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Abstract Weight-adjusted waist index (WWI) is a new marker of central obesity. This study explored the association of WWI with all-cause and cardiovascular disease (CVD) mortality in individuals with diabetes or prediabetes. 6551 participants with diabetes or prediabetes from the National Health and Nutrition Examination Survey (NHANES) records between 2005 and 2018 were included. The association of WWI with all-cause and CVD mortality was assessed using Kaplan-Meier survival analysis, Cox proportional hazards model (Cox regression), and restricted cubic spline (RCS). The predictive value of WWI for mortality was analyzed using time-dependent receiver operating characteristic curves (ROC). There were 1083 all-cause deaths and 360 CVD deaths. Multivariable-adjusted Cox regression analyses showed WWI was positively correlated with the risk of all-cause and CVD mortality in subjects with diabetes or prediabetes. Multivariate-adjusted RCS analyses showed a linear and positive correlation of WWI with all-cause mortality risk, and a nonlinear relationship with CVD mortality, with a threshold of 12.35. The area under the curve (AUC) for 3, 5, and 10-years survival for all-cause mortality was 0.795, 0.792, and 0.812, respectively, and for CVD mortality was 0.815, 0.833, and 0.831, respectively. WWI is a valuable predictor of all-cause mortality risk in patients with diabetes and prediabetes, and a valuable predictor of CVD mortality risk when patients with diabetes and prediabetes are considered as a whole.

Abstract This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic model (PBPK/PD) of meropenem for critically ill patients. A PBPK model of meropenem in healthy adults was established using PK-Sim software and subsequently extrapolated to critically ill patients based on anatomic and physiological parameters. The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between predicted and observed values of pharmacokinetic parameters Cmax, AUC0-∞, and CL to evaluate the accuracy of the PBPK model. The model was verified using meropenem plasma samples obtained from Intensive Care Unit (ICU) patients, which were determined by HPLC-MS/MS. After that, the PBPK model was combined with a PKPD model, which was developed based on f%T > MIC. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients. The developed PBPK model successfully predicted the meropenem disposition in critically ill patients, wherein the MFE average and GMFE of all predicted PK parameters were within the 1.25-fold error range. The therapeutic drug monitoring (TDM) of meropenem was conducted with 92 blood samples from 31 ICU patients, of which 71 (77.17%) blood samples were consistent with the simulated value. The TDM results showed that meropenem PBPK modeling is well simulated in critically ill patients. Monte Carlo simulations showed that extended infusion and frequent administration were necessary to achieve curative effect for critically ill patients, whereas excessive infusion time (> 4 h) was unnecessary. The PBPK/PD modeling incorporating literature and prospective study data can predict meropenem pharmacokinetics in critically ill patients correctly. Our study provides a reference for dose adjustment in critically ill patients.

Abstract Circularly polarized room temperature phosphorescence materials represent a state-of-the-art frontier of optical materials and exhibit promising applications in various fields. Herein, we fabricate a series of full-color circularly polarized room temperature phosphorescence materials, based on anionic cellulose derivatives and achiral luminophores. The ionic achiral substituents promote the spontaneous formation of chiral helical structure of cellulose derivatives via the electrostatic repulsion effect. There are multiple interactions between anionic cellulose derivatives and the doped luminophores, thus the chirality is transferred to luminophores and the non-radiative transition is inhibited. The resultant materials can be easily processed into large-scale film and flexible 3D objects with repeatable folding and curling properties. In addition, their phosphorescence performance shows to be excitation-dependence, time-dependence, visible-light excitation, and multi-responsiveness to humidity, temperature as well as pH value. Importantly, they recognize many enantiomers in an instrument-free visual mode, including amino acids, hydroxyl acids, organic phosphate and hydrobenzoin. These results provide insights into design of advanced optical materials which can be applied in multilevel information handling and chiral sensing.

Highlights The novel ionic cellulose derivative with cyano-imidazolium cation and chloride anion, designed from natural cellulose, promotes the crystallization process, grain growth, and orientation of perovskite in perovskite solar cells (PSCs). The use of ionic cellulose leads to the suppression of defect formation, reduction of grain boundaries, enhancement of carrier extraction, and inhibition of non-radiative recombination, resulting in a high power conversion efficiency of 24.71% in PSCs. The biopolymer-based approach enables excellent stability of PSCs, which maintain over 91.3% of their initial efficiencies after 3000 h in conventional air atmosphere.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a poor prognosis. Mono-immunotherapy, such as blockade of the PD-1/PD-L1 pathway, for PDAC has proven to be less effective. The systemic exertion of 4–1BB signaling enhanced antitumor immunity accompanied by hepatotoxicity, which is an obstacle for its clinical application. Our study exploits an oncolytic virus armed with 4–1BBL (VV-ΔTK-4L) to locally express 4–1BBL in the tumor microenvironment (TME), thus avoiding hepatotoxicity. VV-ΔTK-4L prolonged the survival time of a pancreatic tumor mouse model and modified the immune status of the TME and spleen. In the TME, the quantities of CD45+ cells, NK1.1+ cells, CD11c+ DCs, CD3+ T, CD4+ T, and CD8+ T cells increased. Compared to VV-ΔTK treatment, VV-ΔTK-4L further increases the number of CD8+ T cells with effector phenotypes, and downregulates exhaustion-related molecules on CD8+ T cells, and does not increase the proportion of Foxp3+ T cells. Thus, the TME of pancreatic cancer was converted from “cold” to “hot” by VV-ΔTK-4L. Blockade of the PD-1/PD-L1 pathway combined with VV-ΔTK-4L further significantly improves the survival ratio of a tumor-bearing mouse model. This study provides a systemic therapeutic strategy and approach for PDAC immunotherapy.

Timely and accurate mapping of paddy rice cultivation based on remote sensing technology is crucial and valuable for ensuring food security and sustainable environmental management. In most relevant studies, rice mapping was conducted using time-series images, but conventional rice mapping methods are not specifically designed for time-series data, making it difficult to extract the deep information contained in these data. To address these problems, in this paper, an automatic rice mapping method based on an integrated time-series gradient boosting tree (Auto-ITSGBT) is proposed using GF-6 WFV and Sentinel-2 MSI data. This method accounts for the local and overall shape features of time-series curves, and fully exploits the information related to phenological characteristics between time-series data. The proposed rice mapping method is tested and validated in three typical rice-producing areas, which are located in different provinces of China characterized by diverse climate conditions, planting times or topographies. The results show that the overall accuracy and Kappa coefficient of the method exceeded 95% and 0.93, respectively, at all study sites, respectively. Our method performs better than the existing competing methods, with an overall accuracy improvement of 2% to 4%. To identify the rice planting areas as early as possible, rice mapping was conducted by reducing the number of images one by one. The rice distribution map was obtained in mid-July with an overall accuracy of at least 90%, thus obtaining a spatial distribution map of rice with high accuracy before harvesting.

Host-microbe interactions are virtually bidirectional, but how the host affects their microbiome is poorly understood. Here, we report that the host is a critical modulator to regulate the lifestyle switch and pathogenicity heterogeneity of the opportunistic pathogens Serratia marcescens utilizing the Drosophila and bacterium model system. First, we find that Drosophila larvae efficiently outcompete S. marcescens and typically drive a bacterial switch from pathogenicity to commensalism toward the fly. Furthermore, Drosophila larvae reshape the transcriptomic and metabolic profiles of S. marcescens characterized by a lifestyle switch. More importantly, the host alters pathogenicity and heterogeneity of S. marcescens in the single-cell resolution. Finally, we find that larvae-derived AMPs are required to recapitulate the response of S. marcescens to larvae. Altogether, our findings provide an insight into the pivotal roles of the host in harnessing the life history and heterogeneity of symbiotic bacterial cells, advancing knowledge of the reciprocal relationships between the host and pathogen.

Abstract Purpose To compare different methods of preparing silk fibroin hydrogels, then summarize the applications of silk fibroin hydrogel‐based scaffolds in skin regeneration and finally discuss about future prospects to inspire people interested in this field. Methods A narrative review of the relevant papers was conducted. Notably, for applications in skin regeneration, this review provides a categorized summary and discussion of studies from the past decade. Results Silk fibroin is a naturally occurring, biocompatible biomaterial that is easily producible. Thanks to its exceptional processability, silk fibroin has found diverse applications in skin regeneration. These applications encompass sponges, fiber fabrics, thin films, and hydrogels. Hydrogels, in particular, are noteworthy due to their water‐containing network structure, closely resembling natural tissues. They provide a biomimetic three‐dimensional growth environment for cells and have the capacity to incorporate growth factors. Consequently, there are abundant studies of silk fibroin hydrogel‐based scaffolds in skin regeneration. Besides, some commercialized medical devices are also made of silk fibroin. Conclusion Silk fibroin hydrogel could be prepared with multiple methods and it is widely used in constructing scaffolds for efficient skin regeneration. In the future, silk fibroin hydrogel‐based skin scaffolds could be more biomimetic and smart.

Natural biomaterials, particularly fibrous proteins, are extensively utilized in skin tissue engineering. However, their application is impeded by batch-to-batch variance, limited chemical or physical versatility, and environmental concerns. Recent advancements in gene editing and fermentation technology have catalyzed the emergence of recombinant fibrous protein biomaterials, which are gaining traction in skin tissue engineering. The modular and highly customizable nature of recombinant synthesis enables precise control over biomaterial design, facilitating the incorporation of multiple functional motifs. Additionally, recombinant synthesis allows for a transition from animal-derived sources to microbial sources, thereby reducing endotoxin content and rendering recombinant fibrous protein biomaterials more amenable to scalable production and clinical use. In this review, we provide an overview of prevalent recombinant fibrous protein biomaterials (collagens, elastin, silk proteins and their chimeric derivatives) used in skin tissue engineering (STE) and compare them with their animal-derived counterparts. Furthermore, we discuss their applications in STE, along with the associated challenges and future prospects.

Background: Chronic subdural hematoma (CSDH) is a prevalent form of intracranial haemorrhage encountered in neurosurgical practice, and its incidence has notably risen in recent years. Currently, there is a lack of studies that have comprehensively classified the cells present in hematomas removed during surgery, and their correlation with CSDH recurrence remains elusive. This study aims to analyse the subcellular populations and occupancy levels within peripheral blood. Methods: This study analyses the subcellular populations and occupancy levels within peripheral blood and postoperatively removed hematomas by single-cell sequencing and attempts to analyse the effect of different cell occupancies within peripheral blood and intraoperatively removed hematomas on CSDH. Results: The single-cell sequencing results showed that the cells were classified into 25 clusters by differential gene and UMAP dimensionality reduction clustering analyses and further classified into 17 significant cell populations by cell markers: pDCs, CD8 T cells, CD4 T cells, MigDCs, cDC2s, cDC1s, plasma cells, neutrophils, naive B cells, NK cells, memory B cells, M2 macrophages, CD8 Teffs, CD8 MAIT cells, CD4 Tregs, CD19 B cells, and monocytes. Further research showed that the presence of more cDC2 and M2 macrophages recruited at the focal site in patients with CSDH and the upregulation of the level of T-cell occupancy may be a red flag for further brain damage. ROS, a marker of oxidative stress, was significantly upregulated in cDC2 cells and may mediate the functioning of transcription proteins of inflammatory factors, such as NFκB, which induced T cells' activation. Moreover, cDC2 may regulate M2 macrophage immune infiltration and anti-inflammatory activity by secreting IL1β and binding to M2 macrophage IL1R protein. Conclusion: The detailed classification of cells in the peripheral blood and hematoma site of CSDH patients helps us to understand the mechanism of CSDH generation and the reduction in the probability of recurrence by regulating the ratio of cell subpopulations.

ObjectivesCodeine, a prodrug used as an opioid agonist, is metabolized to the active product morphine by CYP2D6. This study aimed to establish physiologically based pharmacokinetic (PBPK) models of codeine and morphine and explore the influence of CYP2D6 genetic polymorphisms on the pharmacokinetics of codeine and morphine.MethodsAn initial PBPK modeling of codeine in healthy adults was established using PK-Sim® software and subsequently extrapolated to CYP2D6 phenotype-related PBPK modeling based on the turnover frequency (Kcat) of CYP2D6 for different phenotype populations (UM, EM, IM, and PM). The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between the predicted and observed values of the pharmacokinetic parameters to evaluate the accuracy of PBPK modeling. The validated models were then used to support dose safety for different CYP2D6 phenotypes.ResultsThe developed and validated CYP2D6 phenotype-related PBPK model successfully predicted codeine and morphine dispositions in different CYP2D6 phenotypes. Compared with EMs, the predicted AUC0-∞ value of morphine was 98.6% lower in PMs, 60.84% lower in IMs, and 73.43% higher in UMs. Morphine plasma exposure in IMs administered 80 mg of codeine was roughly comparable to that in EMs administered 30 mg of codeine. CYP2D6 UMs may start dose titration to achieve an optimal individual regimen and avoid a single dose of over 20 mg. Codeine should not be used in PMs for pain relief, considering its insufficient efficacy.ConclusionPBPK modeling can be applied to explore the dosing safety of codeine and can be helpful in predicting the effect of CYP2D6 genetic polymorphisms on drug–drug interactions (DDIs) with codeine in the future.

Abstract Constructing room-temperature phosphorescent materials with multiple emission and special excitation modes is fascinating and challenging for practical applications. Herein, we demonstrate a facile and general strategy to obtain ecofriendly ultralong phosphorescent materials with multi-mode emission, adjustable excitation-dependence, and visible-light excitation using a single organic component, cellulose trimellitate. Based on the regulation of the aggregation state of anionic cellulose trimellitates, such as CBtCOONa, three types of phosphorescent materials with different emission modes are fabricated, including blue, green and color-tunable phosphorescent materials with a strong excitation-dependence. The separated molecularly-dispersed CBtCOONa exhibits blue phosphorescence while the aggregated CBtCOONa emits green phosphorescence; and the CBtCOONa with a coexistence state of single molecular chains and aggregates exhibits color-tunable phosphorescence depending on the excitation wavelength. Moreover, aggregated cellulose trimellitates demonstrate unique visible-light excitation phosphorescence, which emits green or yellow phosphorescence after turning off the visible light. The aggregation-regulated phenomenon provides a simple principle for designing the proof-of-concept and on-demand phosphorescent materials by using a single organic component. Owing to their excellent processability and environmental friendliness, the aforementioned cellulose-based phosphorescent materials are demonstrated as advanced phosphorescence inks to prepare various disposable complex anticounterfeiting patterns and information codes.

Tumor-associated macrophages (TAMs) are the main component of tumor-infiltrating immune cells in the lung tumor microenvironment. TAMs recruited to the lung cancer can create a suitable microenvironment for the growth and metastasis of lung cancer by secreting tumor promoting factors and interfering with the function of T cells. Currently, numerous studies have reported that small molecular drugs affect lung cancer progression by selectively targeting TAMs. The main ways include blocking the recruitment of monocytes or eliminating existing TAMs in tumor tissue, reprogramming TAMs into pro-inflammatory M1 macrophages or inhibiting M2 polarization of macrophages, interrupting the interaction between tumor cells and macrophages, and modulating immune function. Signaling pathways or cytokines such as CCL8, CCL2/CCR2, CSF-1/CSF-1R, STAT3, STAT6, MMPs, Caspase-8, AMPK α1, TLR3, CD47/SIRPα, have been reported to be involved in this process. Based on summarizing the role and mechanisms of TAMs in lung cancer progression, this paper particularly focuses on systematically reviewing the effects and mechanisms of small molecule drugs on lung cancer TAMs, and classified the small molecular drugs according to the way they affect TAMs. The study aims to provide new perspectives and potential therapeutic drugs for targeted macrophages treatment in lung cancer, which is of great significance and will provide more options for immunotherapy of lung cancer.

Chronic kidney disease (CKD) presents a significant global health challenge, characterized by complex pathophysiology. This study utilized a multi-omic approach, integrating genomic data from the CKDGen consortium alongside transcriptomic, metabolomic, and proteomic data to elucidate the genetic underpinnings and identify therapeutic targets for CKD and kidney function. We employed a range of analytical methods including cross-tissue transcriptome-wide association studies (TWASs), Mendelian randomization (MR), summary-based MR (SMR), and molecular docking. These analyses collectively identified 146 cross-tissue genetic associations with CKD and kidney function. Key Golgi apparatus-related genes (GARGs) and 41 potential drug targets were highlighted, with MAP3K11 emerging as a significant gene from the TWAS and MR data, underscoring its potential as a therapeutic target. Capsaicin displayed promising drug–target interactions in molecular docking analyses. Additionally, metabolome- and proteome-wide MR (PWMR) analyses revealed 33 unique metabolites and critical inflammatory proteins such as FGF5 that are significantly linked to and colocalized with CKD and kidney function. These insights deepen our understanding of CKD pathogenesis and highlight novel targets for treatment and prevention.

Gap junctions mediate intercellular communications across cellular networks in the nervous and immune systems. Yet their roles in intestinal innate immunity are poorly understood. Here, we show that the gap junction/innexin subunit inx-14 acts in the C. elegans gonad to attenuate intestinal defenses to Pseudomonas aeruginosa PA14 infection through the PMK-1/p38 pathway. RNA-Seq analyses revealed that germline-specific inx-14 RNAi downregulated Notch/GLP-1 signaling, while lysosome and PMK-1/p38 pathways were upregulated. Consistently, disruption of inx-14 or glp-1 in the germline enhanced resistance to PA14 infection and upregulated lysosome and PMK-1/p38 activity. We show that lysosome signaling functions downstream of the INX-14/GLP-1 signaling axis and upstream of PMK-1/p38 pathway to facilitate intestinal defense. Our findings expand the understanding of the links between the reproductive system and intestinal defense, which may be evolutionarily conserved in higher organism.

Context Bushen Yiyuan recipe (BYR) is an effective Chinese prescription with antifatigue and antioxidation effects.Objective The effects of BYR on testosterone synthesis in rat Leydig cells with exercise-induced low serum testosterone levels (EILST) are assessed.Materials and methods Thirty-two Sprague-Dawley rats were chronically trained for 6 weeks to establish an EILST model. EILST rats were divided into model (physiological saline), EFE (700 mg/kg ethanol extract of Epimedii folium, the dried leaves of Epimedium brevicornu Maxim [Berberidaceae]), and BYR groups (350 and 700 mg/kg) for 6 weeks. Expression of HMG-CoA, LDL-R, SR-BI, STAR and CYP11A1 were quantified by RT qPCR and Western blots.Results Compared with the model group (115.52 ± 13.05 μg/dL; 67.83 ± 14.29; 0.32 ± 0.04; 0.33 ± 0.02; 0.38 ± 0.01), serum testosterone, testosterone/cortisol ratio, HMG-CoA, STAR and CYP11A1 relative protein expression significantly increased in low-dose BYR (210.60 ± 5.08 μg/dL; 119.38 ± 13.02; 0.47 ± 0.01; 0.46 ± 0.03; 0.46 ± 0.02), high-dose BYR (220.57 ± 14.71 μg/dL; 124.26 ± 14.79; 0.49 ± 0.02; 0.42 ± 0.03; 0.51 ± 0.02), and EFE groups (206.83 ± 5.54 μg/dL; 119.53 ± 25.04; 0.45 ± 0.02; 0.42 ± 0.02; 0.41 ± 0.02) (all p

In this investigation, we leverage the combination of the Dark Energy Spectroscopic Instrument (DESI) Legacy Imaging Surveys Data Release 9, Survey Validation 3, and Year 1 data sets to estimate the conditional luminosity functions and conditional stellar mass functions (CLFs and CSMFs) of galaxies across various halo mass bins and redshift ranges. To support our analysis, we utilize a realistic DESI mock galaxy redshift survey (MGRS) generated from a high-resolution Jiutian simulation. An extended halo-based group finder is applied to both MGRS catalogs and DESI observation. By comparing the r - and z -band luminosity functions (LFs) and stellar mass functions (SMFs) derived using both photometric and spectroscopic data, we quantified the impact of photometric redshift (photo- z ) errors on the galaxy LFs and SMFs, especially in the low-redshift bin at the low-luminosity/mass end. By conducting prior evaluations of the group finder using MGRS, we successfully obtain a set of CLF and CSMF measurements from observational data. We find that at low redshift, the faint-end slopes of CLFs and CSMFs below ∼10 ^9 h ^−2 L _⊙ (or h ^−2 M _⊙ ) evince a compelling concordance with the subhalo mass functions. After correcting the cosmic variance effect of our local Universe following Chen et al., the faint-end slopes of the LFs/SMFs turn out to also be in good agreement with the slope of the halo mass function.

Accurate delineation of individual agricultural plots, the foundational units for agriculture-based activities, is crucial for effective government oversight of agricultural productivity and land utilization. To improve the accuracy of plot segmentation in high-resolution remote sensing images, the paper collects GF-2 satellite remote sensing images, uses ArcGIS10.3.1 software to establish datasets, and builds UNet, SegNet, DeeplabV3+, and TransUNet neural network frameworks, respectively, for experimental analysis. Then, the TransUNet network with the best segmentation effects is optimized in both the residual module and the skip connection to further improve its performance for plot segmentation in high-resolution remote sensing images. This article introduces Deformable ConvNets in the residual module to improve the original ResNet50 feature extraction network and combines the convolutional block attention module (CBAM) at the skip connection to calculate and improve the skip connection steps. Experimental results indicate that the optimized remote sensing plot segmentation algorithm based on the TransUNet network achieves an Accuracy of 86.02%, a Recall of 83.32%, an F1-score of 84.67%, and an Intersection over Union (IOU) of 86.90%. Compared to the original TransUNet network for remote sensing land parcel segmentation, whose F1-S is 81.94% and whose IoU is 69.41%, the optimized TransUNet network has significantly improved the performance of remote sensing land parcel segmentation, which verifies the effectiveness and reliability of the plot segmentation algorithm.

Abstract Background In many organisms, aging is characterized by a loss of mitochondrial homeostasis. Multiple factors such as respiratory metabolism, mitochondrial fusion/fission, or mitophagy have been linked to cell longevity, but the exact impact of each one on the aging process is still unclear. Results Using the deletion mutant collection of the fission yeast Schizosaccharomyces pombe, we have developed a genome-wide screening for mutants with altered chronological lifespan. We have identified four mutants associated with proteolysis at the mitochondria that exhibit opposite effects on longevity. The analysis of the respiratory activity of these mutants revealed a positive correlation between increased respiration rate and prolonged lifespan. We also found that the phenotype of the long-lived protease mutants could not be explained by impaired mitochondrial fusion/fission activities, but it was dependent on mitophagy induction. The anti-aging role of mitophagy was supported by the effect of a mutant defective in degradation of mitochondria, which shortened lifespan of the long-lived mutants. Conclusions Our characterization of the mitochondrial protease mutants demonstrates that mitophagy sustains the lifespan extension of long-lived mutants displaying a higher respiration potential.

Objective: The aim of this retrospective study was to evaluate the prevalence of taurodontism in a group of adult dental patients in Northwest China with the aid of cone-beam computed tomography (CBCT). Methods: This study used Shifman and Chanannel's criteria to statistically analyze the prevalence of taurodontism in the premolars and molars of the Chinese population. CBCT images of 5488 teeth from 580 subjects of Chinese origin were evaluated. The measured data were statistically analyzed and the chi-square test was also used to compare the prevalence of taurodontism between male and female subjects and between the upper and lower jaws (P 0.05). Taurodontism was found in 7.45% of all teeth examined. Taurodonts were significantly more common in the maxilla (9.06%) than in the mandible (5.15%) (P

IntroductionCardiac surgery-associated acute kidney injury (CSA-AKI) is a common hospital-acquired AKI that carries a grave disease burden. Recently, gut-kidney crosstalk has greatly changed our understanding of the pathogenesis of kidney diseases. However, the relationship between gut microbial dysbiosis and CSA-AKI remains unclear. The purpose of this study was to investigate the possible contributions of gut microbiota alterations in CSA-AKI patients.MethodsPatients undergoing cardiac surgery were enrolled and divided into acute kidney injury (AKI) and Non_AKI groups. Faecal samples were collected before the operation. Shotgun metagenomic sequencing was performed to identify the taxonomic composition of the intestinal microbiome. All groups were statistically compared with alpha- and beta-diversity analysis, and linear discriminant analysis effect size (LEfSe) analysis was performed.ResultsA total of 70 individuals comprising 35 AKI and 35 Non_AKI were enrolled in the study. There was no significant difference between the AKI and Non_AKI groups with respect to the alpha-and beta-diversity of the Shannon index, Simpson or Chao1 index values except with respect to functional pathways (p

ABSTRACT Several previous studies have shown that oral microbial disorders may be closely related to the occurrence and development of type 2 diabetes mellitus (T2DM). However, whether the function of oral microorganisms and their metabolites have changed in patients with T2DM who have not suffered from any oral diseases has not been reported. We performed metagenomic analyses and nontargeted metabolic analysis of saliva and supragingival plaque samples from patients with T2DM who have not suffered any oral diseases and normal controls. We found that periodontal pathogens such as Porphyromonas gingivalis and Prevotella melaninogenica were significantly enriched, while the abundances of dental caries pathogens such as Streptococcus mutans and Streptococcus sobrinus were not significantly different in patients with T2DM compared to those in normal controls. Metabolomic analyses showed that the salivary levels of cadaverine and L-(+)-leucine of patients with T2DM were significantly higher than those of normal controls, while the supragingival plaque levels of N-acetyldopamine and 3,4-dimethylbenzoic acid in patients with T2DM were significantly higher than those in the normal controls. Additionally, we identified the types of oral microorganisms related to the changes in the levels of circulating metabolites, and the oral microorganisms were involved in the dysregulation of harmful metabolites such as cadaverine and n, n-dimethylarginine. Overall, our study first described the changes in the composition of oral microorganisms and their metabolites in patients with T2DM who have not suffered any oral diseases, which will provide a direct basis for finding oral biomarkers for early warning of oral diseases in T2DM. IMPORTANCE The incidence of oral diseases in type 2 diabetic patients might increase, and the severity might also be more serious. At present, the relationship between oral microorganisms and type 2 diabetes mellitus (T2DM) has become a hot topic in systemic health research. However, whether the function of oral microorganisms and their metabolites have changed in patients with T2DM who have not suffered from any oral diseases has not been reported. We found that even if the oral condition of T2DM is healthy, their oral microbes and metabolites have changed, thus increasing the risk of periodontal disease. Our study first described the changes in the composition of oral microorganisms and their metabolites in T2DM who have not suffered any oral diseases and revealed the correlation between oral microorganisms and their metabolites, which will provide a direct basis for finding oral biomarkers for early warning of oral diseases in patients with T2DM.

ObjectiveTo evaluate the characteristics of full compensation and its association with the prevalence of total astigmatism (TA), and to analyze the effects of TA on uncorrected distance visual acuity (UDVA).MethodsWith random cluster sampling based on a school-based cross-sectional design, children aged 4 to 18 years were recruited in September 2020, Shandong Province, China. TA, anterior corneal astigmatism (ACA), and ocular residual astigmatism (ORA) were converted to vectorial components (J0, J45), followed by an assessment of the compensatory effect of ACA by ORA. Astigmatism was defined as a cylinder that was better than or equal to 0.75 diopters (D). Logistic regression analysis was used to assess the related factors for children with full compensation, and the generalized linear model was used to assess the influence of TA on UDVA.ResultsOut of 4,494 eligible children, data of 4,145 children (92.3%, 9.23 ± 3.15 years, 50.4% boys) were included in the statistical analysis. The prevalence of TA (27.9%) increased significantly with age (Ptrend < 0.001). The distribution of full compensation in J0 and J45 components were similar (22.1% and 25.6%, respectively), which decreased with age (Ptrend < 0.001). The closer the refractive status was to emmetropization, the higher the proportion of full compensation and the lower the prevalence of TA were. Shorter axial length (J0: Odds Ratio (OR) = 0.76, 95% confidence interval (CI): 0.61 to 0.94, P = 0.010), better UDVA (J0: OR = 0.37, 95% CI: 0.21 to 0.65, P < 0.001; J45: OR = 0.34, 95% CI: 0.20 to 0.59, P < 0.001), and longer average corneal curvature radius (J0: OR = 3.72, 95% CI: 2.18 to 6.34, P < 0.001; J45: OR = 2.82, 95% CI: 1.67 to 4.76, P < 0.001) were associated with full compensation. Higher TA was associated with a worse UDVA (β = 0.03, 95% CI: 0.02 to 0.04, P < 0.001).ConclusionsThe prevalence of TA gradually increased with age, and showed a U-shaped distribution with increased refraction. Full compensation was associated with smaller TA and better UDVA. This indicated that considering the compensatory effect of ORA is vital for astigmatism correction in clinical work, which may improve the visual quality.

How to achieve multicolor organic room-temperature phosphorescence (RTP) is still challenging and striking. Herein, we discovered a new principle to construct eco-friendly color-tunable RTP nanomaterials based on the nano-surface confining effect. Cellulose nanocrystal (CNC) immobilized cellulose derivatives (CX) containing aromatic substituents via hydrogen-bonding interactions, which effectively inhibit the motion of cellulose chains and luminescent groups to suppress the nonradiative transitions. Meanwhile, CNC with a strong hydrogen-bonding network can isolate oxygen. CX with different aromatic substituents regulate the phosphorescent emission. After mixing CNC and CX directly, a series of polychromatic ultralong RTP nanomaterials were obtained. The RTP emission of the resultant CX@CNC can be finely adjusted through the introduction of various CX and the regulation of the CX/CNC ratio. Such a universal, facile, and effective strategy can be used to fabricate various colorful RTP materials with wide color gamut. Because of the complete biodegradability of cellulose, the multicolor phosphorescent CX@CNC nanomaterials can be used as eco-friendly security inks to fabricate disposable anticounterfeiting labels and information-storage patterns via conventional printing and writing processes.

Polymyxin B (PB) is a dose-dependent drug used to treat multidrug-resistantgram-negative bacteria, for which a suitable method is needed to determine clinical samples. A simple, economical, and efficient high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method was developed and validated for polymyxin B1 (PB1), polymyxin B1-Ile (PB1-I), polymyxin B2 (PB2), and polymyxin B3 (PB3) in human plasma. Chromatographic column was Waters BEH C18 column (2.1 × 50 mm, 1.7 μm). Phase A was water with 0.2% formic acid (FA), and phase B was acetonitrile containing 0.2% FA. The elution method is gradient elutio. The total analysis time was 5 min. The pretreatment method involved protein precipitation using acetonitrile containing 0.2% trifluoroacetic acid and 0.1% FA as the precipitant. The recovery rate was 92–99%. The total quantity of PB1 and PB1-I was measured in the linear range of 100–8000 ng/mL. Simultaneously, the total amounts of PB2 and PB3 were measured in the linear range of 11.9–948.5 ng/mL. This validated method was successfully applied to the pharmacokinetics of PB in critically ill patients.

BackgroundPatients with head trauma may develop hydrocephalus after decompressive craniectomy. Many studies have referred one-stage cranioplasty (CP) and ventriculoperitoneal shunt (VPS) was applied to treat cranial defect with post-traumatic hydrocephalus (PTH), but the safety and efficiency of the procedure remain controversial.MethodsThis is a retrospective cohort study including 70 patients of PTH following decompressive craniectomy who underwent simultaneous (50) and separated (20) procedures of cranioplasty and VPS from March 2014 to March 2021 at the authors’ institution with at least 30 days of follow-up. Patient characteristics, clinical findings, and complications were collected and analyzed.ResultsFifty patients with PTH underwent improved simultaneous procedures and 20 patients underwent staged surgeries. Among the cases, the overall complication rate was 22.86%. Complications suffered by patients who underwent one-stage procedure of CP and VPS did not differ significantly, compared with patients in the group of staged procedures (22% vs. 25%, p = 0.763). The significant difference was not observed in the two groups, regarding the complications of subdural/epidural fluid collection (4%/6% vs. 0/2%, p = 1.000/1.000), epidural hemorrhage (6% vs. 4%, p = 0.942), dysfunction of shunting system (0 vs. 2%, p = 0.286), postoperative seizure (8% vs. 4%, p = 1.000), and reoperation case (0 vs. 2%, p = 0.286). No case of subdural hemorrhage, incision/intracranial/abdominal infection, shunting system dysfunction, or reoperation was observed in the group of simultaneous procedure. Complications including subdural/epidural fluid collection, subdural hemorrhage, and incision/intracranial infection were not shown in the case series of the staged procedure group.ConclusionThe improved simultaneous procedure of cranioplasty and VPS is effective and safe to treat cranial defect and post-traumatic hydrocephalus with low risk of complications.

ObjectiveTo investigate anisometropia's prevalence and associated factors in school-aged children.MethodsA cross-sectional school-based study was conducted in Shandong Province, China, including children aged 4 to 17 from 9 schools. Anisometropia was defined as the differences between the two eyes in spherical equivalent (SE) or cylinder degree of 1.00 diopter (D) or more [SE or cylindrical (CYL) difference ≥ 1.00 D] after cycloplegic autorefraction. The Generalized Linear Model (GLM) was used to analyze the effects of ocular parameters [the differences between eyes in axial length (AL), habitual visual acuity (HVA), and corneal astigmatism (CA)] and lifestyle parameters (time spent indoor near work and outdoor activities) on anisometropia.ResultsTotal 4,198 (93.4%) of the 4,494 children were included in the statistical analysis. The mean difference in inter-eye SE was 0.42 ± 0.61 D. The prevalence of anisometropia was 13.2% (95%CI: 12.1 to 14.2%) (SE anisometropia's prevalence:10.3%; CYL anisometropia's prevalence: 4.1%), increased with older age (OR = 1.10, P = 0.002), the worse myopic eye (myopia vs. premyopia, OR = 1.87, P = 0.002), the worse hyperopic eye (hyperopia vs. premyopia, OR = 1.77, P = 0.013), larger difference in inter-eye AL (0.1–0.3 vs. ≤ 0.1, OR = 1.67, P = 0.008; >0.3 vs. ≤ 0.1, OR = 28.61, P < 0.001), HVA (>0.2 vs. ≤ 0.2, OR = 3.01, P < 0.001), CA (OR = 6.24, P < 0.001), the worse stereoacuity (>100 vs. ≤ 100, OR = 1.59, P = 0.001), longer indoor near work time per day on weekends (4–8 vs. 0.3 vs. ≤ 0.1, β: 0.556, 95%CI: 0.050 to 1.063), HVA (>0.2 vs. ≤ 0.2, β: 0.511, 95%CI: 0.312 to 0.710), and CA (β: 0.488, 95%CI: 0.289 to 0.688), stereoacuity (>100 vs. ≤ 100, β: 0.299, 95%CI: 0.110 to 0.488) had a positive impact on the difference in inter-eye SE.ConclusionsOcular parameters and lifestyle parameters are associated with the occurrence of anisometropia in children aged 4 to 17 years, including the difference in inter-eye AL, HVA, CA, stereoacuity, indoor near work time, and outdoor activity time. Preventing myopia and early treating anisometropic amblyopia may be effective ways to reduce the prevalence of anisometropia.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide with poor clinical outcomes, and the infection of hepatitis B virus (HBV) is the leading cause of this disease. Mounting evidence shows that RNA binding proteins (RBPs) can modulate the progression of cancers. However, the functions and clinical implications of RBP-related mRNAs in HBV-related HCC remain largely unclear. Therefore, we aim to develop a prognostic model based on the RBP-related mRNAs for HBV-related HCC patients. Firstly, we identified 626 differentially expressed RBP-related mRNAs in the HBV-related HCC through the Pearson correlation analysis. Subsequently, the Kaplan-Meier survival, univariate, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses were used to construct a prognostic model comprised of five RBP-related mRNAs. Furthermore, the patients were categorized into the high- and low-risk groups by the prognostic model and the patients in the high-risk group had a poor prognosis. Additionally, the prognostic model was an independent predictor of prognosis, and the accuracy of the prognostic model was proved by the receiver operator characteristic (ROC) analysis. Furthermore, the functional enrichment analysis revealed that various cancer-promoting processes were enriched in the high-risk group. Taken together, our study may provide the HBV-related HCC biomarkers of prognosis to improve the clinical outcomes of patients.

Impaired cholesterol synthesizing ability is considered a risk factor for the development of Alzheimer’s disease (AD), as evidenced by reduced levels of key proteases in the brain that mediate cholesterol synthesis; however, cholesterol deposition has been found in neurons in tangles in the brains of AD patients. Although it has been shown that statins, which inhibit cholesterol synthesis, reduce the incidence of AD, this seems paradoxical for AD patients whose cholesterol synthesizing capacity is already impaired. In this study, we aimed to investigate the effects of aerobic exercise on cholesterol metabolism in the brains of APP/PS1 mice and to reveal the mechanisms by which aerobic exercise improves cognitive function in APP/PS1 mice. Our study demonstrates that the reduction of SEC24D protein, a component of coat protein complex II (COPII), is a key factor in the reduction of cholesterol synthesis in the brain of APP/PS1 mice. 12 weeks of aerobic exercise was able to promote the recovery of SEC24D protein levels in the brain through activation of protein kinase B (AKT), which in turn promoted the expression of mem-brane-bound sterol regulatory element-binding protein 2 (SREBP2) nuclear translocation and the expression of key proteases mediating cholesterol synthesis. Simultaneous aerobic exercise restored cholesterol transport capacity in the brain of APP/PS1 mice with the ability to efflux excess cholesterol from neurons and reduced neuronal lipid rafts, thereby reducing cleavage of the APP amyloid pathway. Our study emphasizes the potential of restoring intracerebral cholesterol homeostasis as a therapeutic strategy to alleviate cognitive impairment in AD patients.

Abstract Background Contemporary to the rapidly evolving landscape of cancer immunotherapy is the equally changing understanding of immune tumor microenvironments (TMEs) which is crucial to the success of these therapies. Their reliance on a robust host immune response necessitates clinical grade measurements of immune TMEs at diagnosis. In this study, we describe a stable tumor immunogenic profile describing immune TMEs in multiple tumor types with ability to predict clinical benefit from immune checkpoint inhibitors (ICIs). Methods A tumor immunogenic signature (TIGS) was derived from targeted RNA-sequencing (RNA-seq) and gene expression analysis of 1323 clinical solid tumor cases spanning 35 histologies using unsupervised analysis. TIGS correlation with ICI response and survival was assessed in a retrospective cohort of NSCLC, melanoma and RCC tumor blocks, alone and combined with TMB, PD-L1 IHC and cell proliferation biomarkers. Results Unsupervised clustering of RNA-seq profiles uncovered a 161 gene signature where T cell and B cell activation, IFNg, chemokine, cytokine and interleukin pathways are over-represented. Mean expression of these genes produced three distinct TIGS score categories: strong (n = 384/1323; 29.02%), moderate (n = 354/1323; 26.76%), and weak (n = 585/1323; 44.22%). Strong TIGS tumors presented an improved ICI response rate of 37% (30/81); with highest response rate advantage occurring in NSCLC (ORR = 36.6%; 16/44; p = 0.051). Similarly, overall survival for strong TIGS tumors trended upward (median = 25 months; p = 0.19). Integrating the TIGS score categories with neoplastic influence quantified via cell proliferation showed highly proliferative and strong TIGS tumors correlate with significantly higher ICI ORR than poorly proliferative and weak TIGS tumors [14.28%; p = 0.0006]. Importantly, we noted that strong TIGS and highly [median = not achieved; p = 0.025] or moderately [median = 16.2 months; p = 0.025] proliferative tumors had significantly better survival compared to weak TIGS, highly proliferative tumors [median = 7.03 months]. Importantly, TIGS discriminates subpopulations of potential ICI responders that were considered negative for response by TMB and PD-L1. Conclusions TIGS is a comprehensive and informative measurement of immune TME that effectively characterizes host immune response to ICIs in multiple tumors. The results indicate that when combined with PD-L1, TMB and cell proliferation, TIGS provides greater context of both immune and neoplastic influences on the TME for implementation into clinical practice.

BackgroundChronic subdural haematoma (CSDH) has various causes, including trauma, coagulopathies, and intracranial hypotension. However, CSDH associated with extracranial malignancy is rare. Here, we report an extremely rare case of CSDH due to prostate cancer metastasis to a haematoma capsule.Case DescriptionA 79-year-old man with a history of prostate cancer had a progressive decline in consciousness during hospitalization for cancer treatment. CSDH was diagnosed from computed tomography (CT) imaging. We urgently performed burr hole drainage, and the patient’s symptoms improved rapidly after surgery. After removing the drainage tube, the patient’s symptoms worsened again, and the repeat head CT suggested recurrence of CSDH. In a second operation, most of the haematoma capsule was excised under craniotomy, and the thickened haematoma capsule was sent for routine pathologic examination. Pathological findings confirmed the metastasis of prostate cancer to the haematoma capsule, which we believed to be related to a rapid recurrence of CSDH. After the second operation, the disease course progressed without CSDH recurrence.ConclusionsFor patients with malignant tumours diagnosed with CSDH, the possibility of metastasis to a haematoma capsule needs to be considered. Burr holes and drainage can easily lead to a rapid relapse. Excision of the haematoma capsule is the key to successful treatment.

ABSTRACT Sepsis-associated encephalopathy (SAE) is common in septic patients and is associated with adverse outcomes. The gut microbiota has been recognized as a key mediator of neurological disease development. However, the exact role of the gut microbiota in regulating SAE remains elusive. Here, we investigated the role of the gut microbiota in SAE and its underlying mechanisms. Cecal ligation and puncture (CLP) was conducted to induce sepsis in mice. Neurological scores were recorded to distinguish SAE-resistant (SER) (score of >6 at 36 h postoperatively) from SAE-susceptible (SES) (score of ≤6 at 36 h postoperatively) mice. 16S rRNA gene sequencing and metabolomics analyses were used to characterize the gut microbiota in the two groups. Fecal microbiota transplantation was performed to validate the role of the gut microbiota in SAE progression. The gut microbiota was more severely disrupted in SES mice than in SER mice after sepsis modeling. Interestingly, mice receiving postoperative feces from SES mice exhibited more severe cortical inflammation than mice receiving feces from SER mice. Indole-3-propionic acid (IPA), a neuroprotective molecule, was more enriched in feces from SER mice than in feces from SES mice. IPA alleviated CLP-induced anxiety and spatial memory impairment in septic mice. Moreover, IPA markedly inhibited NLRP3 inflammasome activation and interleukin-1β (IL-1β) secretion in lipopolysaccharide-stimulated microglia. These responses were attenuated after antagonizing the aryl hydrocarbon receptor. Our study indicates that the variability in sepsis-induced gut dysbiosis mediates the differential susceptibility to SAE in CLP-induced experimental sepsis mice, and microbially derived IPA is possibly involved in SAE development as a neuroprotective compound. IMPORTANCE The bidirectional interactions between the gut microbiota and sepsis-associated encephalopathy (SAE) are not well characterized. We found that the gut microbiota was more severely disturbed in SAE-susceptible (SES) mice than in SAE-resistant (SER) mice after sepsis modeling. Mice gavaged with postoperative feces from SES mice exhibited more severe neuroinflammation than mice gavaged with feces from SER mice. The gut microbiota from SER mice enriched a neuroprotective metabolite, IPA, which appeared to protect mice from SAE. The potential underlying mechanism of the protective effect of IPA may be mediated via the inhibition of NLRP3 inflammasome activation and IL-1β secretion in microglia. These anti-inflammatory effects of IPA may be regulated by aryl hydrocarbon receptors. These results enhance our understanding of the role of the intestinal microbiota in sepsis. In particular, gut microbiota-derived IPA may serve as a potential therapeutic agent to prevent neuroinflammation in SAE.

ABSTRACT The effects of using gut microbiota metabolites instead of live microorganisms to modulate sepsis-induced gut dysbiosis remain largely unknown. We assessed the effects of microbiota metabolite indole-3-propionic acid (IPA) on gut microbiota in mice during sepsis. Sepsis models were constructed by cecal ligation and puncture (CLP) methods. Fecal microbiota composition analysis was performed to characterize the gut microbiota composition. Fecal microbiota transplantation was performed to validate the roles of gut microbiota on sepsis progression. IPA-treated mice exhibited lower serum inflammatory mediator levels and a higher survival rate than those of saline-treated mice after modeling of sepsis, which were negated in the presence of antibiotics. Compared with saline-treated mice after modeling, IPA-treated mice showed a markedly different intestinal microbiota composition, with an enrichment of Bifidobacteriaceae family and a depletion of Enterobacteriaceae family. Mice gavaged with postoperative feces from IPA-treated animals displayed better survival than mice gavaged with feces from saline-treated animals. Overall, these data suggest that IPA offers a microbe-modulated survival advantage in septic mice, indicating that some microbiota metabolites could replace live microorganisms as potential options for regulation of sepsis-induced gut dysbiosis. IMPORTANCE The role of gut microbiota in the pathophysiology of sepsis is gaining increasing attention and developing effective and safe sepsis therapies targeting intestinal microorganisms is promising. Given the safety of probiotic supplementation or fecal microbiota transplantation in critically ill patients, identifying an abiotic agent to regulate the intestinal microbiota of septic patients is of clinical significance. This study revealed that IPA, a microbiota-generated tryptophan metabolite, ameliorated sepsis-induced mortality and decreased the serum levels of proinflammatory cytokines by modulating intestinal microbiota. Although IPA did not increase the abundance and diversity of the microbiota of septic mice, it significantly decreased the number of Enterobacteriaceae family. These findings indicate that a specific microbiota metabolite (e.g., IPA) can mediate the intestinal microbiota apart from FMT or probiotics.

Bioleaching processes or microbially mediated iron/sulfur redox processes in acid mine drainage (AMD) result in mineral dissolution and transformation, the release of mercury and other heavy metal ions, and changes in the occurrence forms and concentration of mercury. However, pertinent studies on these processes are scarce. Therefore, in this work, the Fe/S redox-coupled mercury transformation mediated by Acidithiobacillus ferrooxidans ATCC 23270 under aerobic and/or anaerobic conditions was studied by combining analyses of solution behavior (pH, redox potential, and Fe/S/Hg ion concentrations), the surface morphology and elemental composition of the solid substrate residue, the Fe/S/Hg speciation transformation, and bacterial transcriptomics. It was found that: (1) the presence of Hg2+ significantly inhibited the apparent iron/sulfur redox process; (2) the addition of Hg2+ caused a significant change in the composition of bacterial surface compounds and elements such as C, N, S, and Fe; (3) Hg mainly occurred in the form of Hg0, HgS, and HgSO4 in the solid substrate residues; and (4) the expression of mercury-resistant genes was higher in earlier stages of growth than in the later stages of growth. The results indicate that the addition of Hg2+ significantly affected the iron/sulfur redox process mediated by A. ferrooxidans ATCC 23270 under aerobic, anaerobic, and coupled aerobic–anaerobic conditions, which further promoted Hg transformation. This work is of great significance for the treatment and remediation of mercury pollution in heavy metal-polluted areas.

Upstream open reading frames (uORFs) have widespread regulatory functions in eukaryotes, their genomic distribution and evolution is understudied. Here, the authors characterise ~17 million putative uORFs across 478 eukaryotic species, showing how evolution has shaped uORF contents and distribution.

Abstract Background Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial/macrophage activation and neuroinflammation are key cellular events following TBI, but the regulatory and functional mechanisms are still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, regulates multiple features of microglial/macrophage physiology. However, its function in regulating the innate immune response and microglial/macrophage M1/M2 polarization in TBI has not been addressed. The present study aimed to evaluate the role of Mer in regulating microglial/macrophage M1/M2 polarization and neuroinflammation following TBI. Methods The controlled cortical impact (CCI) mouse model was employed. Mer siRNA was intracerebroventricularly administered, and recombinant protein S (PS) was intravenously applied for intervention. The neurobehavioral assessments, RT-PCR, Western blot, magnetic-activated cell sorting, immunohistochemistry and confocal microscopy analysis, Nissl and Fluoro-Jade B staining, brain water content measurement, and contusion volume assessment were performed. Results Mer is upregulated and regulates microglial/macrophage M1/M2 polarization and neuroinflammation in the acute stage of TBI. Mechanistically, Mer activates the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition of Mer markedly decreases microglial/macrophage M2-like polarization while increases M1-like polarization, which exacerbates the secondary brain damage and sensorimotor deficits after TBI. Recombinant PS exerts beneficial effects in TBI mice through Mer activation. Conclusions Mer is an important regulator of microglial/macrophage M1/M2 polarization and neuroinflammation, and may be considered as a potential target for therapeutic intervention in TBI.

Abstract Hypoxic stress plays a pivotal role in cancer progression; however, how hypoxia drives tumors to become more aggressive or metastatic and adaptive to adverse environmental stress is still poorly understood. In this study, we revealed that CSN8 might be a key regulatory switch controlling hypoxia-induced malignant tumor progression. We demonstrated that the expression of CSN8 increased significantly in colorectal cancerous tissues, which was correlated with lymph node metastasis and predicted poor patient survival. CSN8 overexpression induces the epithelial-mesenchymal transition (EMT) process in colorectal cancer cells, increasing migration and invasion. CSN8 overexpression arrested cell proliferation, upregulated key dormancy marker (NR2F1, DEC2, p27) and hypoxia response genes (HIF-1α, GLUT1), and dramatically enhanced survival under hypoxia, serum deprivation, or chemo-drug 5-fluorouracil treatment conditions. In particular, silenced CSN8 blocks the EMT and dormancy processes induced by the hypoxia of 1% O2 in vitro and undermines the adaptive capacity of colorectal cancer cells in vivo. The further study showed that CSN8 regulated EMT and dormancy partly by activating the HIF-1α signaling pathway, which increased HIF-1α mRNA expression by activating NF-κB and stabilized the HIF-1α protein via HIF-1α de-ubiquitination. Taken together, CSN8 endows primary colorectal cancer cells with highly aggressive/metastatic and adaptive capacities through regulating both EMT and dormancy induced by hypoxia. CSN8 could serve as a novel prognostic biomarker for colorectal cancer and would be an ideal target of disseminated dormant cell elimination and tumor metastasis, recurrence, and chemoresistance prevention.

BackgroundTherapy for large or deep cystic brain metastases is a troublesome procedure in clinical departments. Stereotactic cyst aspiration, combined with Gamma Knife radiosurgery, can be an effective treatment for cystic brain metastases. However, there is still a possibility that a reaccumulation of cystic fluid may lead to poor efficacy or even reoperation.Case presentationWe present a case of a 67-year-old man who was diagnosed with lung cancer brain metastasis. The intracranial lesion seen on imaging appeared to be cystic and located deep inside the brain with associated limb dysfunction. The patient did not respond well to chemotherapy and underwent cyst aspiration with Ommaya reservoir implantation under neuronavigation. Repeated cystic fluid reaccumulation and exacerbation of symptoms occurred during treatment. We performed repeated aspiration via the Ommaya reservoir to control the symptoms and combined it with radiotherapy. During the follow-up period of 14 months, the intracranial tumor was effectively and satisfactorily controlled.ConclusionsWe highlight that Ommaya reservoir implantation during stereotactic cyst aspiration is necessary to prevent fluid reaccumulation, thereby avoiding the need for a second surgical procedure.

As a new type of natural flavonoids, dihydromyricetin (DMY) has attracted more and more attention. It has a series of pharmacological effects, such as anti-inflammatory, anti-tumor, anti-oxidation, antibacterial and so on, and it is almost no toxicity and with excellent safety. Therefore, even if the bioavailability is poor, it is often added to daily food, beverages and even medicines. In recent years, some researchers have found that DMY can treat some diseases by anti-oxidation, anti-inflammation, promoting cell death and regulate the activity of lipid and glucose metabolism. In addition, the mechanism of DMY on these diseases was also related to the signal pathway of AMPK, PI3K/Akt, PPAR and the participation of microRNAs. This review describes the mechanism of DMY in metabolic related diseases from three aspects: metabolic diseases, liver diseases, and cancers, hoping to provide some new ideas for clinical researches.

Purpose: To assess the significance of mutation mutual exclusion information in the optimization of radiomics algorithms for predicting gene mutation.Methods: We retrospectively analyzed 258 non-small cell lung cancer (NSCLC) patients. Patients were randomly divided into training (n = 180) and validation (n = 78) cohorts. Based on radiomics features, radiomics score (RS) models were developed for predicting KRAS proto-oncogene mutations. Furthermore, a composite model combining mixedRS and epidermal growth factor receptor (EGFR) mutation status was developed.Results: Compared with CT model, the PET/CT radiomics score model exhibited higher AUC for predicting KRAS mutations (0.834 vs. 0.770). By integrating EGFR mutation information into the PET/CT RS model, the AUC, sensitivity, specificity, and accuracy for predicting KRAS mutations were all elevated in the validation cohort (0.921, 0.949, 0.872, 0.910 vs. 0.834, 0.923, 0.641, 0.782). By adding EGFR exclusive mutation information, the composite model corrected 64.3% false positive cases produced by the PET/CT RS model in the validation cohort.Conclusion: Integrating EGFR mutation status has potential utility for the optimization of radiomics models for prediction of KRAS gene mutations. This method may be used when repeated biopsies would carry unacceptable risks for the patient.

BackgroundT-cell lymphoproliferative disease (T-LPD), characterized by primary Epstein–Barr virus (EBV) infection and clonal proliferation of T cells, occurs both in systemic and non-lymphatic organs. However, isolated indolent EBV-positive T-LPD involving the central nervous system has not been reported.Case PresentationA 48-year-old male who complained of headache, blurred vision, and weakness of the left lower limb for 1 month was hospitalized in our department. Neither neurological deficit nor palpable lymphadenopathy had been found. Bone marrow and laboratory tests had shown no abnormality as well. Enhanced MRI demonstrated enhanced cotton-like lesions up to 20 mm in diameter located in the right frontal, temporal, parietal and left parietal, occipital lobes with perifocal edema. Neuronavigation-assisted mini-craniotomy was performed to achieve total excision of the right temporal superficial lesion and identify the diagnosis. Pathological and EBV analysis described the lesion as indolent EBV-positive T-cell lymphoproliferative disease of the central nervous system (CNS). Then, a therapeutic regimen including whole-brain irradiation, chemotherapy, prednisolone, and aciclovir was given. Serial radiological imaging showed no signal of recurrence at 5 months' follow-up.ConclusionPrimary indolent T-LPD in the central nervous system is quite rare, and it needs to be distinguished from aggressive cerebral T-cell lymphoma, metastatic tumors, and other CNS lesions.

Aims. Ulcerative colitis (UC) is a type of chronic idiopathic inflammatory bowel disease with a multifactorial pathogenesis and limited treatment options. The aim of the present study is to investigate the hydrogen deuterium exchange mass spectrometry (HDX-MS) behaviors of fermented deoxyanthocyanidins and their molecular mechanisms to alleviate UC by using quantum chemistry and network pharmacology. Methods. Tandem MS indicated at least two fragmentation pathways through which deuterated vinylphenol-deoxyanthocyanidins could generate different product ions. Quantum calculations were conducted to determine the transition states of the relevant molecules and analyze their optimized configuration, vibrational characteristics, intrinsic reaction coordinates, and corresponding energies. The potential targets of deoxyanthocyanidins in UC were screened from a public database. The R package was used for Gene Ontology (GO) and KEGG pathway analyses, and the protein–protein interactions (PPIs) of the targets were assessed using Search Tool for the Retrieval of Interacting Genes (STRING). Finally, molecular docking was implemented to analyze the binding energies and action modes of the target compounds through the online tool CB-Dock. Results. Quantum calculations indicated two potential fragmentation pathways involving the six-membered ring and dihydrogen cooperative transfer reactions of the vinylphenol-deoxyanthocyanidins. A total of 146 and 57 intersecting targets of natural and fermented deoxyanthocyanidins were separately screened out from the UC database and significant overlaps in GO terms and KEGG pathways were noted. Three shared hub targets (i.e., PTGS2, ESR1, and EGFR) were selected from the two PPI networks by STRING. Molecular docking results showed that all deoxyanthocyanidins have a good binding potential with the hub target proteins and that fermented deoxyanthocyanidins have lower binding energies and more stable conformations compared with natural ones. Conclusions. Deoxyanthocyanidins may provide anti-inflammatory, antioxidative, and immune system regulatory effects to suppress UC progression. It is proposed for the first time that fermentation of deoxyanthocyanidins can help adjust the structure of the intestinal microbiota and increase the biological activity of the natural compounds against UC. Furthermore, HDX-MS is a helpful strategy to analyze deoxyanthocyanidin metabolites with unknown structures.

The novel thermosensitive star-shaped tetra-hydroxy-phenylporphyrin-cored (THPP) double hydrophilic poly(N-isopropylacrylamide)-b-poly(methylacrylamide glucose) block copolymers (THPP-(PNIPAM-b-PMAGA)4) were synthesized via the reversible addition-fragmentation chain transfer (RAFT) polymerization. Notably, the low critical solution temperatures (LCSTs) of THPP-(PNIPAM-b-PMAGA)4 were above normal body temperature (37 °C) which depended on the hydrophilic PMAGA contents of copolymers. When the temperature was higher than the LCST of the copolymer, the copolymer could be neutralized into micelles in aqueous and could be coated with antitumor drugs and released around tumor cells. The MTT study indicated that THPP-(PNIPAM-b-PMAGA)4 had a low toxicity to L929 and HeLa cells in the absence of light. However, THPP-(PNIPAM-b-PMAGA)4 showed a high toxicity with HeLa cells under light irradiation which could be used as a potential photosensitizer for photodynamic therapy (PDT). In addition, THPP-(PNIPAM-b-PMAGA)4 showed specific a recognition function with Concanavalin A (Con A) to achieve active targeted drug delivery. This work provides a new approach for the development of tumor targeting and chemotherapy/PDT.

When performing the diffuse optical tomography (DOT) of the breast, the mismatch between the forward model and the experimental conditions will significantly hinder the reconstruction accuracy. Therefore, the reference measurement is commonly used to calibrate the measured data before the reconstruction. However, it is complicated to customize corresponding reference phantoms based on the breast shape and background optical parameters of different subjects in clinical trials. Furthermore, although high-density (HD) DOT configuration has been proven to improve imaging quality, a large number of source-detector (SD) pairs also increase the difficulty of multi-channel correction. To enhance the applicability of the breast DOT, a data self-calibration method based on an HD parallel-plate DOT system is proposed in this paper to replace the conventional relative measurement on a reference phantom. The reference predicted data can be constructed directly from the measurement data with the support of the HD-DOT system, which has nearly a hundred sets of measurements at each SD distance. The proposed scheme has been validated by Monte Carlo (MC) simulation, breast-size phantom experiments, and clinical trials, exhibiting the feasibility in ensuring the quality of the DOT reconstruction while effectively reducing the complexity associated with relative measurements on reference phantoms.

Mercury (Hg) is a highly toxic and persistent heavy metal pollutant. The acid mine drainage (AMD) environment in sulfide-mining areas is a typical Hg pollution source. In this paper, the transformation of Hg2+ during anaerobic S0 reduction by an AMD environmental enrichment culture was studied by multiple spectroscopic and microscopic techniques. The experimental results showed that the microbial S0 reduction of the AMD enrichment culture was significantly inhibited in the presence of Hg2+. The results of cell surface morphology and composition analysis showed that there was obvious aggregation of flocculent particles on the cell surface in the presence of Hg2+, and the components of extracellular polymeric substances on the cell surface changed significantly. The results of surface morphology and C/S/Hg speciation transformation analyses of the solid particulate showed that Hg2+ gradually transformed to mercuric sulfide and Hg0 under anaerobic S0 reduction by the AMD enrichment culture. The microbial community structure results showed that Hg2+ significantly changed the enrichment community structure by decreasing their evenness. The dominant microorganisms with S0 reduction functions are closely related to mercury transformation and are the key driving force for the transformation of substrate solid particulate and cellular substances, as well as the fixation of Hg2+.

Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of the central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological, and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of β2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, for example, celastrol, might be a novel strategy for colorectal cancer treatment.

Objective: To present our classification for peripheral nerve schwannomas as well as explore the surgical strategies and operative management of peripheral nerve schwannomas based on the intraoperative neurophysiological monitoring (INM) technique and to decrease the risk of postoperative neurological deficits in the management of these schwannomas. Materials and methods: A retrospective study was conducted on 92 cases of peripheral nerve microsurgery performed, using the INM technique. We also made the classification for peripheral nerve schwannomas into two types according to operative findings and proceeded corresponding surgical strategies. Results: All tumors were removed completely under microscopy and INM. Three patients developed residual neurological deficits at final follow-up. There were different results about temporary (18/92, 19.6%) and permanent (3/92, 3.3%) neurological deficits. The incidence of temporary and permanent neurological deficits in type II group was significantly higher than that in type I group (p

Abstract Background Though esophageal cancer is three to four times more common among males than females worldwide, this type of cancer still ranks in the top incidence among women, even more than the female specific cancer types. The occurrence is currently attributed to extrinsic factors, including tobacco use and alcohol consumption. However, limited attention has been given to gender-specific intrinsic genetic factors, especially in female. Methods We re-annotated a large cohort of microarrays on 179 ESCC patients and identified female-specific differently expressed lncRNAs. The associations between FMR1-AS1 and the risk and prognosis of ESCC were examined in 206 diagnosed patients from eastern China and validated in 188 additional patients from southern China. The effects of FMR1-AS1 on the malignant phenotypes on female ESCC cells were detected in vitro and in vivo. ChIRP-MS, reporter gene assays and EMSA were conducted to identify the interaction and regulation among FMR1-AS1, TLR7 and NFκB. Results We found FMR1-AS1 expression is exclusively altered and closely associated with the level of sXCI in female ESCC patients, and its overexpression may correlate to poor clinical outcome. ChIRP-MS data indicate that FMR1-AS1 could be packaged into exosomes and released into tumor microenvironment. Functional studies demonstrated that FMR1-AS1 could bind to endosomal toll-like receptor 7 (TLR7) and activate downstream TLR7-NFκB signaling, promoting the c-Myc expression, thus inducing ESCC cell proliferation, anti-apoptosis and invasion ability. Exosome incubation and co-xenograft assay indicate that FMR1-AS1 exosomes may secreted from ESCC CSCs, transferring stemness phenotypes to recipient non-CSCs in tumor microenvironment. Furthermore, we also found a correlation between the serum levels of FMR1-AS1 and the overall survival (OS) of the female ESCC patients. Conclusions Our results highlighted exosomal FMR1-AS1 in maintaining CSC dynamic interconversion state through the mechanism of activating TLR7-NFκB signaling, upregulating c-Myc level in recipient cells, which may be taken as an attractive target approach for advancing current precision cancer therapeutics in female patients.

Abstract Background Regulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations. Methods NGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120 days post-test were gathered from tested patients’ medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated. Results Excluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively). Conclusions We found an appropriate “dose-response” relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance.