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Background137Cs in atmospheric aerosol is the product of past nuclear weapon tests and nuclear accidents. When 137Cs is released into the atmosphere, it will deposit in dry land and marine environment, causing pollution of soil surface, water, agricultural products, and animal byproducts, and affecting public health.ObjectiveTo identify the variation pattern of 137Cs activity concentration in aerosol and its correlation with dust concentration in Beijing area from 2017 to 2020.Methods A total of 958 aerosol samples were collected from November 1, 2017 to June 30, 2020 in Beijing with a high volume air sampler at a sampling flow rate about 600 m3·h−1 and a collection time for each sample about 24 h. The activity concentration of 137Cs in the aerosol samples was determined with a low-background high-purity germanium γ spectrometer. The dust concentration was calculated using the difference in the mass of the aerosol filter before and after sampling. The detection rate of 137Cs and dust concentration in different seasons were compared. Spearman rank correlation test was used to analyze the correlation between 137Cs activity concentration and dust concentration.Results From 2017 to 2020, the 137Cs activity concentrations of 33 from 958 aerosol samples in Beijing were above the minimum detectable activityconcentration, the overall detection rate of 137Cs was 3.4%, and the activity concentration ranged from 1.86 to 45.53 μBq·m−3, with a median value of 4.85 μBq·m−3. The detection rate of 137Cs was highest in spring, followed by autumn, and lowest in winter and summer (8.4%, 3.0%, 1.1%, and 0.5%, respectively). The dust concentration ranged from 0.03 to 1.55 mg·m−3, with an average value of 0.18 mg·m−3. There was a statistically significant difference in the dust concentrations in spring, summer, autumn, and winter (F=45.51, P

Abstract To compare the diagnostic performance between plain CT-based model and plain plus contrast CT-based modelin the classification of malignancy for solitary solid pulmonary nodules. Between January 2012 and July 2021, 527 patients with pathologically confirmed solitary solid pulmonary nodules were collected at dual centers with similar CT examinations and scanning parameters. Before surgery, all patients underwent both plain and contrast-enhanced chest CT scans. Two clinical characteristics, fifteen plain CT characteristics, and four enhanced characteristics were used to develop two logistic regression models: model 1 (plain CT only) and model 2 (plain + contrast CT). The diagnostic performance of the two models was assessed separately in the development and external validation cohorts using the AUC. 392 patients from Center A were included in the training cohort (median size, 20.0 [IQR, 15.0–24.0] mm; mean age, 55.8 [SD, 9.9] years; male, 53.3%). 135 patients from Center B were included in the external validation cohort (median size, 20.0 [IQR, 16.0–24.0] mm; mean age, 56.4 [SD, 9.6] years; male, 51.9%). Preoperative patients with 201 malignant (adenocarcinoma, 148 [73.6%]; squamous cell carcinoma, 35 [17.4%]; large cell carcinoma,18 [9.0%]) and 326 benign (pulmonary hamartoma, 118 [36.2%]; sclerosing pneumocytoma, 35 [10.7%]; tuberculosis, 104 [31.9%]; inflammatory pseudonodule, 69 [21.2%]) solitary solid pulmonary nodules were gathered from two independent centers. The mean sensitivity, specificity, accuracy, PPV, NPV, and AUC (95%CI) of model 1 (Plain CT only) were 0.79, 0.78, 0.79, 0.67, 0.87, and 0.88 (95%CI, 0.82–0.93), the model 2 (Plain + Contrast CT) were 0.88, 0.91, 0.90, 0.84, 0.93, 0.93 (95%CI, 0.88–0.98) in external validation cohort, respectively. A logistic regression model based on plain and contrast-enhanced CT characteristics showed exceptional performance in the evaluation of malignancy for solitary solid lung nodules. Utilizing this contrast-enhanced CT model would provide recommendations concerning follow-up or surgical intervention for preoperative patients presenting with solid lung nodules.

Abstract Background Liguzinediol (Lig) has emerged as a promising candidate for mitigating Doxorubicin (DOX)-induced cardiotoxicity, a significant limitation in the clinical application of this widely used antineoplastic drug known for its efficacy. This study aimed to explore the effects and potential mechanisms underlying Lig’s protective role against DOX-induced cardiotoxicity. Methods C57BL/6 mice were treated with DOX. Cardiac function changes were observed by echocardiography. Cardiac structure changes were observed by HE and Masson staining. Immunofluorescence was applied to visualize the cardiomyocyte apoptosis. Western blotting was used to detect the expression levels of AMP-activated protein kinase (AMPK), sirtuin 3 (SIRT3), Caspase-3 and gasdermin E N-terminal fragment (GSDME-N). These experiments confirmed that Lig had an ameliorative effect on DOX-induced cardiotoxicity in mice. Results The results demonstrated that Lig effectively countered myocardial oxidative stress by modulating intracellular levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Lig reduced levels of creatine kinase (CK) and lactate dehydrogenase (LDH), while ameliorating histopathological changes and improving electrocardiogram profiles in vivo. Furthermore, the study revealed that Lig activated the AMPK/SIRT3 pathway, thereby enhancing mitochondrial function and attenuating myocardial cell apoptosis. In experiments with H9C2 cells treated with DOX, co-administration of the AMPK inhibitor compound C (CC) led to a significant increase in intracellular ROS levels. Lig intervention reversed these effects, along with the downregulation of GSDME-N, interleukin-1β (IL-1β), and interleukin-6 (IL-6), suggesting a potential role of Lig in mitigating Caspase-3/GSDME-mediated pyroptosis. Conclusion The findings of this study suggest that Lig effectively alleviates DOX-induced cardiotoxicity through the activation of the AMPK/SIRT3 pathway, thereby presenting itself as a natural product with therapeutic potential for preventing DOX-associated cardiotoxicity. This novel approach may pave the way for the development of alternative strategies in the clinical management of DOX-induced cardiac complications.

Abstract Cognitive dysfunction increases as menopause progresses. We previously found that estrogen receptors (ERs) contribute to dyslipidemia, but the specific relationship between ERs, dyslipidemia and cognitive dysfunction remains poorly understood. In the present study, we analyzed sequencing data from female hippocampus and normal breast aspirate samples from normal and Alzheimer’s disease (AD) women, and the results suggest that abnormal ERs signaling is associated with dyslipidemia and cognitive dysfunction. We replicated a mouse model of dyslipidemia and postmenopausal status in LDLR−/− mice and treated them with β-estradiol or simvastatin, and found that ovariectomy in LDLR−/− mice led to an exacerbation of dyslipidemia and increased hippocampal apoptosis and cognitive impairment, which were associated with reduced estradiol levels and ERα, ERβ and GPER expression. In vitro, a lipid overload model of SH-SY-5Y cells was established and treated with inhibitors of ERs. β-estradiol or simvastatin effectively attenuated dyslipidemia-induced neuronal apoptosis via upregulation of ERs, whereas ERα, ERβ and GPER inhibitors together abolished the protective effect of simvastatin on lipid-induced neuronal apoptosis. We conclude that decreased estrogen and its receptor function in the postmenopausal stage promote neuronal damage and cognitive impairment by exacerbating dyslipidemia, and that estrogen supplementation or lipid lowering is an effective way to ameliorate hippocampal damage and cognitive dysfunction via upregulation of ERs. Graphical Abstract

Abstract Solitary fibrous tumors (SFTs) are rare mesenchymal tumors with unpredictable evolution and with a recurrence or metastasis rate of 10-40%. Current medical treatments for relapsed SFTs remain ineffective. Here, we identify potential therapeutic targets and risk factors, including IDH1 p.R132S, high PD-L1 expression, and predominant macrophage infiltration, suggesting the potential benefits of combinational immune therapy and targeted therapy for SFTs. An integrated risk model incorporating mitotic count, density of Ki-67+ cells and CD163+ cells, MTOR mutation is developed, applying a discovery cohort of 101 primary non-CNS patients with negative tumor margins (NTM) and validated in three independent cohorts of 210 SFTs with the same criteria, and in 36 primary CNS SFTs with NTM. Compared with the existing models, our model shows significantly improved efficacy in identifying high-risk primary non-CNS and CNS SFTs with NTM for tumor progression.Our findings hold promise for advancing therapeutic strategies and refining risk prediction in SFTs.

Abstract Pulmonary arterial hypertension (PAH) is a pathophysiological state of abnormally elevated pulmonary arterial pressure caused by drugs, inflammation, toxins, viruses, hypoxia, and other risk factors. We studied the therapeutic effect and target of tetramethylpyrazine (tetramethylpyrazine [TMP]; ligustrazine) in the treatment of PAH and we speculated that dramatic changes in myocardin levels can significantly affect the progression of PAH. In vivo, the results showed that administration of TMP significantly prolonged the survival of PAH rats by reducing the proliferative lesions, right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and the Fulton index in the heart and lung of PAH rats. In vitro, TMP can regulate the levels of smooth muscle protein 22‐alpha (SM22‐α), and myocardin as well as intracellular cytokines such as NO, transforming growth factor beta (TGF‐β), and connective tissue growth factor (CTGF) in a dose‐dependent manner (25, 50, or 100 μM). Transfection of myocardin small interfering RNA (siRNA) aggravated the proliferation of pulmonary artery smooth muscle cells (PSMCs), and the regulatory effect of TMP on α‐smooth muscle actin (α‐SMA) and osteopontin (OPN) disappeared. The application of 10 nM estrogen receptor alpha (ERα) inhibitor MPP promoted the proliferation of PSMCs, but it does not affect the inhibition of TMP on PSMCs proliferation. Finally, we found that TMP promoted the nucleation of myocardin‐related transcription factor‐A (MRTF‐A) and combined it with myocardin. In conclusion, TMP can inhibit the transformation of PSMCs from the contractile phenotype to the proliferative phenotype by promoting the formation of the nuclear (MRTF‐A/myocardin) transcription complex to treat PAH.

PURPOSETo evaluate the feasibility and usefulness of cine magnetic resonance urography (cine MRU) as a novel postoperative examination after upper urinary tract reconstruction surgery.METHODSNinety-six patients underwent cine MRU for postoperative evaluation between August 2015 and August 2020. The morphological observations included regular peristalsis, anastomosis, urine flow signals, and reflux. The quantitative evaluations included luminal diameter, peristaltic amplitude, contraction ratio, peristaltic waves, and ureteric jets. The surgical outcomes were classified as success, gray area, or failure by combining the results of cine MRU, symptoms, and the degree of hydronephrosis.RESULTSThere was no obvious stenosis of the anastomosis in 83 patients (86.46%). Regular peristalsis of the ureter and signals of urination was observed in 85 (88.54%) and 84 patients (87.50%), respectively. In addition, three patients (3.13%) showed urine reflux. The patients in both the success group and the gray area group showed significantly different creatinine levels (success 86.2 ± 22.3 μmol/L vs. failure 110.7 ± 8.2 μmol/L, P = 0.016; gray area 81.0 ± 20.0 μmol/L vs. failure 110.7 ± 8.2 μmol/L, P = 0.009) and estimated glomerular filtration rate (success: 88.5 ± 23.1 mL/min·1.73 m2, failure: 61.6 ± 14.1 mL/min·1.73 m2, P = 0.014; gray area: 94.7 ± 24.6 mL/min·1.73 m2, failure: 61.6 ± 14.1 mL/min·1.73 m2, P = 0.007) compared to those in the failure group. The ipsilateral split renal function was 33.6 ± 15.0, 24.5 ± 13.4, and 20.1 ± 0.4 mL/min in the success, gray area, and failure groups, respectively (P = 0.354).CONCLUSIONCine MRU demonstrates the morphology and function of the reconstructed upper urinary tract. The results of cine MRU can be used to evaluate the surgical effect, providing guidance for further treatment.

Abstract Background Genes related to the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex are frequently mutated across cancers. SWI/SNF-mutant tumors are vulnerable to synthetic lethal inhibitors. However, the landscape of SWI/SNF mutations and their associations with tumor mutational burden (TMB), microsatellite instability (MSI) status, and response to immune checkpoint inhibitors (ICIs) have not been elucidated in large real-world Chinese patient cohorts. Methods The mutational rates and variation types of six SWI/SNF complex genes (ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, and PBRM1) were analyzed retrospectively by integrating next-generation sequencing data of 4591 cases covering 18 cancer types. Thereafter, characteristics of SWI/SNF mutations were depicted and the TMB and MSI status and therapeutic effects of ICIs in the SWI/SNF-mutant and SWI/SNF-non-mutant groups were compared. Results SWI/SNF mutations were observed in 21.8% of tumors. Endometrial (54.1%), gallbladder and biliary tract (43.4%), and gastric (33.9%) cancers exhibited remarkably higher SWI/SNF mutational rates than other malignancies. Further, ARID1A was the most frequently mutated SWI/SNF gene, and ARID1A D1850fs was identified as relatively crucial. The TMB value, TMB-high (TMB-H), and MSI-high (MSI-H) proportions corresponding to SWI/SNF-mutant cancers were significantly higher than those corresponding to SWI/SNF-non-mutant cancers (25.8 vs. 5.6 mutations/Mb, 44.3% vs. 10.3%, and 16.0% vs. 0.9%, respectively; all p

Abstract Background Cysteine dioxygenase 1 (CDO1) is frequently methylated, and its expression is decreased in many human cancers including breast cancer (BC). However, the functional and mechanistic aspects of CDO1 inactivation in BC are poorly understood, and the diagnostic significance of serum CDO1 methylation remains unclear. Methods We performed bioinformatics analysis of publicly available databases and employed MassARRAY EpiTYPER methylation sequencing technology to identify differentially methylated sites in the CDO1 promoter of BC tissues compared to normal adjacent tissues (NATs). Subsequently, we developed a MethyLight assay using specific primers and probes for these CpG sites to detect the percentage of methylated reference (PMR) of the CDO1 promoter. Furthermore, both LentiCRISPR/dCas9‐Tet1CD‐based CDO1‐targeted demethylation system and CDO1 overexpression strategy were utilized to detect the function and underlying mechanism of CDO1 in BC. Finally, the early diagnostic value of CDO1 as a methylation biomarker in BC serum was evaluated. Results CDO1 promoter was hypermethylated in BC tissues, which was related to poor prognosis (p

Abstract Background Clear cell renal cell carcinoma (ccRCC) is characterized by the accumulation of lipid-reactive oxygen species. Ferroptosis, due to the lipid peroxidation, has been reported to be strongly correlated with tumorigenesis and progression. However, the functions of the ferroptosis process in ccRCC remain unclear. Methods After sample cleaning, data integration, and batch effect removal, we used the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases to screen out the expression and prognostic value of ferroptosis-related lncRNAs and then performed the molecular subtyping using the K-means method. Then, the functional pathway enrichment and immune microenvironment infiltration between the different clusters were carried out. The results showed a significant difference in immune cell infiltration between the two clusters and the associated marker responded to individualized differences in treatment. Then, least absolute shrinkage and selection operator (LASSO) Cox regression was used to establish a prognostic signature based on 5 lncRNAs. This signature could accurately predicted patient prognosis and served as an independent clinical risk factor. We then combined significant clinical parameters in multivariate Cox regression and the prognostic signature to construct a clinical predictive nomogram, which provides appropriate guidance for predicting the overall survival of ccRCC patients. Results The prognostic differentially expressed ferroptosis-related LncRNAs (DEFRlncRNAs) were found, and 5 lncRNAs were finally used to establish the prognostic signature in the TCGA cohort, with subsequently validation in the internal and external cohorts. Moreover, we conducted the molecular subtyping and divided the patients in the TCGA cohort into two clusters showing differences in Hallmark pathways, immune infiltration, immune target expression, and drug therapies. Differences between clusters contributed to individualizing treatment. Furthermore, a nomogram was established to better predict the clinical outcomes of the ccRCC patients. Conclusions Our study conducted molecular subtyping and established a novel predictive signature based on the ferroptosis-related lncRNAs, which contributed to the prognostic prediction and individualizing treatment of ccRCC patients.

Abstract Introduction To describe our initial experience with ileal ureteral replacement (IUR) for the management of ureteral avulsion (UA) during ureteroscopic lithotripsy. Methods Between September 2010 and April 2021, ten patients received ileal ureteral replacement for ureteral avulsion during ureteroscopic lithotripsy. Anterograde urography and computed tomography urography (CTU) were applied to evaluate the lesion. Follow-up was performed with magnetic resonance urography and renal ultrasound as well as clinical assessment of symptoms. We retrospectively analysed the clinical data of ten patients treated with ileal ureteral replacement for the treatment of ureteral avulsion. Results Four patients underwent open ileal ureteral replacement, two underwent laparoscopic ileal ureteral replacement, and four underwent robotic-assisted ileal ureteral replacement. The mean operative time (OT) was 310 min (range 191–530). The mean estimated blood loss (EBL) was 193 mL (range 10–1000). The mean length of the ileal graft was 21 cm (range 12–25). The median postoperative hospital time was 13 days (range 7–19). All surgeries were effectively completed, and no case required open conversion in laparoscopic and robotic-assisted surgeries. There was no obvious hydronephrosis according to contrast-enhanced computed tomography 3-dimensional reconstruction images without serious complications or progressive hydronephrosis during a median follow-up duration of 51 months (range 5–131), and the success rate was 100%. Conclusions Our initial results and experience showed that ileal ureteral replacement for the management of ureteral avulsion during ureteroscopic lithotripsy is safe and feasible.

Wen et al. discuss how implementing a 5G network in hospitals can be used to reduce nosocomial infections. Such systems can reduce the spread of COVID-19.

R is one of the most powerful programming languages for conducting data analysis, modeling, and visualization. Although it is widely utilized in biodiversity conservation research, the comprehensive trends in R and R package usage and patterns in the field still remain unexplored. We conducted a comprehensive analysis of R and R package usage frequencies spanning fifteen years, from 2008 to 2022, encompassing over 24,100 research articles published in eight top biodiversity conservation journals. Within this extensive dataset, 10,220 articles (42.3% of the total) explicitly utilized R for data analysis. The use ratio of R demonstrated a consistent linear growth, escalating from 11.1% in 2008 to an impressive 70.6% in 2022. The ten top utilized R packages were vegan, lme4, MuMIn, nlme, mgcv, raster, MASS, ggplot2, car, and dismo. The frequency of R package utilization varied among journals, underscoring the distinct emphases each journal places on specific focuses of biodiversity conservation research. This analysis highlights the pivotal role of R, with its powerful statistical and data visualization capabilities, in empowering researchers to conduct in-depth analyses and gain comprehensive insights into various dimensions of biodiversity conservation science.

The functionalization of biosensor interfaces constitutes a crucial aspect of biosensing systems, as it directly governs key characteristics, including sensitivity, selectivity, accuracy, and rapidity. Among the diverse range of functionalization strategies available for biosensor interfaces, the click reaction has emerged as an exceptionally straightforward and stable approach for modifying electrodes and sensing films. Notably, the electro-click reaction enables the reagent-free functionalization of the biosensing interface, offering significant advantages, such as high speed, selectivity, and minimal pollution. Consequently, this strategy has garnered substantial attention and is widely regarded as a promising avenue for enhancing biosensor interface functionalization. Within this comprehensive review, we commence by presenting the latest advancements in functionalized biosensor interfaces, organizing the regulatory strategies into distinct categories based on the mediators employed, ranging from nanomaterials to biomolecules. Subsequently, we provide a comprehensive summary with an emphasis on recently developed electro-click strategies for functionalizing electrochemical and optical biosensor interfaces, covering both principles and applications. It is our anticipation that gaining a profound understanding of the principles and applications underlying electro-click strategies for biosensor interface functionalization will facilitate the design of highly selective and sensitive biosensor systems for diverse domains, such as clinical, pharmaceutical, environmental, and food analyses.

Aiming at the problems of low machining accuracy and more serious tool wear in the traditional diamond grinding machining (DGM) microstructure of hard and brittle materials, this paper proposes high-speed rotary ultrasonic machining (HRUM) technology and develops a HRUM machine tool. The hardware part of the machine tool mainly includes the spindle module, micro-motion system module, ultrasonic machining tank module, and data acquisition (DAQ) system module. The LabView-based controlled machining control system, including motion selection, initialization, coarse tool setting, constant force tool setting, control machining, and coordinate display module, is developed. Comparative experimental research of the HRUM and DGM of small holes in Al2O3 ceramics is carried out in the developed HRUM machine tool. The results demonstrate that HRUM effectively reduces axial cutting forces, reduces binder adhesion, and suppresses slippage while improving tool-cutting ability and extending tool life compared to DGM under the same machining parameters. This technology has essential research significance for the high-precision and efficient machining of microstructures in hard and brittle materials.

Abstract Background Previous studies showed that doxorubicin could lead to osteoarthritis (OA) by inducing chondrocyte inflammation and apoptosis. Besides, it is reported that platelet-rich plasma (PRP) could suppress the activation of inflammatory NF-κB signaling. Here, we aimed to determine whether PRP was able to exert a protective effect against doxorubicin-induced chondrocyte damages. Methods To determine whether PRP protects chondrocytes against destabilization of the medial meniscus (DMM)-induced osteoarthritis, mice were treated with PRP and doxorubicin, and the cartilage destruction was observed through Safranin O-fast green staining and osteoarthritis scoring. ELISA assay was used to check the release of TNF-α and ILs. In vitro, we treated chondrocytes with doxorubicin and PRP; CCK-8 was used to measure cell viability. Western blot, real-time PCR, and ELISA were applied to check apoptosis-related signaling and inflammation-associated factors. Results The results from the mouse model suggested that PRP attenuated doxorubicin-induced cartilage destruction in vivo. Doxorubicin promoted chondrocyte apoptosis while PRP ameliorated this damage. PRP inhibited doxorubicin-induced dysregulation of cell matrix-related factors, including SOX9, Col2A1, Col10A1, and Aggrecan, reduced protein levels of doxorubicin-induced inflammatory markers, COX-2, and iNOS, and blocked doxorubicin-induced phosphorylation of IκB and NF-κB in articular chondrocytes. Conclusions PRP improved doxorubicin-induced damage on chondrocytes. This research might provide a new theoretical basis for the clinical treatment of osteoarthritis caused by doxorubicin.

Abstract Background A prospective cohort study was performed to evaluate whether the Optical Quality Analysis System (OQAS) can serve as a valuable additional indicator for appropriate posterior capsulotomy referral. Methods One hundred and five eyes from 96 patients undergoing capsulotomy were divided into precapsulotomy logMAR CDVA ≤0.1 group and logMAR CDVA > 0.1 group. CDVA, and the Visual Function 14 index (VF-14) score were estimated before and 1 month after capsulotomy. The objective scattering index (OSI) value was measured by using the OQAS. Posterior capsule opacification (PCO) severity was assessed with Evaluation of PCO 2000 (EPCO 2000) software. Results In logMAR CDVA > 0.1 group, the correlations of OSI, logMAR CDVA, EPCO score and VF-14 score were very strong preoperatively. In logMAR CDVA ≤0.1 group, preoperatively, OSI was correlated with logMAR CDVA (r = 0.451), EPCO score (r = 0.789), and VF-14 score (r = 0.852). LogMAR CDVA has weak correlation with VF-14 score (r = − 0.384) and EPCO score (r = 0.566). VF-14 score was correlated with EPCO score (r = − 0.669). In the logMAR CDVA ≤0.1 group, there was no significant difference in logMAR CDVA between precapsulotomy and postcapsulotomy (P > 0.05). In the two groups, all the other optical quality parameters were significantly improved after capsulotomy (P 0.1 group, the area under the curve of the ROC of the OSI was 0.996 (P = 0.000). In logMAR CDVA ≤0.1 group, the area under the curve of the ROC of the OSI was 0.943 (P = 0.000). Conclusions The OSI was useful for evaluating of PCO and prediction of beneficial capsulotomy. Especially for patients with slight PCO and better visual acuity, OSI is more valuable than CDVA and completely objective examination. Trial registration The study protocol was registered at the Chinese Clinical Trial Registry. Register: ChiCTR1800018842 (Registered Date: October 13th, 2018).

Abstract Prostate cancer (PCa) is a complex disease. An ongoing accumulation of mutations results in increased genetic diversity, with the tumor acquiring distinct subclones. However, non‐genetic intra‐tumoral heterogeneity, the cellular differentiation state and the interplay between subclonal evolution and transcriptional heterogeneity are poorly understood. Here, the authors perform single‐cell RNA sequencing from 14 untreated PCa patients. They create an extensive cell atlas of the PCa patients and mapped developmental states onto tumor subclonal evolution. They identify distinct subclones across PCa patients and then stratify tumor cells into four transcriptional subtypes, EMT‐like (subtype 0), luminal A‐like (subtype 1), luminal B/C‐like (subtype 2), and basal‐like (subtype 3). These subtypes are hierarchically organized into stem cell‐like and differentiated status. Strikingly, multiple subclones within a single primary tumor present with distinct combinations of preferential subtypes. In addition, subclones show different communication strengths with other cell types within the tumor ecosystem, which may modulate the distinct transcriptional subtypes of the subclones. Notably, by integrating TCGA data, they discover that both tumor cell transcriptional heterogeneity and cellular ecosystem diversity correlate with features of a poor prognosis. Collectively, their study provides the analysis of subclonal and transcriptional heterogeneity and its implication for patient prognosis.

Abstract Background Inner ear supporting cells (SCs) in the neonatal mouse cochlea are a potential source for hair cell (HC) regeneration, but several studies have shown that the regeneration ability of SCs decreases dramatically as mice age and that lost HCs cannot be regenerated in adult mice. To better understand how SCs might be better used to regenerate HCs, it is important to understand how the gene expression profile changes in SCs at different ages. Methods Here, we used Sox2 GFP/+ mice to isolate the Sox2+ SCs at postnatal day (P)3, P7, P14, and P30 via flow cytometry. Next, we used RNA-seq to determine the transcriptome expression profiles of P3, P7, P14, and P30 SCs. To further analyze the relationships between these age-related and differentially expressed genes in Sox2+ SCs, we performed gene ontology (GO) analysis. Results Consistent with previous reports, we also found that the proliferation and HC regeneration ability of isolated Sox2+ SCs significantly decreased as mice aged. We identified numerous genes that are enriched and differentially expressed in Sox2+ SCs at four different postnatal ages, including cell cycle genes, signaling pathway genes, and transcription factors that might be involved in regulating the proliferation and HC differentiation ability of SCs. We thus present a set of genes that might regulate the proliferation and HC regeneration ability of SCs, and these might serve as potential new therapeutic targets for HC regeneration. Conclusions In our research, we found several genes that might play an important role in regulating the proliferation and HC regeneration ability of SCs. These datasets are expected to serve as a resource to provide potential new therapeutic targets for regulating the ability of SCs to regenerate HCs in postnatal mammals.

ARHGEF6 belongs to the family of guanine nucleotide exchange factors (GEFs) for Rho GTPases, and it specifically activates Rho GTPases CDC42 and RAC1. Arhgef6 is the X-linked intellectual disability gene also known as XLID46, and clinical features of patients carrying Arhgef6 mutations include intellectual disability and, in some cases, sensorineural hearing loss. Rho GTPases act as molecular switches in many cellular processes. Their activities are regulated by binding or hydrolysis of GTP, which is facilitated by GEFs and GTPase-activating proteins, respectively. RAC1 and CDC42 have been shown to play important roles in hair cell (HC) stereocilia development. However, the role of ARHGEF6 in inner ear development and hearing function has not yet been investigated. Here, we found that ARHGEF6 is expressed in mouse cochlear HCs, including the HC stereocilia. We established Arhgef6 knockdown mice using the clustered regularly interspaced short palindromic repeat-associated Cas9 nuclease (CRISPR-Cas9) genome editing technique. We showed that ARHGEF6 was indispensable for the maintenance of outer hair cell (OHC) stereocilia, and loss of ARHGEF6 in mice caused HC stereocilia deficits that eventually led to progressive HC loss and hearing loss. However, the loss of ARHGEF6 did not affect the synapse density and did not affect the mechanoelectrical transduction currents in OHCs at postnatal day 3. At the molecular level, the levels of active CDC42 and RAC1 were dramatically decreased in the Arhgef6 knockdown mice, suggesting that ARHGEF6 regulates stereocilia maintenance through RAC1/CDC42.

Swanson's literature-based discovery focus on resurrecting previously published but neglected knowledge. In this study, we propose a two-step model of the discovery process and generate a hypothesis between anandamide and gastric cancer. Further, the potential relationship was confirmed by follow-up experimentation. The anandamide treatment resulted in cell cycle redistribution of gastric cancer cells. Most importantly, the variation of cell cycle was mediated by some genes from the B-terms of the closed discovery, indicating the potential role of the B-terms. Swanson's literature-based discovery not only collates data for possible interactions, but also provides the potential to observe the larger background behind these direct links and is an invaluable discovery tool for investigators.

Taking a shear wall structure in a high-intensity area of 20 floors as an example, the seismic reduction scheme of the structure was determined, and the Etabs software was used to conduct time history analysis on the seismic and non-seismic structures. The floor shear force, overturning moment, and short-term surface pressure of the isolation support were obtained. The results showed that under frequent earthquake action, the average maximum floor shear force in the direction of the isolated upper structure was only about 28 % of that of the non-isolated structure. The maximum inter story shear ratio was 0.34, and the maximum floor shear force in the direction was only about 25 % of that of the non-isolated structure. The maximum inter story shear ratio was 0.31. The average maximum overturning moment of the upper structure in the direction after isolation is about 30 % of that of the non-isolated structure. The maximum overturning moment ratio is 0.36, and the average overturning moment of the maximum floor in the direction is about 22 % of that of the non-isolated structure. The maximum overturning moment ratio is 0.26. Under rare earthquake action, the maximum inter story displacement angles in the and directions of each floor of the seismic isolation structure are 1/302 and 1/446, respectively. The maximum surface pressure value of the isolation bearing under rare earthquake is 28.9 MPa, the minimum surface pressure value is 5.58 MPa, and the maximum displacement is 579 mm, which meets the requirements of the specifications. Overall, the seismic performance of the seismic isolation structure is good, and the isolation scheme is feasible. [ABSTRACT FROM AUTHOR]