the shape information of different landslides, a shape feature extraction branch is designed, which uses the adjacent feature maps at different scales in the PVT model to improve the boundary information. After the feature extraction step, a decoder with deconvolutional layers follows, which combines the multiple features and gradually recovers the original resolution of the combined features. A softmax layer is connected with the combined features to acquire the final pixel-wise result. The proposed ShapeFormer model was tested on two public datasets—the Bijie dataset and the Nepal dataset—which have different spectral and spatial characteristics. The results, when compared with those of some of the state-of-the-art methods, show the potential of the proposed method for use with multisource optical remote sensing data for landslide detection.

The Litang fault (LTF), located in the southeast of the Qinghai-Tibetan Plateau, is known for its high level of present-day seismicity, whereas its Pleistocene activity has been scarcely documented. This study focused on a tract of banded travertine deposits precipitated from thermal waters along the NW–SE-trending LTF trace. The role of travertine deposits in recording neotectonic activity has been studied by identifying their internal structure. Typical soft-sediment deformation structures observed within the banded travertines include micro folds, liquefied breccia, and liquefied diapirs. These deformed structures, which are restricted to a single unit separated unconformably by undeformed layers, can be traced for tens of meters, indicating that they were formed by seismic shaking triggered by LTF activity. The deformation of the banded travertine layers is attributed to the combined effects of seismic shaking, liquefaction, and fluidization, and it can be related to a paleo earthquake event with a magnitude of MS ​> ​5. The U-series ages obtained from the banded travertine deposits perturbed by the earthquakes are in the range of 130.59–112.94 ka, indicating an important fault-assisted neotectonic activity that occurred during the Middle–Late Pleistocene. Analysis of such structures, in combination with the use of U-series dating methods, can yield a reliable timing of neotectonic activity and provide new evidence for understanding the seismotectonic setting of the Litang area.

Summary: Tumor relapse is the leading adverse prognostic factor in medulloblastoma (MB). However, there is still no established mouse model for MB relapse, impeding our efforts to develop strategies to treat relapsed MB. We present a protocol for generating a mouse model for relapsed MB using irradiation by optimizing mouse breeding and age, as well as irradiation dosage and timing. We then detail procedures for determining tumor relapse based on tumor cell trans-differentiation in MB tissue, immunohistochemistry, and tumor cell isolation.For complete details on the use and execution of this protocol, please refer to Guo et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a type of autoimmune encephalitis. The underlying mechanism(s) remain largely unknown. Recent evidence has indicated that the gut microbiome may be involved in neurological immune diseases via the "gut-brain axis". This study aimed to explore the possible relationship between anti-NMDAR encephalitis and the gut microbiome. Methods Fecal specimens were collected from 10 patients with anti-NMDAR encephalitis and 10 healthy volunteers. The microbiome analysis was based on Illumina sequencing of the V3-V4 hypervariable region of the 16S rRNA gene. The alpha, beta, and taxonomic diversity analyses were mainly based on the QIIME2 pipeline. Results There were no statistical differences in epidemiology, medication, and clinical characteristics (except for those related to anti-NMDAR encephalitis) between the two groups. ASV analysis showed that Prevotella was significantly increased, while Bacteroides was reduced in the gut microbiota of the patients, compared with the controls. Alpha diversity results showed a decrease in diversity in the patients compared with the healthy controls, analyzed by the Shannon diversity, Simpson diversity, and Pielou_E uniformity based on the Kruskal–Wallis test (P = 0.0342, 0.0040, and 0.0002, respectively). Beta diversity analysis showed that the abundance and composition of the gut microbiota was significantly different between the two groups, analyzed by weighted and unweighted UniFrac distance (P = 0.005 and 0.001, respectively). Conclusions The abundance and evenness of bacterial distribution were significantly lower and jeopardized in patients with anti-NMDAR encephalitis than in healthy controls. Thus, our findings suggest that gut microbiome composition changes might be associated with the anti-NMDAR encephalitis. It could be a causal agent, or a consequence.

ObjectivesIGU (IGU), a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective and safe as monotherapy in a small population with refractory lupus nephritis (LN). The aim of this prospective study was to evaluate the efficacy and safety of IGU as an add-on therapy in patients with refractory LN in the context of clinical practice.MethodsThis is a single-arm observational study. We have enrolled LN patients since 2019 at Renji Hospital. All participants should have recurrent or refractory LN with at least one immunosuppressant (IS) and have a baseline urine protein/creatinine ratio (UPCR) >1.0. After enrollment, we added IGU (25 mg twice daily) to one of their previous immunosuppressants (IS) without increasing the dose of steroids. The primary outcome was the complete renal response (CRR) in the 6th month. UPCR decrease of over 50% was defined as partial response (PR). Extended follow-up was performed after the initial 6 months.ResultsWe enrolled 26 eligible participants. 11/26 patients had chronic kidney disease (CKD) stage 2/3 at the baseline. The IS combined with IGU included mycophenolate mofetil, tacrolimus, and cyclosporin A. No IS change was allowed. 80.7% of patients had baseline steroids less than 0.5mg/kg daily and there was no steroids escalation during the IGU treatment. The CRR rate was 42.3% (11/26) at month 6. With a median follow-up of 52 weeks (range: 23-116 weeks), the CRR rate at the last visit was 50% (13/26) and 73.1% (19/26) of patients had UPCR decrease of over 50%. Six patients withdrew, three for no response and three for renal flare after initial CRR. One patient had an estimated glomerular filtration rate worsening of over 20% and was classified as renal flare. Three mild to moderate adverse events were recorded.ConclusionsOur investigation merits further investigation in IGU as a potentially tolerable component of combination therapy for refractory LN.

Objective To examine whether increases in physician volume in primary healthcare facilities are associated with reduced utilisation of hospital outpatient and inpatient services after China facilitated the establishment of the hierarchical medical system.Design We used a two-way fixed-effects regression to examine the association between the annual number of physicians in primary healthcare facilities and that of patient visits per physician, inpatient admissions and total expenses per outpatient visit in public hospitals during 2010–2014 and 2015–2019. Variables were log transformed to ensure the normal distribution of the data.Setting Province-level data of all 31 provinces in mainland China from 2010 to 2019 were collected from the China Health Statistics Yearbook published by the China Health Commission.Participants All 31 provinces in mainland China.Primary and secondary outcome measures The annual number of outpatient visits per physician, hospital admission and total expenses per outpatient visit in public hospitals.Results During 2015–2019, we found that, on average, a 1% increase in the number of primary healthcare physicians was accompanied by a 0.19% (95% CI −0.33% to −0.05%) reduction in the annual number of visits per physician in public hospitals, and a 0.31% (95% CI −0.52% to −0.10%) reduction in patient visits in city-administered hospitals. No significant associations were found between 2010 and 2014. We also did not observe any significant associations between primary healthcare physician volume and hospital admissions or outpatient expenses during neither 2010–2014 and 2015–2019.Conclusions In the context of the hierarchical medical system, enhancing physician volume in primary healthcare facilities helps reduce outpatient visits in public hospitals, especially city-administered hospitals. However, more efforts are required to be continuously made to improve primary healthcare capacity to avoid preventable hospital admissions and outpatient expenses.

Abstract Objectives Rheumatoid arthritis (RA) is a disease characterised by bone destruction and systemic inflammation, and interleukin‐6 (IL‐6) is a therapeutic target for treating it. The study aimed at investigating the sources of IL‐6 and the influence of hypoxia‐inducible factor‐1α (HIF‐1α) on IL‐6 production by B cells in RA patients. Methods The phenotype of IL‐6‐producing cells in the peripheral blood of RA patients was analysed using flow cytometry. Bioinformatics, real‐time polymerase chain reaction, Western blot and immunofluorescence staining were used to determine the IL‐6 production and HIF‐1α levels in B cells. A dual‐luciferase reporter assay and chromatin immunoprecipitation were used to investigate the regulatory role of HIF‐1α on IL‐6 production in human and mouse B cells. Results Our findings revealed that B cells are major sources of IL‐6 in the peripheral blood of RA patients, with the proportion of IL‐6‐producing B cells significantly correlated with RA disease activity. The CD27−IgD+ naïve B cell subset was identified as the typical IL‐6‐producing subset in RA patients. Both HIF‐1α and IL‐6 were co‐expressed by B cells in the peripheral blood and synovium of RA patients, and HIF‐1α was found to directly bind to the IL6 promoter and enhance its transcription. Conclusion This study highlights the role of B cells in producing IL‐6 and the regulation of this production by HIF‐1α in patients with RA. Targeting HIF‐1α might provide a new therapeutic strategy for treating RA.

With the US Food and Drug Administration (FDA) approval of four CD19- and one BCMA-targeted chimeric antigen receptor (CAR) therapy for B cell malignancies, CAR T cell therapy has finally reached the status of a medicinal product. The successful manufacturing of autologous CAR T cell products is a key requirement for this promising treatment modality. By analyzing the composition of 214 apheresis products from 210 subjects across eight disease indications, we found that high CD14+ cell content poses a challenge for manufacturing CAR T cells, especially in patients with non-Hodgkin’s lymphoma and multiple myeloma caused by the non-specific phagocytosis of the magnetic beads used to activate CD3+ T cells. We demonstrated that monocyte depletion via rapid plastic surface adhesion significantly reduces the CD14+ monocyte content in the apheresis products and simultaneously boosts the CD3+ content. We established a 40% CD14+ threshold for the stratification of apheresis products across nine clinical trials and demonstrated the effectiveness of this procedure by comparing manufacturing runs in two phase 1 clinical trials. Our study suggests that CD14+ content should be monitored in apheresis products, and that the manufacturing of CAR T cells should incorporate a step that lessens the CD14+ cell content in apheresis products containing more than 40% to maximize the production success.

Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up. Methods/design This study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test. Discussion Most patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20–35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients. Trial registration ClinicalTrials.gov NCT 02936375 . Registered on October 18, 2016.

Among all malignancies worldwide, gastric cancer is the fifth most common cancer with the third highest mortality rate. One of the main reasons for the low survival rate is the recurrence and metastasis that occurs in many patients after surgery. Numerous studies have shown that abnormal TRIM33 expression is associated with the progression of malignant tumors. TRIM33 can function either as a tumor suppressor or tumor promoter in different cancers. Our data showed that TRIM33 was highly expressed in stomach cancer, and in human gastric cancer tissues, low expression of TRIM33 was associated with poor prognosis in patients with gastric cancer. To clarify the function of TRIM33 in survival and epithelial–mesenchymal transition in gastric cancer cells, we investigated the effect of TRIM33 knockdown in several gastric cancer cell lines. Downregulation of TRIM33 in BGC-823 and SGC-7901 cells enhanced the proliferation, colony formation, and migratory ability of these gastric cancer cells. It also promoted epithelial–mesenchymal transition; transfection of cells with siRNA targeting TRIM33 led to the upregulation of vimentin and N-Cadherin expression, and downregulation of E-Cadherin expression. Meanwhile, the transforming growth factor beta pathway was activated: levels of transforming growth factor beta were elevated and the expressions of p-Smad2, Smad2, Smad3, and Smad4 were activated. To confirm the role of TRIM33 in vivo, a xenograft model was established in nude mice. Immunohistochemical analysis identified that the protein levels of TRIM33, p-Smad2, Smad2, Smad3, Smad4, vimentin, and N-Cadherin were increased, and E-Cadherin levels were decreased, in xenograft tumors from the si-TRIM33 group. Taken together, these results suggest that TRIM33 may be a potential marker for the diagnosis and prognosis of gastric cancer. Furthermore, it may also serve as a novel target for gastric cancer treatment.

Abstract. Background:. Clinical observational studies revealed that 99Tc-methylene diphosphonate (99Tc-MDP) could reduce joint pain and swollenness in rheumatoid arthritis (RA) patients. This multicenter, randomized, double-blind, double-dummy study aimed to evaluate the effects of 99Tc-MDP plus methotrexate (MTX) vs. MTX alone or 99Tc-MDP alone on disease activity and structural damage in MTX-naïve Chinese patients with moderate to severe RA. Methods:. Eligible patients with moderate to severely active RA were randomized to receive 99Tc-MDP plus MTX (n = 59) vs. MTX (n = 59) alone or 99Tc-MDP (n = 59) alone for 48 weeks from six study sites across four provinces in China. The primary outcomes were the American College of Rheumatology 20% improvement (ACR20) response rates at week 24 and changes in modified total Sharp score at week 48. Results:. At week 24, the proportion of participants achieving ACR20 was significantly higher in the MTX + 99Tc-MDP combination group (69.5%) than that in the MTX group (50.8%) or 99Tc-MDP group (47.5%) (P = 0.03 for MTX + 99Tc-MDP vs. MTX, and MTX + 99Tc-MDP vs.99Tc-MDP, respectively). The participants in the MTX + 99Tc-MDP group and the 99Tc-MDP group had significantly less important radiographic progression than the participants in the MTX group over the 48 weeks (MTX + 99Tc-MDP vs. MTX: P = 0.03, 99Tc-MDP vs. MTX: P = 0.03, respectively). There was no significant difference in terms of adverse events (AEs) among the groups. No serious AEs were observed. Conclusions:. This study demonstrated that the combination of 99Tc-MDP with MTX inhibited structural damage and improved disease activity in RA patients compared with MTX and 99Tc-MDP monotherapies, without increasing the rate of AEs. Additional clinical studies of 99Tc-MDP therapy in patients with RA are warranted. Trial Registration:. Chictr.org, ChiCTR-IPR-14005684; http://www.chictr.org.cn/showproj.aspx?proj=10088.

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is a central and acute demyelinating disease of the central nervous system with unusual clinical course. The development of novel biomarkers for NMOSD is critical for implementing effective clinical treatment. CD226 is known to be expressed on many types of peripheral lymphoid cells. However, the expression level and function of CD226 on type 1 T regulatory (Tr1) cells during NMOSD is unknown. Methods Eighteen patients with NMOSD and 10 healthy volunteers were enrolled in the test group to probe the difference of CD226 expression on Tr1 cells using flow cytometric analysis. Results The expression of CD226 on Tr1 cells exhibited significantly increased tendency in NMOSD patients. Additionally, methylprednisolone and rituximab treatment decreased the expression of CD226 on Tr1 cells. Furthermore, the expression of CD226 on Tr1 cells was correlated with disease severity. Conclusion This study provides a new basic insight into CD226 expression pattern on Tr1 cells, which have great potential to be biomarkers for monitoring the development and treatment of NMOSD.

ObjectiveTo investigate the microbial spectrum isolated from foot ulcers among diabetic patients in China, which was conducted to help clinicians choose optimal antibiotics empirically.MethodThe PubMed, MEDLINE, Web of Science, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), WanFang, and VIP databases were searched for studies published between 2015 to 2019, that report primary data on diabetic foot infection (DFI) and antibiotic susceptibility in China.ResultA total of 63 articles about DFI and antibiotic susceptibility tests among diabetic patients in China were included. There were 11,483 patients with an average age of 60.2 ± 10.1 years and a mean course of 10.6 ± 5.0 years between 2010 and 2019, covering most geographical regions of China. The prevalence of Gram-positive (GP) bacteria (43.4%) was lower than that of Gram-negative (GN) (52.4%). The most prevalent pathogens isolated were Staphylococcus aureus (17.7%), Escherichia coli (10.9%), Pseudomonas aeruginosa (10.5%), Klebsiella pneumoniae (6.2%), Staphylococcus epidermidis (5.3%), Enterococcus faecalis (4.9%), and fungus (3.7%). The prevalence of polymicrobial infection was 22.8%. GP bacteria were sensitive to linezolid, vancomycin, and teicoplanin. More than 50% of GN bacteria were resistant to third-generation cephalosporins, while the resistance rates of piperacillin/tazobactam, amikacin, meropenem, and imipenem were relatively low. Among the 6017 strains of the isolated organisms, 20% had multi-drug resistance (MDR). Staphylococcus aureus (30.4%) was the most predominant MDR bacteria, followed by extended-spectrum β-lactamase (ESBL) (19.1%).ConclusionThe microbial infection of foot ulcers among diabetic patients in China is diverse. The microbial spectrum is different in different geographic regions and Staphylococcus aureus is the predominant bacteria. Polymicrobial and MDR bacterial infections on the foot ulcers are common. This study could be valuable in guiding the empirical use of antibiotics for diabetic foot infections.

Abstract Background This study intends to investigate the immunological effects of tumor ablation with irreversible electroporation (IRE). Methods We evaluated the systemic immune response in patients with hepatocellular carcinoma (HCC) after IRE treatment. Furthermore, we analyzed the tumor infiltrating T lymphocytes and the level of serum cytokines in IRE and control groups of tumor-bearing mice. Results We observed that IRE induced an increase in WBC, neutrophil and monocyte counts and a decrease in lymphocyte count 1 day post-IRE and returned to baseline values within 7 days in the patients. Meanwhile, circulating CD4+ T cell subsets, but not CD8+, decreased 1 day post-IRE. The activated T cells and natural killer (NK) cells increased, and regulatory T (Treg) cells decreased. Furthermore, a significant increase in cytotoxic CD8+ T cells infiltration was observed on ablative tumors in mice. The level of serum IFN-γ also significantly increased in the IRE group. Conclusions Our study demonstrated that IRE upregulated activated T cells and downregulated Tregs in the peripheral blood of patients. Meanwhile, the results from the animal model indicated that IRE could induce antitumor adaptive immunity dominated by the infiltration of cytotoxic CD8+ T cells into the tumors, accompanied by reduced Tregs.

Abstract Background Rebound pain after a single-shot nerve block challenges the real benefit of this technique. We aimed to investigate whether perineural dexamethasone addition decreased the incidence of rebound pain after a single-shot nerve block. Methods We randomly allocated 132 patients scheduled for open reduction internal fixation of an upper extremity closed fracture under single-shot peripheral nerve block and sedation into two groups. Patients in the dexamethasone group received nerve block with 0.375% ropivacaine and 8 mg dexamethasone, while those in the control group received ropivacaine only. Sixty-three patients in the dexamethasone group and 60 patients in the control group were analyzed for the incidence of rebound pain 48 h after block administration, which was the primary outcome. The secondary outcomes included the highest self-reported numeric rating scale (NRS) pain score, and NRS at 8, 12, 24, and 48 h after the block, sufentanil consumption, sleep quality on the night of surgery, patient satisfaction with the pain therapy, blood glucose at 6 h after the block, pain and paresthesia at 30 days after surgery. Results The incidence of rebound pain was significantly lower in the dexamethasone group (7 [11.1%] of 63 patients) than in the control group (28 [48.8%] of 60 patients [RR = 0.238, 95% CI (0.113–0.504), p = 0.001]. Dexamethasone decreased opioid consumption in 24 h after surgery (p

Studying the hydrogeochemical characteristics of hot springs provides essential geochemical information for monitoring earthquake precursors and understanding the relationship between fluids, fractures, and earthquakes. This paper investigates the hydrogeochemical characteristics of hot springs along the Tingri–Nyima Rift (TNR) in southern Tibet, a seismically active zone at the collision front of the Indian and Asian-European plates. The major elements, hydrogen, and oxygen isotopes of seven thermal springs were analyzed from July 2019 to September 2021. The findings indicate that Mount Everest’s meteoric water, which has a recharge elevation of roughly 7.5–8.4 km, is the main source of recharge for the hot springs. The water samples have two main hydrochemical types: HCO3-Na and Cl-Na. The temperature of the geothermal reservoir is between 46.5 and 225.4 °C, while the circulation depth is between 1.2 and 5.0 km based on silica-enthalpy mixing models and traditional geothermometers. Furthermore, continuous measurements of major anions and cations at the Yundong Spring (T06) near Mount Everest reveal short-term (8 days) seismic precursor anomalies of hydrochemical compositions before an ML4.7 earthquake 64.36 km away from T06. Our study suggests that seismicity in the northern section of the TNR is controlled by both hydrothermal activity and tectonic activity, while seismicity in the southern section is mainly influenced by tectonic activity. In addition to magnitude and distance from the epicenter, geological forces from deep, large fissures also affect how hot springs react to seismic occurrences. A fluid circulation model is established in order to explain the process of groundwater circulation migration. The continuous hydrochemical monitoring of hot springs near Everest is critical for studying the coupling between hot springs, fractures, and earthquakes, as well as monitoring information on earthquake precursory anomalies near Everest.

Cerebrovascular events, especially ischemic stroke, are common complications of essential thrombocythemia (ET). Compared to JAK2V617 F mutation, CALR mutation is considered as a lower risk factor of thrombosis in ET. Until now stroke in ET with CALR mutation has rarely been reported. We retrospectively investigated patients diagnosed with stroke and ET in Xijing hospital of Air Force Medical University, from 2015 to 2021. Clinical characteristics (including medical history, physical and auxiliary examination and prognosis) were recorded and associated literature was reviewed. Among the 19 patients diagnosed with both stroke and ET we retrieved, two cases were positive for CALR mutation. In case 1, a 71-year-old man developed the first ischemic event under the treatment of anagrelide, followed by a hemorrhagic stroke after receiving aspirin and clopidogrel for 4 months. Ischemic stroke reccurred and the neurological function deteriorated progressively. In case 2, a 44-year-old man presented with hypoxic-ischemic encephalopathy due to serious myocardial infarction and subsequent brain imaging indicated three times of ischemic stroke events. The patient gradually got improved through cytoreductive and antiplatelet therapy and rehabilitation. Literature review showed that cerebrovascular event is the most serious neurological complication of ET and may be the presenting symptom. Most of reported cases with ET accompanied by stroke were positive for JAK2 V617 F mutation, but with rare CALR mutation. ET with CALR mutation can cause both hemorrhagic and ischemic stroke. Identification of such rare causes of stroke is of great importance to provide precise and individualized prevention and therapy.

The toxic high-temperature fire smoke plume in tunnel fire will seriously threaten the safety of personnel and tunnel structure. Therefore, it is very important to study the fire smoke plume movement law in tunnel fire for controlling and exhausting smoke. However, previous studies mainly focused on single fire source. In fact, most of the catastrophic fires have multiple fire sources. When multiple fires burn at the same time, the competitive entrainment air will cause the flame to tilt and even merge with each other, which will increase the burning rate and accelerate the spread of the fire. In this paper, the influence of fire heat release rate and distance between fires on fire smoke plume generation in tunnel is studied by a series of numerical simulations. The investigation results show that when the spacing is non-zero, the fire smoke plume generation rate is greater than that when the spacing is zero, because of the additional entrainment region. The fire smoke plume generation rate increases with HRR in spreading stage tunnel fire. In addition, a prediction model considering the heat release rate and burner edge spacing is proposed.

ObjectiveThe significance of anti-dense fine speckles 70 (DFS70) antibodies in systemic lupus erythematosus (SLE) is still unclear, especially in lupus nephritis (LN) patients. We investigated the prevalence, clinical and pathological relevance of anti-DFS70 antibodies in LN patients.MethodsAnti-DFS70 antibodies were measured using enzyme-linked immunosorbent assays in 377 biopsy-proven LN patients, 268 non-LN SLE patients, 232 chronic kidney disease (CKD) patients, and 78 healthy individuals (HI). Demographic, clinical, and pathological parameters were compared between LN patients with and without anti-DFS70 antibodies. Stepwise multivariable logistic regression was performed to identify covariates associated with anti-DFS70 antibodies.ResultsThe prevalence of anti-DFS70 antibodies in LN (19.6%) was comparable to non-LN SLE patients (19.8%, P=0.9630), but was significantly higher than CKD patients (13.4%, P=0.0468) and HI (9.0%, P=0.0252). Using multivariable logistic regression analysis, the titer of anti-double-stranded DNA (dsDNA) antibodies (adjusted odds ratio=1.002, 95% confidence interval 1.001-1.003, P=0.004) was associated with positive anti-DFS70 antibodies in LN patients. In addition, anti-DFS70 antibodies were more prevalent in proliferative LN (22.0%, 68/309) compared to membrane LN patients (10.2%, 6/59, P=0.0376). Furthermore, LN patients with positive anti-DFS70 antibodies had significantly higher activity index (AI) compared to patients who were negative (8.0 vs 6.0, P=0.0131). However, the chronicity index was similar between the groups (3.0 vs 3.0, P=0.8412).ConclusionAnti-DFS70 antibodies were not associated with LN development in SLE patients but were associated with anti-dsDNA antibodies, proliferative LN, and renal AI. This suggests their potential to serve as a non-histological biomarker for LN subclass and activity status.

Abstract Background A number of simulators have been developed for emulating next-generation sequencing data by incorporating known errors such as base substitutions and indels. However, their practicality may be degraded by functional and runtime limitations. Particularly, the positional and genomic contextual information is not effectively utilized for reliably characterizing base substitution patterns, as well as the positional and contextual difference of Phred quality scores is not fully investigated. Thus, a more effective and efficient bioinformatics tool is sorely required. Results Here, we introduce a novel tool, SimuSCoP, to reliably emulate complex DNA sequencing data. The base substitution patterns and the statistical behavior of quality scores in Illumina sequencing data are fully explored and integrated into the simulation model for reliably emulating datasets for different applications. In addition, an integrated and easy-to-use pipeline is employed in SimuSCoP to facilitate end-to-end simulation of complex samples, and high runtime efficiency is achieved by implementing the tool to run in multithreading with low memory consumption. These features enable SimuSCoP to gets substantial improvements in reliability, functionality, practicality and runtime efficiency. The tool is comprehensively evaluated in multiple aspects including consistency of profiles, simulation of genomic variations and complex tumor samples, and the results demonstrate the advantages of SimuSCoP over existing tools. Conclusions SimuSCoP, a new bioinformatics tool is developed to learn informative profiles from real sequencing data and reliably mimic complex data by introducing various genomic variations. We believe that the presented work will catalyse new development of downstream bioinformatics methods for analyzing sequencing data.

Abstract Objectives Iguratimod, a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective against murine lupus. The aim of this study was to make a preliminary evaluation of the efficacy and safety of iguratimod as salvage therapy in patients with refractory lupus nephritis (LN). Methods We enrolled eligible patients with refractory LN, which we defined as having failed or relapsed on at least two immunosuppressant agents. After enrollment, we substituted iguratimod (25 mg twice daily) for their previous immunosuppressant agents without increasing the dose of steroids. The primary outcome was complete/partial remission (PR/CR) at week 24. Patients who achieved remission continued iguratimod as maintenance therapy over an extended follow-up. Results The study cohort comprised 14 patients with refractory LN, 10 of whom had recent treatment failure and 4 repeated relapses with inadequate initial responses. At enrollment, none of the patients had detectable evidence of extra-renal involvement. The median prednisone dosage was 10 mg/d (IQR 0–10 mg/day). Thirteen patients were eligible for response evaluation, with one patient missed. The renal response rate was 92.3% (12/13) at week 24, with 38.5% (5/13) achieving CR and 53.8% (7/13) achieving PR. We then continued to follow up the responding patients for up to 144 weeks. Twenty-five percent of the patients (3/12) had renal relapse after initial PR. The estimated glomerular filtration rate of all patients maintained stable during follow-up. One patient had a severe adverse reaction (anemia) but recovered fully after stopping iguratimod. Conclusions Our study supports the potential of iguratimod for treatment of refractory LN. Iguratimod could be a promising candidate drug for this condition.

With the development of artificial intelligence technology, agricultural robot plays a significantly important role for agricultural intelligence. Crop row line detection is a critical and fundamental step for agricultural robot navigation. Although there are some crop row lines detection methods, few of them can meet the real-time requirement for agricultural robot under complex fields conditions. In view of this, a real-time crop detection system implemented on a SoC FPGA (System-on-a-Chip Field Programmable Gate Array) is first proposed in this paper, which contains crop segmentation and crop row detection, where we design parallel pipeline architecture to enhance real-time performance by using line buffer and sliding windows technologies. At the same time, the fixed point representation is used to reduce the memory resource in this system. The proposed system is evaluated and implemented on Xilinx Zynq UltraScale+ MPSoC ZCU102 SoC-FPGA. The experimental results show that the proposed system can process an image with 1920×1080 resolution only within 210 ms with the average accuracy of 89.7%, which satisfies the real-time requirements of the crop rows recognition.

Radiofrequency ablation (RFA) has been clinically used as a minimally invasive procedure for the treatment of many solid tumors. However, the current imaging techniques have some shortages in RFA guidance, especially for the assessment of the margin of ablation. Herein, we developed a novel optical imaging platform to guide RFA utilizing fluorescence resonance energy transfer from a thermally sensitive fluorescent protein conjugated to a near-infrared fluorescent dye. Additionally, attaching receptor-targeting ligands further equipped the system with high specificity to tumors overexpressing the targeted receptor.

In order to improve the effect of college English teaching reform, this paper combines information technology to improve the college English teaching mode. According to the digital processing requirements of English teaching resources, in order to make the loop establishment circuit time of automatic gain control independent of the input signal, this paper uses a logarithmic amplifier to detect it. Moreover, this paper combines the SC algorithm and the SC algorithm based on the time-domain PN sequence to propose a new frame synchronization algorithm. The algorithm has precise frame synchronization points and reduces the usage of hardware resources. Finally, this paper constructs a college English teaching system based on information technology. The experimental research results show that the college English teaching system based on information technology proposed in this paper has a good teaching effect.

Ischemic stroke caused by arterial occlusion is the most common type of stroke and is one of the leading causes of disability and death, with the incidence increasing each year. Fyn is a nonreceptor tyrosine kinase belonging to the Src family of kinases (SFKs), which is related to many normal and pathological processes of the nervous system, including neurodevelopment and disease progression. In recent years, more and more evidence suggests that Fyn may be closely related to cerebral ischemia-reperfusion, including energy metabolism disorders, excitatory neurotoxicity, intracellular calcium homeostasis, free radical production, and the activation of apoptotic genes. This paper reviews the role of Fyn in the pathological process of cerebral ischemia-reperfusion, including neuroexcitotoxicity and neuroinflammation, to explore how Fyn affects specific signal cascades and leads to cerebral ischemia-reperfusion injury. In addition, Fyn also promotes the production of superoxide and endogenous NO, so as to quickly react to produce peroxynitrite, which may also mediate cerebral ischemia-reperfusion injury, which is discussed in this paper. Finally, we revealed the treatment methods related to Fyn inhibitors and discussed its potential as a clinical treatment for ischemic stroke.

BackgroundTo investigate the association of D-dimer with gut inflammation in spondyloarthritis (SpA).MethodsSixty-five patients with SpA and 70 healthy controls were included. Demographic, clinical, and laboratory parameters were collected. The differences of clinical and laboratory parameters were compared between patients with SpA and healthy controls, and between patients with SpA, with and without gut inflammation. The associations of D-dimer with laboratory data were analyzed. The predictive value of D-dimer was obtained by a receiver operator characteristic (ROC) curve analysis. The independent risk factors for gut inflammation in SpA were investigated by binary logistic regression analysis.ResultsPatients with SpA had higher D-dimer than healthy controls (P = 0.016). D-dimer was positively correlated with platelet (PLT), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), and negatively correlated with hemoglobin (Hb). Besides, significant differences were observed in D-dimer between SpA patients with and without gut inflammation (P < 0.001). Furthermore, SpA patients with gut inflammation were more likely to have peripheral joint involvement than those without gut inflammation (P < 0.001). The AUC of D-dimer was 0.865 at cut-off value of 0.29 mg/L, with a sensitivity of 82.6%, and a specificity of 81%. Elevated D-dimer (OR = 15.451, 95% CI: 3.030–78.780, P = 0.001) was independently associated with gut inflammation in SpA.ConclusionD-dimer may be a potential biomarker for identifying SpA patients with gut inflammation.

Single-cell DNA sequencing (scDNA-seq) enables high-resolution profiling of genetic diversity among single cells and is especially useful for deciphering the intra-tumor heterogeneity and evolutionary history of tumor. Specific technical issues such as allele dropout, false-positive errors, and doublets make scDNA-seq data incomplete and error-prone, giving rise to a severe challenge of accurately inferring clonal architecture of tumor. To effectively address these issues, we introduce a new computational method called SCClone for reasoning subclones from single nucleotide variation (SNV) data of single cells. Specifically, SCClone leverages a probability mixture model for binary data to cluster single cells into distinct subclones. To accurately decipher underlying clonal composition, a novel model selection scheme based on inter-cluster variance is employed to find the optimal number of subclones. Extensive evaluations on various simulated datasets suggest SCClone has strong robustness against different technical noises in scDNA-seq data and achieves better performance than the state-of-the-art methods in reasoning clonal composition. Further evaluations of SCClone on three real scDNA-seq datasets show that it can effectively find the underlying subclones from severely disturbed data. The SCClone software is freely available at https://github.com/qasimyu/scclone.

General anesthesia has been shown to induce significant changes in the functional connectivity of the cerebral cortex. However, traditional methods such as electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) lack the spatial resolution to study the effects of general anesthesia on individual cortical neurons. This study aimed to use high-resolution two-photon imaging, which can provide single-neuron resolution, to investigate the characteristics of consciousness under general anesthesia. We used C57BL/6J and Thy1-GCamp6s mice and found that at similar levels of sedation, as measured by EEG, dexmedetomidine did not significantly inhibit the spontaneous activity of neuronal somata in the S1 cortex, but preserved the frequency of calcium events in neuronal spines. In contrast, propofol and ketamine dramatically inhibited the spontaneous activity of both neuronal somata and spines. The S1 cortex still responded to whisker stimulation under dexmedetomidine anesthesia, but not under propofol or ketamine anesthesia. Our results suggest that dexmedetomidine anesthesia has unique neuronal properties associated with its ability to facilitate easy awakening in the clinic. These findings provide insights into the development of more effective strategies for monitoring consciousness during general anesthesia.

Abstract The Anninghe fault (ANHF) and the Zemuhe fault (ZMHF), located in the southeast of the Tibetan Plateau, have a high level of seismic hazard and are among the most active faults in China. This study performed the first measurements of soil gas CO2 at three sites across the ANHF and the ZMHF. The fault locking (FL) depth and extent of different segments of the ANHF and the ZMHF were inverted using the negative dislocation model based on global positioning system velocity data acquired during 2009–2015. Results showed that the degassing intensity of CO2 in the ZMHF is substantially higher than in the ANHF, which is spatially consistent with the degree of inverted FL. The inversion results revealed that the level of coupling, including the locking depth and extent, along the southern segment of the ANHF is markedly greater than in the northern segment of the ZMHF. Soil gas CO2 geochemistry yielded different spatially anomalous features, indicating that the faults have different properties and permeability. The intensive locking of the ANHF and ZMHF segments has reduced permeability through self‐sealing processes, which has restricted the escape of gas from the deep crust. Correspondingly, a creeping fault with a low level of coupling could maintain high permeability, which would be favorable for CO2 migration.

Structural network pruning is an effective way to reduce network size for deploying deep networks to resource-constrained devices. Existing methods mainly employ knowledge distillation from the last layer of network to guide pruning of the whole network, and informative features from intermediate layers are not yet fully exploited to improve pruning efficiency and accuracy. In this paper, we propose a block-wisely supervised network pruning (BNP) approach to find the optimal subnet from a baseline network based on knowledge distillation and Markov Chain Monte Carlo. To achieve this, the baseline network is divided into small blocks, and block shrinkage can be independently applied to each block under a same manner. Specifically, block-wise representations of the baseline network are exploited to supervise subnet search by encouraging each block of student network to imitate the behavior of the corresponding baseline block. A score metric measuring block accuracy and efficiency is assigned to each block, and block search is conducted under a Markov Chain Monte Carlo scheme to sample blocks from the posterior. Knowledge distillation enables effective feature representations of the student network, and Markov Chain Monte Carlo provides a sampling scheme to find the optimal solution. Extensive evaluations on multiple network architectures and datasets show BNP outperforms the state of the art. For instance, with 0.16% accuracy improvement on the CIFAR-10 dataset, it yields a more compact subnet of ResNet-110 than other methods by reducing 61.24% FLOPs.

Single-cell sequencing (SCS) now promises the landscape of genetic diversity at single cell level, and is particularly useful to reconstruct the evolutionary history of tumor. There are multiple types of noise that make the SCS data notoriously error-prone, and significantly complicate tumor tree reconstruction. Existing methods for tumor phylogeny estimation suffer from either high computational intensity or low-resolution indication of clonal architecture, giving a necessity of developing new methods for efficient and accurate reconstruction of tumor trees. We introduce GRMT (Generative Reconstruction of Mutation Tree from scratch), a method for inferring tumor mutation tree from SCS data. GRMT exploits the k-Dollo parsimony model to allow each mutation to be gained once and lost at most k times. Under this constraint on mutation evolution, GRMT searches for mutation tree structures from a perspective of tree generation from scratch, and implements it to an iterative process that gradually increases the tree size by introducing a new mutation per time until a complete tree structure that contains all mutations is obtained. This enables GRMT to efficiently recover the chronological order of mutations and scale well to large datasets. Extensive evaluations on simulated and real datasets suggest GRMT outperforms the state-of-the-arts in multiple performance metrics. The GRMT software is freely available at https://github.com/qasimyu/grmt.

AIM: To investigate the effect of cardiovascular risk factors on the occurrence of nonarteritic anterior ischemic optic neuropathy(NAION)and visual functions of the patients.METHODS: Sixty-eight patients diagnosed as initial ipsilateral NAION(68 eyes)in NAION group and another 68 patients(68 eyes)matched in age, gender and systemic diseases in Control group were selected from June 2014 to June 2016 were enrolled in this study and evaluated for their levels of homocysteine(Hcy), blood lipids, folic acid and vitamin B12, as well as carotid Doppler ultrasonography. The visual functions were also examined in patients with NAION.RESULTS: The levels of Hcy(24.8±13.9μmol/L), total plasma cholesterol(4.5±1.0mmol/L), triglyceride(2.0±0.9 mmol/L)and low-density lipoprotein(2.9±0.8mmol/L)in NAION patients were significantly higher(PPCONCLUSION: Hyperhomocysteinemia, hyperlipidemia and low vitamin B12 are the risk factors of in NAION patients. These risk factors, however, are not related to the extent of visual field damage. To some extent, the amplitude and peak latency of visual evoked potentials can reflect the extent of visual field damage.