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Abstract Objectives The performance of the new Respiratory Pathogen panel (fluorescent probe melting curve, FPMC) for the qualitative detection of 12 organisms (chlamydia pneumoniae, mycoplasma pneumoniae, adenovirus, influenza A virus, influenza B virus, parainfluenza virus, rhinovirus, etc.) was assessed. Methods Prospectively collected nasopharyngeal swab (NPS) and sputum specimens (n = 635) were detected by using the FPMC panel, with the Sanger sequencing method as the comparative method. Results The overall percent concordance between the FPMC analysis method and the Sanger sequencing method was 100% and 99.66% for NPS and sputum specimens, respectively. The FPMC testified an overall positive percent concordance of 100% for both NPS and sputum specimens. The FPMC analysis method also testified an overall negative percent concordance of 100% and 99.38% for NPS and sputum specimens, respectively. Conclusions The FPMC analysis method is a stable and accurate assay for rapid, comprehensive detecting for respiratory pathogens.

Abstract Bladder carcinoma (BC) accounts for > 90% of all urothelial cancers. Pathological diagnosis through cytoscopic biopsy is the gold standard, whereas non-invasive diagnostic tools remain lacking. The “Atyp.C” parameter of the Sysmex UF-5000 urine particle analyzer represents the ratio of nucleus to cytoplasm and can be employed to detect urinary atypical cells. The present study examined the association between urinary Atyp.C values and BC risk. This two-center, retrospective case–control study identified clinical primary or newly recurrent BC (study period, 2022–2023; n = 473) cases together with controls with urinary tract infection randomly matched by age and sex (1:1). Urinary sediment differences were compared using non-parametric tests. The correlations between urinary Atyp.C levels and BC grade or infiltration were analyzed using Spearman’s rank correlation. The BC risk factor odds ratio of Atyp.C was calculated using conditional logistic regression, and potential confounder effects were adjusted using stepwise logistic regression (LR). Primary risk factors were identified by stratified analysis according to pathological histological diagnosis. The mean value of urinary Atyp.C in BC cases (1.30 ± 3.12) was 8.7 times higher than that in the controls (0.15 ± 0.68; P

Abstract Background Intracerebral hemorrhage (ICH) is a devastating neurological disease causing severe sensorimotor dysfunction and cognitive decline, yet there is no effective treatment strategy to alleviate outcomes of these patients. The Mas axis-mediated neuroprotection is involved in the pathology of various neurological diseases, however, the role of the Mas receptor in the setting of ICH remains to be elucidated. Methods C57BL/6 mice were used to establish the ICH model by injection of collagenase into mice striatum. The Mas receptor agonist AVE0991 was administered intranasally (0.9 mg/kg) after ICH. Using a combination of behavioral tests, Western blots, immunofluorescence staining, hematoma volume, brain edema, quantitative-PCR, TUNEL staining, Fluoro-Jade C staining, Nissl staining, and pharmacological methods, we examined the impact of intranasal application of AVE0991 on hematoma absorption and neurological outcomes following ICH and investigated the underlying mechanism. Results Mas receptor was found to be significantly expressed in activated microglia/macrophages, and the peak expression of Mas receptor in microglia/macrophages was observed at approximately 3–5 days, followed by a subsequent decline. Activation of Mas by AVE0991 post-treatment promoted hematoma absorption, reduced brain edema, and improved both short- and long-term neurological functions in ICH mice. Moreover, AVE0991 treatment effectively attenuated neuronal apoptosis, inhibited neutrophil infiltration, and reduced the release of inflammatory cytokines in perihematomal areas after ICH. Mechanistically, AVE0991 post-treatment significantly promoted the transformation of microglia/macrophages towards an anti-inflammatory, phagocytic, and reparative phenotype, and this functional phenotypic transition of microglia/macrophages by Mas activation was abolished by both Mas inhibitor A779 and Nrf2 inhibitor ML385. Furthermore, hematoma clearance and neuroprotective effects of AVE0991 treatment were reversed after microglia depletion in ICH. Conclusions Mas activation can promote hematoma absorption, ameliorate neurological deficits, alleviate neuron apoptosis, reduced neuroinflammation, and regulate the function and phenotype of microglia/macrophages via Akt/Nrf2 signaling pathway after ICH. Thus, intranasal application of Mas agonist ACE0991 may provide promising strategy for clinical treatment of ICH patients.

AbstractBackground Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with an increased risk of death, but its underlying mechanisms are not fully understood. Circular RNAs (circRNAs) have recently been implicated in various biological processes. The aim of this study was to investigate the key circRNAs related to RA.Methods A microarray assay was used to identify the differentially expressed circRNAs (DEcircRNAs) in peripheral blood mononuclear cells (PBMCs) from patients with RA compared to patients with osteoarthritis (OA) and healthy controls. Then, quantitative real-time PCR was applied to verify the DEcircRNAs, and correlations between the levels of DEcircRNAs and laboratory indices were analysed. We also performed extensive bioinformatic analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG) pathway and potential circRNA–miRNA–mRNA network analyses to predict the function of these DEcircRNAs.Results A total of 35,342 and 6146 DEcircRNAs were detected in RA patients compared to controls and OA patients, respectively. Nine out of the DEcircRNAs in RA were validated by real-time PCR. There were correlations between the levels of DEcircRNAs and some of the laboratory indices. GO analyses revealed that these DEcircRNAs in RA were closely related to cellular protein metabolic processes, gene expression, the immune system, cell cycle, posttranslational protein modification and collagen formation. Functional annotation of host genes of these DEcircRNAs was implicated in several significantly enriched pathways, including metabolic pathways, ECM–receptor interaction, the PI3K–Akt signalling pathway, the AMPK signalling pathway, leukocyte transendothelial migration, platelet activation and the cAMP signalling pathway, which might be responsible for the pathophysiology of RA.Conclusions The findings of this study may help to elucidate the role of circRNAs in the specific mechanism underlying RA.Key messagesMicroarray assays showed that a total of 35,342 and 6146 DEcircRNAs were detected in RA patients compared to controls and OA patients, respectively.Nine out of the DEcircRNAs in RA were validated by real-time PCR, and the levels of the DEcircRNAs were related to some of the laboratory indices.GO analyses revealed that the DEcircRNAs in RA were closely related to cellular protein metabolic processes, gene expression, the immune system, etc.Functional annotation of host genes of the DEcircRNAs in RA was implicated in several significantly enriched pathways, including metabolic pathways, ECM–receptor interaction, the PI3K–Akt signalling pathway, etc.

Abstract Background Serum exosomes play important roles in intercellular communication and are promising biomarkers of several autoimmune diseases. However, the biological functions and potential clinical importance of long non-coding RNAs (lncRNAs) and mRNAs from serum exosomes in rheumatoid arthritis (RA) have not yet been studied. Methods Serum exosomal lncRNAs and mRNAs were isolated from patients with RA and osteoarthritis (OA) and healthy controls. The differentially expressed lncRNAs (DE-lncRNAs) and mRNA profiles in the serum exosomes of patients with RA were analysed using high-throughput sequencing, and their functions were predicted using Gene Ontologyenrichment, Kyoto Encyclopedia of Genes and Genomes pathway, and gene set enrichment analysis. We constructed a DE-lncRNA-mRNA network and a protein–protein interaction network of differentially expressed mRNAs (DE-mRNAs) in RA using the Cytoscape software. The expression of several candidate a DE-lncRNAs and DE-mRNAs in the serum of patients with RA, patients with OA, and healthy controls was confirmed by qRT-PCR. We assessed the diagnostic ability of DE-lncRNAs and DE-mRNAs in patients with RA using receiver operating characteristic analysis. Furthermore, we analysed the characteristics of immune cell infiltration in RA by digital cytometry using the CIBERSORT algorithm and determined the correlation between immune cells and several DE-lncRNAs or DE-mRNAs in RA. Results The profiles of serum exosomal lncRNAs and mRNAs in patients with RA were different from those in healthy controls and patients with OA. The functions of both DE-lncRNAs and DE-mRNAs in RA are associated with the immune response and cellular metabolic processes. The RT-PCR results show that NONHSAT193357.1, CCL5, and MPIG6B were downregulated in patients with RA. The combination of three DE-mRNAs, CCL5, MPIG6B, and PFKP, had an area under the curve of 0.845 for differentiating RA from OA. Digital cytometry using the CIBERSORT algorithm showed that the neutrophil counts were higher in patients with RA than those in healthy controls and patients with OA. Conclusions These findings help to elucidate the role of serum exosomal lncRNAs and mRNAs in the specific mechanisms underlying RA.

Abstract Background Identification of factors relevant to balance performance impairments in the elderly population was critical for developing effective interventions and preventions. However, there have been very limited data available based on large scale studies. The present study identified factors that independently contributed to performance impairments in overall balance, domains of static balance, postural stability, and dynamic balance, and individual items. Methods A total of 1984 community-dwelling Chinese elderly from urban areas of Shanghai were recruited. Information on demographic characteristic, exercise, and health status were collected with a face-to-face interview. Balance performances were assessed on site by trained investigators based on the X16 balance testing scale. To identify the effectors, ordinal logistic regression analysis was applied for overall balance, static balance, postural stability, and dynamic balance. Binary logistic regression analysis was used for 16 items. Results The community-dwelling elderly residents were aged from 60 to 97 years old. With increases of age, risks of impairments in overall balance increased gradually (ORs from 1.26 to 3.20, all P

Abstract Background Several risk factors of immune checkpoint inhibitors (ICIs)-associated acute kidney injury (AKI) have been reported sporadically. To identify the risk factors of ICIs-associated AKI in a large-scale population, therefore we conducted a systematic review and a real-world retrospective study. Methods We search literature concerning risk factors of ICIs-associated AKI in ClinicalTrials.gov and electronic databases (PubMed, Cochrane Library, Embase) up to January 2022. Meta-analysis was performed by using odds ratios (ORs) with 95%CIs. In a separate retrospective pharmacovigilance study by extracting data from US FDA Adverse Event Reporting System (FAERS) database, disproportionality was analyzed using the reporting odds ratio (ROR). Results A total of 9 studies (5927 patients) were included in the meta-analysis. The following factors were associated with increased risk of ICIs-associated AKI, including proton pump inhibitors(PPIs) (OR = 2.07, 95%CI 1.78–2.42), angiotensin-converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) (OR = 1.56, 95%CI 1.24–1.95), nonsteroidal anti-inflammatory drugs (NSAIDs) (OR = 1.29, 95%CI 1.01–1.65), diuretics (OR = 2.00, 95%CI 1.38–2.89), diabetes mellitus (OR = 1.28, 95%CI 1.04–1.57), genitourinary cancer (OR = 1.46, 95%CI 1.15–1.85), combination therapy of ICIs (OR = 1.93, 95%CI 1.25–2.97) and extrarenal immune-related adverse events(irAEs) (OR = 2.51, 95%CI 1.96–3.20). Furthermore, analysis from FAERS database verified that concurrent exposures of PPIs (ROR = 2.10, 95%CI 1.91–2.31), ACEIs/ARBs (ROR = 3.25, 95%CI 2.95–3.57), NSAIDs (ROR = 3.06, 95%CI 2.81–3.32) or diuretics (ROR = 2.82, 95%CI 2.50–3.19) were observed significant signals associated with AKI in ICIs-treated patients. Conclusions Concurrent exposures of PPIs, ACEIs/ARBs, NSAIDs or diuretics, diabetes mellitus, genitourinary cancer, combination therapy, and extrarenal irAEs seem to increase the risk of AKI in ICIs-treated patients.

BackgroundDue to its nutritional advantages over total gastrectomy, proximal gastrectomy (PG) with anti-reflux techniques has gained significant attention in East Asian countries in recent years. The double flap technique (DFT) and modified side overlap and fundoplication by Yamashita (mSOFY) are two promising anti-reflux interventions following PG. However, anastomotic stenosis after DFT and gastroesophageal reflux after mSOFY have been reported in several patients. To address these concerns, a hybrid reconstruction procedure was designed, namely, right-sided overlap with single flap valvulopasty (ROSF), for proximal gastrectomy, with the aim of reducing anastomotic stricture and reflux. Among the 38 patients who underwent ROSF at our hospital, one developed Stooler grade II anastomotic stenosis. Herein, we present the successful management of this patient through endoscopic stricturotomy (ES).Case summaryA 72-year-old female complaining of “epigastric pain and discomfort for more than 1 month” was diagnosed with adenocarcinoma of the esophagogastric junction (Siewert type II). She underwent laparoscopic-assisted PG and ROSF procedures at our hospital and recovered well after surgery. However, she started experiencing progressive difficulty in eating and vomiting approximately 3 weeks after the intervention. Endoscopy revealed Stooler grade II esophagogastric anastomotic stenosis. ES with insulated tip (IT) Knife nano was eventually performed, and the patient was able to resume a normal diet without experiencing any discomfort during the 5-month follow-up period.ConclusionEndoscopic stricturotomy using IT Knife nano successfully treated anastomotic stenosis following ROSF with no associated complications. Thus, ES to treat anastomotic stenosis after PG with valvulopasty can be considered a safe option and should be performed in centers with the required expertise.

Abstract Engineered extracellular vesicles (EVs) are considered excellent delivery vehicles for a variety of therapeutic agents, including nucleic acids, proteins, drugs, and nanomaterials. Recently, several studies have indicated that clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated 9 (Cas9) delivered by EVs enable efficient DNA editing. However, an RNA editing tool delivered by EVs is still unavailable. Here, a signal peptide‐optimized and EVs‐delivered guide RNA (gRNA) and CRISPR/CasRx (Cas13d) system capable of rapidly inhibiting the expression of targeted genes with quick catabolism after performing their functions is developed. EVs with CRISPR/CasRx and tandem gRNAs targeting pivotal cytokines are further packed whose levels increase substantially over the course of acute inflammatory diseases and find that these engineered EVs inhibit macrophage activation in vitro. More importantly, this system attenuates lipopolysaccharide (LPS)‐triggered acute lung injury and sepsis in the acute phase, mitigating organ damage and improving the prognosis in vivo. In summary, a potent tool is provided for short‐acting RNA editing, which could be a powerful therapeutic platform for the treatment of acute diseases.

Abstract Background Colorectal poorly differentiated adenocarcinoma is rarely founded, especially in early-stage. Endoscopic features of early poorly differentiated colorectal cancer in magnifying endoscopy and chromoendoscopy haven’t been clarified. Case presentation A 49-year-old man was referred to our hospital for endoscopic treatment of a lateral spread tumor located in the rectum. We performed pre-resection endoscopic examination for the patient. In magnifying endoscopy with crystal violet staining, the lesion showed irregular microvessels and turned out to be poorly stained with predominantly non-structural pit pattern and a few roundish pits scattered on the surface. The histology revealed a poorly differentiated adenocarcinoma of the rectum invading the deep submucosal layer with negative lymphovascular invasion. Conclusions In this case report, we presented a case of poorly differentiated colorectal adenocarcinoma detected at an early stage, showing interesting endoscopic findings in magnifying endoscopy with crystal violet staining.

Abstract Background Verrucous cell carcinoma of the esophagus (VCCE) is an extremely rare tumor and generally detected at advanced stage. Despite of its slow growth and well differentiation, it has very poor prognosis with high mortality. Therefore, early detection is a critical to improve patients’ survival. However, no early cases of VCCE have been reported and the endoscopic features of early VCCE are not well described. We herein report the endoscopic and histologic features of an early VCCE. Case presentation A 54-year-old man with a history of excessive alcohol and tobacco use was admitted to our hospital because of chronic persistent swallowing dysfunction for six months. White light endoscopy revealed a flat lesion covered with scattered leukoplakia in the middle esophagus. Magnifying endoscopy with narrow-band imaging showed tiny irregular papillary microsurface structure. The lesion was considered as early esophageal cancer and completely resected with endoscopic submucosal dissection. Histological examination confirmed that the lesion was early VCCE which was limited within the mucosal lamina propria (m2). Conclusion VCCE is rare with poor prognosis. This is a report of early VCCE and description of its endoscopic features which will contribute to early detection of these cancers.

Abstract Background Population aging has been an emerging public and health concern globally. Balance performance can be applied as an indicator of functional status and a predictor of health outcomes in the elderly. However, reference data of balance performance in the elderly generated from large scale studies have been very limited. In research and geriatric assessment settings, the age and gender specific data on balance performance are indispensable prerequisites for identifying subpopulation with and at risk of impairments and subsequently implementing targeted interventions in clinics and public health to improve their balance performance. Methods A total of 1984 elderly subjects aged 60 to 97 years from community settings in urban China were investigated. The balance performances together with 3 individual domains and 16 items were evaluated using the X16 balance testing scale. Results In the elderly, with age increases each item, individual domain, and overall balance performance scores decreased gradually. Meanwhile, individual variations of individual domains and overall balance performance were all increased over age. Relative to levels of 60- years, postural stability and overall balance performance decreased significantly since 65 years old, static balance and dynamic balance capacities started to decrease significantly since 70 years old. There was no significant difference in each balance domain and overall balance performance between men and women. Across age groups, portions of individuals able to perform task 4, 8 and 11 successfully were the lowest amongst their corresponding domains static balance, postural stability, and dynamic balance, respectively. Similar patterns were observed in both men and women. Balance performances were categorized into poor, fair, and good groups with scores of 0 to 10, 11 to 17, and 18 to 20, respectively. With increases of age, proportions with poor and fair balance capacities elevated stably. Conclusions In the elderly, with advances in age, abilities of overall balance performance, individual domains of static balance, postural stability, and dynamic balance, and successful performances on specific tasks declined gradually and stably. The deterioration started to be obvious since 65–75 years. Men and women had similar patterns.

ObjectiveTo our knowledge, the impact of area-level socioeconomic status (SES) has not yet been described in primary central nervous system lymphomas (PCNSLs). Current study sought to explore the association of socioeconomic deprivation, measured using the Area Deprivation Index (ADI), with PCNSL outcomes.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to identify PCNSL patients diagnosed between 2006 and 2015 for our analyses. The impact of ADI on overall survival (OS) and cancer-specific survival (CSS) were investigated. Survival analyses were conducted using Kaplan-Meier method with log-rank tests. The Inverse Probability Weighting (IPW) analysis and multivariate cox proportional hazards regression analysis were employed to make covariate adjustments. Multiple mediation analysis (MMA) was performed to estimate the mediating effects.ResultsA total of 3159 PCNSL patients classified into low and high ADI subgroups according to the median ADI score were studied. The Kaplan-Meier analyses showed that low ADI was significantly associated with higher OS rates (HR 1.15, 95%CI 1.06-1.26, P

The B7-CD28 gene family plays a crucial role in modulating immune functions and has served as potential targets for immunotherapeutic strategies. Therefore, we systematically analyzed B7-CD28 family gene expression profiles and constructed a B7-CD28 family-based prognostic signature to predict survival and immune host status in diffuse gliomas. The TCGA dataset was used as a training cohort, and three CGGA datasets (mRNAseq_325, mRNAseq_693 and mRNA-array) were employed as validation cohorts to intensify the findings that we have revealed in TCGA dataset. Ultimately, we developed a B7-CD28 family-based signature that consisted of CD276, CD274, PDCD1LG2 and CD80 using LASSO Cox analysis. This gene signature was validated to have significant prognostic value, and could be used as a biomarker to distinguish pathological grade and IDH mutation status in diffuse glioma. Additionally, we found that the gene signature was significantly related to intensity of immune response and immune cell population, as well as several other important immune checkpoint genes, holding a great potential to be a predictive immune marker for immunotherapy and tumor microenvironment. Finally, a B7-CD28 family-based nomogram was established to predict patient life expectancy contributing to facilitate personalizing therapy for tumor sufferers. In summary, this is the first mathematical model based on this gene family with the aim of providing novel insights into immunotherapy for diffuse glioma.

A radial well has a unique wellbore configuration. Fracture propagation in radial well deflagration fracturing is studied rarely. The mechanism of interaction between deflagration fractures, natural fractures, and micro-fractures is still unknown. Based on continuum mechanics, damage mechanics, and variational principles, a numerical model of fracture propagation in deflagration fracturing is established with the Hamilton principle and phase-field fracture theory. The effects of horizontal principal stress difference, natural fracture distribution, and micro-fractures around the wellbore on fracture propagation in deflagration fracturing are studied. First, when no natural fractures are developed around the radial well, fractures are initiated at both ends of the radial well. Second, when there are three natural fractures around the radial well, the created fractures have the morphology of shorter fractures in the middle and longer fractures on both sides under stress interference mechanisms. Third, a larger density of natural fractures causes obvious stress superposition, changes the initiation points of radial wells and fracture morphology, and increases fracture width and reservoir stimulation volume. Fourth, as the micro-fractures increase, their interference and induction effects on deflagration fractures are enhanced gradually, and the deflection angle of fractures increases by 38.7%. The study provides a reference for optimizing deflagration fracturing in a radial well.

After multi-stage volume hydraulic fracturing in a shale oil reservoir, massive amounts of water can be imbibed into the matrix pores. One of the key imbibition characteristics of a shale reservoir is the imbibition water and its height distribution. Based on high pressure mercury injection (HPMI) experiments and nuclear magnetic resonance (NMR) analyses, this study quantitatively evaluated the pore-size distribution of Chang 7 continental shale oil reservoirs in Yanchang Formation, Ordos Basin. The pores could be divided into three types as micropores (≤0.1 μm), mesopores (0.1–1.0 μm), and macropores (>1.0 μm), while the volume of micropores and mesopores accounted for more than 90%. This demonstrated that there were strong heterogeneity and micro–nano characteristics. According to the spontaneous imbibition (SI) experiments, the cumulative proportion of imbibition water content was the largest in micropores, exceeding 43%, followed by mesopores around 30%, and that of macropores was the lowest, and basically less than 20%. The negative values of stage water content in the macropore or mesopore indicated that these pores became a water supply channel for other dominant imbibition pores. Additionally, combining the fractal theory with the NMR T2 spectrum, the relative imbibition water and actual height were calculated in different pores, while the height distribution varied with cores and shale oil. The shorter the core, the higher was the relative height, while the radius of macropores filled with imbibition water was reduced. This indicates that the height distribution was affected by the pore structure, oil viscosity, and core length.

Abstract The long-range temporal correlation (LRTC) in resting-state intrinsic brain activity is known to be associated with temporal behavioral patterns, including decision making based on internal criteria such as self-knowledge. However, the association between the neuronal LRTC and the subjective sense of identity remains to be explored; in other words, whether our subjective sense of consistent self across time relates to the temporal consistency of neural activity. The present study examined the relationship between the LRTC of resting-state scalp electroencephalography (EEG) and a subjective sense of identity measured by the Erikson Psychosocial Stage Inventory (EPSI). Consistent with our prediction based on previous studies of neuronal-behavioral relationships, the frontocentral alpha LRTC correlated negatively with identity confusion. Moreover, from the descriptive analyses, centroparietal beta LRTC showed negative correlations with identity confusion, and frontal theta LRTC showed positive relationships with identity synthesis. These results suggest that more temporal consistency (reversely, less random noise) in intrinsic brain activity is associated with less confused and better-synthesized identity. Our data provide further evidence that the LRTC of intrinsic brain activity might serve as a noise suppression mechanism at the psychological level.

Abstract Background Keshan disease is an endemic cardiomyopathy of undefined causes. Being involved in the unclear pathogenesis of Keshan disease, a clear diagnosis, and effective treatment cannot be initiated. However, the rapid development of gut flora in cardiovascular disease combined with omics and big data platforms may promote the discovery of new diagnostic markers and provide new therapeutic options. This study aims to identify biomarkers for the early diagnosis and further explore new therapeutic targets for Keshan disease. Methods This cohort study consists of two parts. Though the first part includes 300 participants, however, recruiting will be continued for the eligible participants. After rigorous screening, the blood samples, stools, electrocardiograms, and ultrasonic cardiogram data would be collected from participants to elucidate the relationship between gut flora and host. The second part includes a prospective follow-up study for every 6 months within 2 years. Finally, deep mining of big data and rapid machine learning will be employed to analyze the baseline data, experimental data, and clinical data to seek out the new biomarkers to predict the pathogenesis of Keshan disease. Discussion Our study will clarify the distribution of gut flora in patients with Keshan disease and the abundance and population changes of gut flora in different stages of the disease. Through the big data platform analyze the relationship between environmental factors, clinical factors, and gut flora, the main factors affecting the occurrence of Keshan disease were identified, and the changed molecular pathways of gut flora were predicted. Finally, the specific gut flora and molecular pathways affecting Keshan disease were identified by metagenomics combined with metabonomic analysis. Trial registration: ChiCTR1900026639. Registered on 16 October 2019.

Cellular markers of endothelial cell proliferation help identify the vasculature of tumours in homeostasis. Here, the authors report Apelin-based synthetic Notch (synNotch) receptors that can target Apj expressed on endothelium and stimulate the synNotch pathways upon Apj binding, and suggest this as a strategy to treat solid tumours.

Object detection of overhead transmission lines is a solution for promoting inspection efficiency for power companies. However, aerial images contain many complex backgrounds and small objects, and traditional algorithms are incompetent in the identification of details of power transmission lines accurately. To address this problem, this paper develops an object detection method based on optimized You Only Look Once v5-small (YOLOv5s). This method is designed to be engineering-friendly, with the objective of maximal detection accuracy and computation simplicity. Firstly, to improve the detecting accuracy of small objects, a larger scale detection layer and jump connections are added to the network. Secondly, a self-attention mechanism is adopted to merge the feature relationships between spatial and channel dimensions, which could suppress the interference of complex backgrounds and boost the salience of objects. In addition, a small object enhanced Complete Intersection over Union (CIoU) is put forward as the loss function of the bounding box regression. This loss function could increase the derived loss for small objects automatically, thereby improving the detection of small objects. Furthermore, based on the scaling factors of batch-normalization layers, a pruning method is adopted to reduce the parameters and achieve a lightweight method. Finally, case studies are fulfilled by comparing the proposed method with classic YOLOv5s, which demonstrate that the detection accuracy is increased by 4%, the model size is reduced by 58%, and the detection speed is raised by 3.3%.

Background: The association between immune checkpoint inhibitors (ICIs) and Stevens-Johnsons syndrome (SJS) /toxic epidermal necrolysis (TEN) is unclear. We assessed the risk of SJS and TEN related to ICIs, via a systematic analysis of SJS/TEN cases reported in clinical trials and the FDA Adverse Event Reporting System (FAERS). Methods: We explored ICIs related SJS/TEN events in randomized control trials available in ClinicalTrials.gov and electronic databases (Pubmed, Embase, the Cochrane Central Register of Controlled Trials) up to 12 January 2021. Meta-analysis was performed by using Peto odds ratios (ORs) with 95% CIs. In a separate retrospective pharmacovigilance study of FAERs, cases of ICIs related SJS/TEN were extracted between the first quarter (Q1) of 2004 and Q4 of 2020. Disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC). PROSPERO registration number: CRD42021232399. Findings: A total of 20 RCTs (11597 patients) were included. ICIs were associated with an increased risk of SJS/TEN (OR= 4.33, 95%CI:1.90–9.87). FAERS pharmacovigilance data identified 411 cases of SJS (n = 253) or TEN (n = 184) related to ICIs therapy. ICIs were significantly associated with SJS/TEN (n = 411; ROR=2.88, 95%CI:2.61–3.17; IC=1.49, 95%CI:1.35–1.65). The median onset time of SJS/TEN was 25.5 days (SJS:21.5 days; TEN:32 days) (n = 190), 97.5% of patients discontinued use of ICIs when suffering from SJS/TEN (n = 201). Of 305 cases that reported outcomes, 113 (37%) resulted in death (SJS:19.9%, TEN:61.6%). Interpretation: These data suggest that ICIs were significantly associated with increased risk of SJS/TEN.

Polystyrene nanoparticles (PS-NPs) are organic pollutants that are widely detected in the environment and organisms, posing potential threats to both ecosystems and human health. PS-NPs have been proven to penetrate the blood–brain barrier and increase the incidence of neurodegenerative diseases. However, information relating to the pathogenic molecular mechanism is still unclear. This study investigated the neurotoxicity and regulatory mechanisms of PS-NPs in human neuroblastoma SHSY-5Y cells. The results show that PS-NPs caused obvious mitochondrial damages, as evidenced by inhibited cell proliferation, increased lactate dehydrogenase release, stimulated oxidative stress responses, elevated Ca2+ level and apoptosis, and reduced mitochondrial membrane potential and adenosine triphosphate levels. The increased release of cytochrome c and the overexpression of apoptosis-related proteins apoptotic protease activating factor-1 (Apaf-1), cysteinyl aspartate specific proteinase-3 (caspase-3), and caspase-9 indicate the activation of the mitochondrial apoptosis pathway. In addition, the upregulation of autophagy markers light chain 3-II (LC3-II), Beclin-1, and autophagy-related protein (Atg) 5/12/16L suggests that PS-NPs could promote autophagy in SHSY-5Y cells. The RNA interference of Beclin-1 confirms the regulatory role of autophagy in PS-NP-induced neurotoxicity. The administration of antioxidant N-acetylcysteine (NAC) significantly attenuated the cytotoxicity and autophagy activation induced by PS-NP exposure. Generally, PS-NPs could induce neurotoxicity in SHSY-5Y cells via autophagy activation and mitochondria dysfunction, which was modulated by mitochondrial oxidative stress. Mitochondrial damages caused by oxidative stress could potentially be involved in the pathological mechanisms for PS-NP-induced neurodegenerative diseases.

BackgroundGastric cancer (GC) is one of the most common malignancies in the world, and the fourth most frequent malignancy worldwide. YTHDF2 (YTH domain family 2, YTHDF2) binds to mRNA containing m6A, thereby regulating the localization and stability of the bound mRNA. YTHDF2 was shown to be associated with some cancer patient prognosis. However, the effect of YTHDF2 on gastric cancer and the molecular mechanism of this effect have not been documented.MethodsTo conduct this research, YTHDF2 expression levels in public databases and gastric cancer patient samples were analyzed. The effects of YTHDF2 on the growth of gastric cancer cells were detected in vivo and in vitro. RNA-seq was used to analyze the signal pathways regulated by YTHDF2, and experiments were carried out for verification.ResultsIn our study, we found that YTHDF2 has lower expression in GC tissues and GC cells, and inhibits the growth of GC cells. In addition, the analysis of clinical data found that the expression level of YTHDF2 is closely related to the stage of GC and the survival of patients with GC. RNA sequencing results showed that overexpression of YTHDF2 significantly reduced protein expression in the FOXC2 (Forkhead box protein C2, FOXC2) signaling pathway. Finally, we found that knockout of FOXC2 reversed the inhibitory effect of YTHDF2 on GC cells.ConclusionIn summary, YTHDF2 inhibits the growth of GC cells by negatively regulating FOXC2 and may serve as a prognostic marker in GC.

[This corrects the article DOI: 10.1371/journal.pone.0244434.].

The value learning process has been investigated using decision-making tasks with a correct answer specified by the external environment (externally guided decision-making, EDM). In EDM, people are required to adjust their choices based on feedback, and the learning process is generally explained by the reinforcement learning (RL) model. In addition to EDM, value is learned through internally guided decision-making (IDM), in which no correct answer defined by external circumstances is available, such as preference judgment. In IDM, it has been believed that the value of the chosen item is increased and that of the rejected item is decreased (choice-induced preference change; CIPC). An RL-based model called the choice-based learning (CBL) model had been proposed to describe CIPC, in which the values of chosen and/or rejected items are updated as if own choice were the correct answer. However, the validity of the CBL model has not been confirmed by fitting the model to IDM behavioral data. The present study aims to examine the CBL model in IDM. We conducted simulations, a preference judgment task for novel contour shapes, and applied computational model analyses to the behavioral data. The results showed that the CBL model with both the chosen and rejected value's updated were a good fit for the IDM behavioral data compared to the other candidate models. Although previous studies using subjective preference ratings had repeatedly reported changes only in one of the values of either the chosen or rejected items, we demonstrated for the first time both items' value changes were based solely on IDM choice behavioral data with computational model analyses.

Engineered T cells therapy holds promise for glioblastoma (GBM) therapy. Genetic modification of T-lymphocytes, using T cell receptors, chimeric antigen receptors, and others, is an attractive antitumor strategy, especially in large solid tumors. Recently, several clinical trials have shown an impressive tumor regression in GBM patients, demonstrating the therapeutic potential of this approach. Still, major challenges, such as antigen specificity, tumor trafficking, hostile immunosuppressive microenvironment, proliferation and persistence of T cells and unexpected adverse effects, may hinder the clinical benefit of this approach. In the present review, we summarize recent developments of engineered T cells therapy against GBM, its challenges and future.

Fetal trabecular muscles in the heart undergo a poorly described morphogenetic process that results into a solidified compact myocardium after birth. Tian et al. show that cardiomyocytes in the fetal compact layer also contribute to this process, forming a hybrid myocardial zone that is composed of cells derived from both trabecular and compact layers.

Although the mechanisms of Alzheimer’s disease are diverse and unclear, the past 20 years have witnessed the unprecedented development of the AD inflammation theory. As a key inflammatory receptor family, the C-C chemokine receptor family is a remarkable participant in the cause of Alzheimer’s disease; of this family, CCR5 is the most widely studied. CCR5 is an essential entrance when HIV infects immune cells and is also involved in other inflammatory and immune activities. New evidence on the inevitably intertwined link between Alzheimer’s disease and CCR5 indicates that CCR5 accelerates the development of Alzheimer’s disease, and few studies disputed it. The role of CCR5 in Alzheimer’s disease remains elusive. However, as the research progresses, this intricate relationship will gradually be uncovered.

The definition of consciousness remains a difficult issue that requires urgent understanding and resolution. Currently, consciousness research is an intensely focused area of neuroscience. However, to establish a greater understanding of the concept of consciousness, more detailed, intrinsic neurobiological research is needed. Additionally, an accurate assessment of the level of consciousness may strengthen our awareness of this concept and provide new ideas for patients undergoing clinical treatment of consciousness disorders. In addition, research efforts that help elucidate the concept of consciousness have important scientific and clinical significance. This review presents the latest progress in consciousness research and proposes our assumptions with regard to the network of consciousness.

Induced pluripotent stem cells (iPS cells) are promising cell source for stem cell replacement strategy applied to brain injury caused by traumatic brain injury (TBI) or stroke. Neural stem cell (NSCs) derived from iPS cells could aid the reconstruction of brain tissue and the restoration of brain function. However, tracing the fate of iPS cells in the host brain is still a challenge. In our study, iPS cells were derived from skin fibroblasts using the four classic factors Oct4, Sox2, Myc, and Klf4. These iPS cells were then induced to differentiate into NSCs, which were incubated with superparamagnetic iron oxides (SPIOs) in vitro. Next, 30 TBI rat models were prepared and divided into three groups ( n = 10). One week after brain injury, group A&B rats received implantation of NSCs (labeled with SPIOs), while group C rats received implantation of non-labeled NSCs. After cell implantation, all rats underwent T2*-weighted magnetic resonance imaging (MRI) scan at day 1, and 1 week to 4 weeks, to track the distribution of NSCs in rats’ brains. One month after cell implantation, manganese-enhanced MRI (ME-MRI) scan was performed for all rats. In group B, diltiazem was infused during the ME-MRI scan period. We found that (1) iPS cells were successfully derived from skin fibroblasts using the four classic factors Oct4, Sox2, Myc, and Klf4, expressing typical antigens including SSEA4, Oct4, Sox2, and Nanog; (2) iPS cells were induced to differentiate into NSCs, which could express Nestin and differentiate into neural cells and glial cells; (3) NSCs were incubated with SPIOs overnight, and Prussian blue staining showed intracellular particles; (4) after cell implantation, T2*-weighted MRI scan showed these implanted NSCs could migrate to the injury area in chronological order; (5) the subsequent ME-MRI scan detected NSCs function, which could be blocked by diltiazem. In conclusion, using an in vivo MRI tracking technique to trace the fate of iPS cells-induced NSCs in host brain is feasible.

The Chang 7 continental shale oil reservoir is tight. The recovery factor is extremely low, the remaining oil is very high, and injecting water to improve oil recovery effectiveness is too hard. Therefore, in this paper, physical simulation experiments of CO2 huff-n-puff shale oil and NMR tests were conducted to study the cycle numbers and permeability on the recovery degree, as well as the characteristics of shale oil mobilization and the remaining oil micro distribution. The results showed that the cumulative oil recovery factors (ORFs) gradually increased in the natural logarithmic form, the single cycle ORFs decreased rapidly in exponential form with the huff-n-puff cycle number, and the biggest economic cycle numbers were between approximately 3 and 5. Furthermore, the higher the permeability, the higher the ORF, but the difference of ORF decreased between the two experimental samples with the cycles. In addition, the gap of production and recovery degree was large between the different scale pores, the ORF of macropores was 6–8 times that of micropores, and the final remaining oil was mainly distributed in the micropores, accounting for 82.29% of the total amount; meanwhile, the macropores comprised less than 0.5%. In the process of huff-n-puff, CO2 flowed into macropores, mesopores, and smallpores under the pressure differential effect, but a small amount of CO2 slowly diffused into micropores, resulting in the ORF of the former with more free oil being higher and the ORF of micropores with more adsorbed oil being lower. Therefore, promoting a better contact and reaction between CO2 and shale oil of micropores is one of the key ways to effectively develop the Chang 7 continental shale oil and enhance oil recovery.

Stroke is a major disease that leads to high mortality and morbidity. Given the ageing population and the potential risk factors, the prevalence of stroke and socioeconomic burden associated with stroke are expected to increase. During the past decade, both prophylactic and therapeutic strategies for stroke have made significant progress. However, current therapies still cannot adequately improve the outcomes of stroke and may not apply to all patients. One of the significant advances in modern medicine is cell-derived neurovascular regeneration and neuronal repair. Progress in stem cell biology has greatly contributed to ameliorating stroke-related brain injuries in preclinical studies and demonstrated clinical potential in stroke treatment. Mesenchymal stem cells (MSCs) have the differentiating potential of chondrocytes, adipocytes, and osteoblasts, and they have the ability to transdifferentiate into endothelial cells, glial cells, and neurons. Due to their great plasticity, MSCs have drawn much attention from the scientific community. This review will focus on MSCs, stem cells widely utilized in current medical research, and evaluate their effect and potential of improving outcomes in ischemic stroke.

In recent years, scientists have made great achievements in understanding the development of human brain and elucidating critical elements of stepwise spatiotemporal control strategies in neural stem cell specification lineage, which facilitates successful induction of neural organoid in vitro including the cerebral cortex, cerebellar, neural tube, hippocampus cortex, pituitary, and optic cup. Besides, emerging researches on neural organogenesis promote the application of 3D organoid system transplantation in treating central nervous system (CNS) diseases. Present review will categorize current researches on organogenesis into three approaches: (a) stepwise, direct organization of region-specific or population-enriched neural organoid; (b) assemble and direct distinct organ-specific progenitor cells or stem cells to form specific morphogenesis organoid; and (c) assemble embryoid bodies for induction of multilayer organoid. However, the majority of these researches focus on elucidating cellular and molecular mechanisms involving in brain organogenesis or disease development and only a few of them conducted for treating diseases. In this work, we will compare three approaches and also analyze their possible indications for diseases in future treatment on the basis of their distinct characteristics.

The growing field of stem cell therapy is moving toward clinical trials in a variety of applications, particularly for neurological diseases. However, this translation of cell therapies into humans has prompted a need to create innovative and breakthrough methods for stem cell tracing, to explore the migration routes and its reciprocity with microenvironment targets in the body, to monitor and track the outcome after stem cell transplantation therapy, and to track the distribution and cell viability of transplanted cells noninvasively and longitudinally. Recently, a larger number of cell tracking methods in vivo were developed and applied in animals and humans, including magnetic resonance imaging, nuclear medicine imaging, and optical imaging. This review has been intended to summarize the current use of those imaging tools in tracking stem cells, detailing their main features and drawbacks, including image resolution, tissue penetrating depth, and biosafety aspects. Finally, we address that multimodality imaging method will be a more potential tracking tool in the future clinical application.

Background/Aims: MicroRNA (miRNA) plays important roles in the development of different cancers. In this study, we investigated the roles and mechanisms of miR-203 in human cervical cancer. Methods: miR-203 expression was detected in cervical cancer tumors and cell lines by qRT-PCR. The methylation status in the promoter region of miR-203 was examined by methylation-specific PCR. The functional effect of miR-203 was determined by both in vitro and in vivo assays. Results: miR-203 was frequently down-regulated in cervical cancer tumors and cell lines. This down-regulation of miR-203 was associated with methylation of the miR-203 promoter. Furthermore, miR-203 down-regulated vascular endothelial growth factor alpha (VEGFA) expression by directly targeting its 3'-untranslated region. Functional assays revealed that miR-203 suppressed cervical cancer cell proliferation, tumor growth, and angiogenesis in nude mice, whereas forced expression of VEGFA rescued this inhibitory effect. Conclusion: Our collective findings indicate that miR-203 functions as a tumor suppressor by targeting VEGFA, resulting in the inhibition of tumor growth and angiogenesis. Thus, miR-203 may be a potential therapeutic target and prognostic marker in cervical cancer.

BACKGROUND: The risk of fatal adverse events (FAEs) due to bevacizumab-based chemotherapy has not been well described; we carried out an updated meta-analysis regarding this issue. METHODS: An electronic search of Medline, Embase and The Cochrane Central Register of Controlled Trials was conducted to investigate the effects of randomized controlled trials on bevacizumab treatment on cancer patients. Random or fixed-effect meta-analytical models were used to evaluate the risk ratio (RR) of FAEs due to the use of bevacizumab. RESULTS: Thirty-four trials were included. Allocation to bevacizumab therapy significantly increased the risk of FAEs; the RR was 1.29 (95% CI:1.05-1.57). This association varied significantly with tumor types (P=0.002) and chemotherapeutic agents (P=0.005) but not with bevacizumab dose (P=0.90). Increased risk was seen in patients with non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. However, FAEs were lower in breast cancer patients treated with bevacizumab. In addition, bevacizumab was associated with an increased risk of FAEs in patients who received concomitant agents of taxanes and/or platinum. CONCLUSION: Compared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of FAEs among patients with special tumor types, particularly when combined with chemotherapeutic agents such as platinum.

Cancer stem-like cells, which have been described as tumor-initiating cells or tumor-propagating cells, play a crucial role in our fundamental understanding of glioblastoma multiforme (GBM) and its recurrence. GBM is a lethal cancer, characterized by florid vascularization and aberrantly elevated vascular endothelial growth factor (VEGF). VEGF promotes tumorigenesis and angiogenesis of human GBM stem-like cells (GBSCs). However, whether and how VEGF contributes to GBSCs proliferation remain largely uncertain. In this study, human GBSCs were isolated from surgical specimens of glioblastoma and cultured in medium favored for stem cell growth. Neural Colony-Forming Cell Assay and ATP assay were performed to measure GBSC proliferation under normoxia (20% O2) and hypoxia (1% O2). Our observations demonstrate that exogenous VEGF stimulates GBSC proliferation in a dose-dependent manner via VEGF Receptor 2 (VEGFR2); while VEGF Receptor 1 (VEGFR1) has a negative feedback effect on VEGFR2 when cells were exposed to higher concentration of VEGF. These results suggest that suppressing VEGFR2-dependent GBSC proliferation is a potentially therapeutic strategy in GBM.

INTRODUCTION: It has been suggested that vitamin D is effective to prevent mortality. However, there is no consistent conclusion that the effects of vitamin D supplementation on all-cause mortality are associated with duration of treatment. We conducted a meta-analysis regarding this issue in an effort to provide a more robust answer. METHODS: A comprehensive search in a number of databases, including MEDLINE, Embase and The Cochrane Central Register of Controlled Trials, was conducted for collecting randomized controlled trials (RCTs) on vitamin D supplementation preventing mortality. Two investigators independently screened the literature according to the inclusive and exclusive criteria and the relative data were extracted. Data analysis was performed by using Review Manager 5.0 software. RESULTS: Data from forty-two RCT s were included. Vitamin D therapy significantly decreased all-cause mortality with a duration of follow-up longer than 3 years with a RR (95% CI) of 0.94 (0.90-0.98). No benefit was seen in a shorter follow-up periods with a RR (95% CI) of 1.04 (0.97-1.12). Results remain robust after sensitivity analysis. The following subgroups of long-term follow-up had significantly fewer deaths: female only, participants with a mean age younger than 80, daily dose of 800 IU or less, participants with vitamin D insufficiency (baseline 25-hydroxyvitamin D level less than 50 nmol/L) and cholecalciferol therapy. In addition, the combination of vitamin D and calcium significantly reduced mortality and vitamin D alone also had a trend to decrease mortality in a longer time follow up. CONCLUSIONS: The data suggest that supplementation of vitamin D is effective in preventing overall mortality in a long-term treatment, whereas it is not significantly effective in a treatment duration shorter than 3 years. Future studies are needed to identify the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration.