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Abstract Bacteria can be dead, alive, or exhibit slowed or suspended life forms, making bacterial death difficult to establish. Here, agar-plating, microscopic-counting, SYTO9/propidium-iodide staining, MTT-conversion, and bioluminescence-imaging were used to determine bacterial death upon exposure to different conditions. Rank correlations between pairs of assay outcomes were low, indicating different assays measure different aspects of bacterial death. Principal-component analysis yielded two principal components, named “reproductive-ability” (PC1) and “metabolic-activity” (PC2). Plotting of these principal components in two-dimensional space revealed a dead region, with borders defined by the PC1 and PC2 values. Sensu stricto implies an unpractical reality that all assays determining PC1 and PC2 must be carried out in order to establish bacterial death. Considering this unpracticality, it is suggested that at least one assay determining reproductive activity (PC1) and one assay determining metabolic activity (PC2) should be used to establish bacterial death. Minimally, researchers should specifically describe which dimension of bacterial death is assessed, when addressing bacterial death.

AbstractContext The Xihuang pill (XHP) is a traditional Chinese medicine formulation that has been historically used in the prevention and treatment of proliferative breast diseases. However, there is a lack of guidelines that offer recommendations for its clinical use.Objective The task force from the Chinese Guangdong Pharmaceutical Association aims to develop evidence-based guidelines for XHP to prevent and treat proliferative breast diseases.Methods We searched six Chinese and English electronic databases, including the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang Medical Database, PubMed, and Embase, up to November 1, 2022. Publications (case reports, clinical observation, clinical trials, reviews) on using XHP to treat proliferative breast diseases were manually searched. The search terms were Xihuang pill, hyperplasia of the mammary gland, breast lump, and mastalgia. The writing team developed recommendations based on the best available evidence.Results Treatment should be customized based on syndrome identification. We recommend using XHP for the prevention and treatment of breast hyperplasia disease when a patient presents the following syndromes: concurrent blood stasis syndrome, concurrent phlegm-stasis syndrome, and concurrent liver fire syndrome. Safety indicators, including blood analysis and liver and kidney function monitoring, should be performed regularly during treatment.Conclusions Current clinical evidence suggests that XHP can be used as a standalone treatment or in conjunction with other medications to prevent and manage breast hyperplasia diseases. More randomized controlled studies are warranted to establish high-quality evidence of its use.

BackgroundOligoasthenoteratozoospermia (OAT) is a widespread cause of male infertility. One of the usual clinical manifestations of OAT is multiple morphological abnormalities of the sperm flagella (MMAF), which are frequently associated with mutations and defects in the dynein family. However, the relationship between the newly identified Dynein Axonemal Heavy Chain 3 (DNAH3) mutation and oligonasthenospermia in humans has not yet been established.MethodsWhole exome sequencing, pathogenicity analysis, and species conservation analysis of mutation sites were conducted on two patients from different unrelated families with DNAH3 mutations. We identified representative mutation sites and predicted the protein structure following these mutations. The sperm characteristics of the two patients with DNAH3 mutations were verified using Papanicolaou staining, scanning electron microscopy, and transmission electron microscopy. Additionally, mRNA and protein levels were assessed through RT-qPCR and Western blotting.ResultsThe biallelic mutations in the first progenitor included a heterozygous deletion and insertion, c.6535_6536 delinsAC (to infect mutation (p.Asp2179Thr), and stop codon premutation, c.3249G > A (p.Trp1083Ter). In Family II, the patient (P2) harbored a DNAH3 heterozygous missense mutation, c. 10439G> A(p.Arg3480Gln), along with a stop codon premutation, (c.10260G > A; p.Trp3420Ter). Patients with premature termination of transcription or translation due to DNAH3 mutations exhibit OAT phenotypes, including fibrous sheath dysplasia and multiple tail malformations. We identified the representative sites after mutation, predicted the protein structure, and assessed changes in the protein levels of DNAH3 and related genes following mutations. Notably,a significant reduction in DNAH3 protein expression was validated in these patients. We may explore in the future how DNAH3 affects sperm motility and quality through regulatory mechanisms involving protein structural changes.ConclusionNovel biallelic mutations in DNAH3, especially those resulting in a premature stop codon, may alter protein expression, structure, and active site, leading to spermatogenic failure and potentially inducing OAT. The discovery of new mutations in DNAH3 may be the key to the diagnosis and treatment of OAT.

ObjectiveThe impact of oral flora on intestinal micro-environment and related diseases has been widely reported, but its role in colorectal cancer (CRC) remains elusive.MethodsA Two-sample Mendelian Randomization (TSMR) analysis was conducted to explore the causal relationship between oral flora and CRC, with the Inverse-Variance Weighted (IVW) serving as the primary method for evaluating this causal relationship. Data on the oral flora were derived from human samples from the tongue and saliva, with all cohort populations originating from Asia. In addition, 2 independent external cohorts were used to validate the positive results and perform a meta-analysis of the final results. Lastly, to balance the effect of positive oral flora on CRC, a Multivariate Mendelian Randomization (MVMR) analysis was also performed.ResultsThe TSMR analysis revealed that 17 oral flora may have a causal relationship with CRC in the training cohort. Among them, s Haemophilus, g Fusobacterium, s Metamycoplasma salivarium, and s Mogibacterium pumilum were validated in two testing cohorts. Intriguingly, after integrating the results of the 3 cohorts for meta-analysis, 16 associations remained significant. In the training cohort, MVMR analysis demonstrated that s Capnocytophaga ochracea and s Metamycoplasma salivarium retained statistical significance. In one of the testing cohorts, s Metamycoplasma salivarium, s Streptococcus anginosus, and s Streptococcus sanguinis retained statistical significance. In the other testing cohort, s Metamycoplasma salivarium, s Haemophilus, and g Fusobacterium remained significant.Conclusions Haemophilus, g Fusobacterium, s Metamycoplasma salivarium, and s Mogibacterium pumilum have a solid causal relationship with the occurrence and development of CRC.

Abstract Background Reintroduction represents an effective strategy for the conservation of endangered wildlife, yet it might inadvertently impact the native ecosystems. This investigation assesses the impact of reintroducing endangered Przewalski's horses into the desert grassland ecosystem of the Kalamaili Nature Reserve (KNR), particularly its effect on the spatial distribution of ticks. In a 25 km2 core area of Przewalski's horse distribution, we set up 441 tick sampling sites across diverse habitats, including water sources, donkey trails, and grasslands, recording horse feces and characteristics to analyze the occurrence rate of ticks. Additionally, we gathered the data of 669 fresh feces of horses. To evaluate the spatial dynamics between these feces and ticks, we used methods such as Fixed Kernel Estimation (FKE), Moran’s I spatial autocorrelation index, and Generalized Linear Models (GLM). Results The dominant species of ticks collected in the core area were adult Hyalomma asiaticum (91.36%). Their occurrence rate was higher near donkey trails (65.99%) and water sources (55.81%), particularly in areas with the fresh feces of Przewalski's horses. The ticks’ three risk areas, as defined by FKE, showed significant overlap and positive correlation with the distribution of Przewalski's horses, with respective overlap rates being 90.25% in high risk, 33.79% in medium risk, and 23.09% in low risk areas. Moran's I analysis revealed a clustering trend of the fresh feces of Przewalski's horses in these areas. The GLM confirmed a positive correlation between the distribution of H. asiaticum and the presence of horse fresh feces, alongside a negative correlation with the proximity to water sources and donkey trails. Conclusions This study reveals the strong spatial correlation between Przewalski's horses and H. asiaticum in desert grasslands, underlining the need to consider interspecific interactions in wildlife reintroductions. The findings are crucial for shaping effective strategies of wildlife conservation and maintaining ecological balance.

A significant demand rises for energy-efficient deep neural networks to support power-limited embedding devices with successful deep learning applications in IoT and edge computing fields. An accurate energy prediction approach is critical to provide measurement and lead optimization direction. However, the current energy prediction approaches lack accuracy and generalization ability due to the lack of research on the neural network structure and the excessive reliance on customized training dataset. This paper presents a novel energy prediction model, NeurstrucEnergy. NeurstrucEnergy treats neural networks as directed graphs and applies a bi-directional graph neural network training on a randomly generated dataset to extract structural features for energy prediction. NeurstrucEnergy has advantages over linear approaches because the bi-directional graph neural network collects structural features from each layer's parents and children. Experimental results show that NeurstrucEnergy establishes state-of-the-art results with mean absolute percentage error of 2.60%. We also evaluate NeurstrucEnergy in a randomly generated dataset, achieving the mean absolute percentage error of 4.83% over 10 typical convolutional neural networks in recent years and 7 efficient convolutional neural networks created by neural architecture search. Our code is available at https://github.com/NEUSoftGreenAI/NeurstrucEnergy.git.

Objective: Inflammation plays an important role in the transformation of pulmonary nodules (PNs) from benign to malignant. Prediction of benignancy and malignancy of PNs is still lacking efficacy methods. Although Mayo or Brock model have been widely applied in clinical practices, their application conditions are limited. This study aims to construct a diagnostic model of PNs by machine learning using inflammation-related biological markers (IRBMs). Methods: Inflammatory related genes (IRGs) were first extracted from GSE135304 chip data. Then, differentially expressed genes (DEGs) and infiltrating immune cells were screened between malignant pulmonary nodules (MN) and benign pulmonary nodule (BN). Correlation analysis was performed on DEGs and infiltrating immune cells. Molecular modules of IRGs were identified through Consistency cluster analysis. Subsequently, IRBMs in IRGs modules were filtered through Weighted gene co-expression network analysis (WGCNA). An optimal diagnostic model was established using machine learning methods. Finally, external dataset GSE108375 was used to verify this result. Results: 4 hub IRGs and 3 immune cells showed significantly difference between MN and BN, C1 and C2 module, namely PRTN3, ELANE, NFKB1 and CTLA4, T cells CD4 naïve, NK cells activated and Monocytes. IRBMs were screened from black module and yellowgreen module through WGCNA analysis. The Support vector machines (SVM) was identified as the optimal model with the Area Under Curve (AUC) was 0.753. A nomogram was established based on 5 hub IRBMs, namely HS.137078, KLC3, C13ORF15, STOM and KCTD13. Finally, external dataset GSE108375 verified this result, with the AUC was 0.718. Conclusion: SVM model established by 5 hub IRBMs was able to effectively identify MN or BN. Accumulating inflammation and immune dysfunction were important to the transformation from BN to MN.

ObjectiveNumerous studies have reported that metformin can reduce the risk of tumor development. However, some of the results of these studies are conflicting, necessitating a more reliable evaluation.MethodsWe conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) of tumors to explore the causal relationship between metformin and tumors. Two cohorts of patients taking metformin were obtained from the UK Biobank. Complete phenotype data of the tumors were obtained from FinnGen_R10. We elucidated the causal relationship using a two-sample Mendelian randomization (MR) analysis. More importantly, we conducted a meta-analysis to ensure relatively unbiased results. In the MR analysis, we used the inverse-variance weighted (IVW) method as the main outcome indicator. Subsequently, two cohorts were integrated for the meta-analysis. Finally, we investigated the mechanisms through mediational MR analysis.ResultsMR analysis revealed that metformin might have a causal relationship with 13 tumor-associated phenotypes in the training cohort. Four phenotypes were validated in the testing cohort. In the training and testing cohorts, metformin exhibited a protective effect against brain meningiomas and malignant neoplasms of the breast (HER-positive), oral cavity, tonsils, and the base of the tongue. Intriguingly, after integrating the results of the two cohorts for the meta-analysis, 12 results were statistically significant. Mediational MR analysis suggested that the effects of metformin on brain meningiomas may be weakened by the presence of the family Oxalobacteraceae.ConclusionMetformin exhibits potential preventive and therapeutic effects on four types of tumors: brain meningioma, malignant neoplasms of the breast (HER-positive), oral cavity and tonsils, and the base of the tongue. Large randomized controlled trials are required to confirm these findings.

ABSTRACTNeuroblastoma (NB) is a type of neuroectodermal tumor that originates from primitive sympathetic ganglion cells. Although many risk factors contributing to the occurrence of NB have been reported in recent years, the role of the gut microbiota in its development remains unclear. A bidirectional Mendelian randomization (MR) analysis was conducted to elucidate the causal relationship between the gut microbiota and NB. In the MR analysis, we employed the inverse-variance weighted (IVW) method as the primary criterion for assessing causality, while also utilizing three additional approaches, including MR-Egger, weighted median model, and weighted mode, for comprehensive evaluation. For gut microbiota that were causally associated with NB, a reverse MR was also used to assess the stability of this causal relationship. Finally, we also used external cohorts for validation and performed a meta-analysis of the results. The IVW results indicated a causal relationship between six gut microbiota and NB. Among the six gut microbiota, genus Lachnospiraceae [IVW odds ratio (OR): 2.66, 95% confidence interval (CI): 1.09–6.51, P value: 0.03] exhibited a detrimental effect against NB. On the other hand, the class Actinobacteria (IVW OR: 0.24, 95% CI: 0.07–0.77, P value: 0.02), the family Bifidobacteriaceae (IVW OR: 0.40, 95% CI: 0.17–0.96, P value: 0.04), the genus Desulfovibrio (IVW OR: 0.50, 95% CI: 0.25–0.97, P value: 0.04), the genus Bifidobacterium (IVW OR: 0.39, 95% CI: 0.16–0.92, P value: 0.03), and the genus Howardella (IVW OR: 0.55, 95% CI: 0.31–0.97, P value: 0.04) displayed a protective effect on NB. A reverse MR analysis did not reveal a causality between NB and the six gut microbiota. Meta-analysis showed that genus Bifidobacterium (meta OR: 0.41, 95% CI: 0.22–0.75, P < 0.01) and genus Lachnospiraceae (meta OR: 2.20, 95% CI: 1.01–4.79, P < 0.05) were still significant.IMPORTANCEBidirectional Mendelian randomization was used to explore the causality between gut microbiota and neuroblastoma (NB). The results showed that there is a causal relationship between the six gut microbiota and NB, of which two gut microbiota were further confirmed in the meta-analysis. This may provide a new perspective on the prevention and treatment of NB.

In this study, amine vapor-sensitive films with ratiometric fluorescence attributes were developed. The pH-sensitive fluorescein 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) and its tetraphenylethylene derivative (TPB) were selected as ratiometric indicators and incorporated into a polyvinyl alcohol (PVA) matrix to produce HPTS/TPB-PVA films. The films responded well to amine vapors, and the interference of aromatic vapors did not substantially affect the fluorescence signals of the films. Under UV light at a wavelength of 365 nm, the fluorescence of the films changed from dark pink to light pink and finally to yellow when the freshness of the fish was visually checked during storage. In addition, the color difference values of the films showed a positive correlation with the total volatile basic nitrogen (TVB-N), ranging from 12.7 to 24.8 mg/100 g at 25 °C and 8.4 to 25.6 mg/100 g at 4 °C, respectively. This indicates that fluorescent films have good potential for quantifying fish freshness in the near future when connected to an automatic data processing system based on color differences.

Abstract Objective The aim of this study was to construct a model used for the accurate diagnosis of Atopic dermatitis (AD) using pyroptosis related biological markers (PRBMs) through the methods of machine learning. Method The pyroptosis related genes (PRGs) were acquired from molecular signatures database (MSigDB). The chip data of GSE120721, GSE6012, GSE32924, and GSE153007 were downloaded from gene expression omnibus (GEO) database. The data of GSE120721 and GSE6012 were combined as the training group, while the others were served as the testing groups. Subsequently, the expression of PRGs was extracted from the training group and differentially expressed analysis was conducted. CIBERSORT algorithm calculated the immune cells infiltration and differentially expressed analysis was conducted. Consistent cluster analysis divided AD patients into different modules according to the expression levels of PRGs. Then, weighted correlation network analysis (WGCNA) screened the key module. For the key module, we used Random forest (RF), support vector machines (SVM), Extreme Gradient Boosting (XGB), and generalized linear model (GLM) to construct diagnostic models. For the five PRBMs with the highest model importance, we built a nomogram. Finally, the results of the model were validated using GSE32924, and GSE153007 datasets. Results Nine PRGs were significant differences in normal humans and AD patients. Immune cells infiltration showed that the activated CD4+ memory T cells and Dendritic cells (DCs) were significantly higher in AD patients than normal humans, while the activated natural killer (NK) cells and the resting mast cells were significantly lower in AD patients than normal humans. Consistent cluster analysis divided the expressing matrix into 2 modules. Subsequently, WGCNA analysis showed that the turquoise module had a significant difference and high correlation coefficient. Then, the machine model was constructed and the results showed that the XGB model was the optimal model. The nomogram was constructed by using HDAC1, GPALPP1, LGALS3, SLC29A1, and RWDD3 five PRBMs. Finally, the datasets GSE32924 and GSE153007 verified the reliability of this result. Conclusions The XGB model based on five PRBMs can be used for the accurate diagnosis of AD patients.

ObjectiveCarcinoid syndrome (CS) commonly results from neuroendocrine tumors. While active substances are recognized as the main causes of the typical symptoms such as diarrhea and skin flush, the cause-and-effect relationship between gut microbiota abundance and CS remains unclear.MethodsThe Single Nucleotide Polymorphisms (SNPs) related to gut microbiota abundance and CS were obtained from the GWAS summary data. The inverse variance weighted (IVW) method was used to assess the causal relationship between gut microbiota abundance and CS. Additionally, the MR-Egger, Weighted Median model, and Weighted model were employed as supplementary approaches. The heterogeneity function of the TwoSampleMR package was utilized to assess whether SNPs exhibit heterogeneity. The Egger intercept and Presso test were used to assess whether SNPs exhibit pleiotropy. The Leave-One-Out test was employed to evaluate the sensitivity of SNPs. The Steiger test was utilized to examine whether SNPs have a reverse causal relationship. A bidirectional mendelian randomization (MR) study was conducted to elucidate the inferred cause-and-effect relationship between gut microbiota abundance and CS.ResultsThe IVW results indicated a causal relationship between 6 gut microbiota taxa and CS. Among the 6 gut microbiota taxa, the genus Anaerofilum (IVW OR: 0.3606, 95%CI: 0.1554–0.8367, p-value: 0.0175) exhibited a protective effect against CS. On the other hand, the family Coriobacteriaceae (IVW OR: 3.4572, 95%CI: 1.0571–11.3066, p-value: 0.0402), the genus Enterorhabdus (IVW OR: 4.2496, 95%CI: 1.3314–13.5640, p-value: 0.0146), the genus Ruminiclostridium6 (IVW OR: 4.0116, 95%CI: 1.2711–12.6604, p-value: 0.0178), the genus Veillonella (IVW OR: 3.7023, 95%CI: 1.0155–13.4980, p-value: 0.0473) and genus Holdemanella (IVW OR: 2.2400, 95%CI: 1.0376–4.8358, p-value: 0.0400) demonstrated a detrimental effect on CS. The CS was not found to have a reverse causal relationship with the above 6 gut microbiota taxa.ConclusionSix microbiota taxa were found to have a causal relationship with CS, and further randomized controlled trials are needed for verification.

The targets and mechanisms of Si-Wu-Tang (SWT) against (Breast cancer) BRCA were identified and a survival model and nomogram was construted by network pharmacology, bioinformatic analysis and in vitro experiments. A total of 72 anti-breast cancer SWT targets were selected, among which eleven genes (MAOA、SQLE、CACNA2D1、GLI1、RORB、ITGB3、TACR1、NR3C2、CA3、RBP4 and PTK6) were used to construct a novel prognostic model of breast cancer. The anti-breast cancer activity of SWT was related to the modulation of the receptor tyrosine kinases signaling pathways. Moreover, two compounds, mairin and senkyunone were found to bind directly to ITGB3 and RORB proteins. Finally, mRNA and protein expression of ITGB3 and RORB was observed to be significantly down-regulated after incubation of MCF-7 cells with SWT. Overall, our results indicated that mairin and senkyunone were the key ingredients present in SWT, and ITGB3 as well as RORB proteins were the major targets affected by SWT. The prognostic model can be used to predict the outcome of BRCA patients.

Introduction: This planned multicenter observational study will evaluate the overall survival of those undergoing integrated Chinese and Western medicine for stage IIIb-IVb non-small cell lung cancer and analyze the factors related to the prognosis. Method and Analysis: The prospective cohort will enroll patients with stage IIIb-IVb NSCLC from March 1, 2019, to December 31, 2025, and follow them for 5 years. We plan to collect data on the patients’ demographics, treatment, overall survival, and factors related to the prognosis. Ethics and Dissemination: The institutional review board and ethics committee reviewed the study protocol. All patients will provide informed consent before enrollment. Trial registration number: ChiCTR1900021430

Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model to simultaneously predict the pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis (LC) patients. Six prodrugs (enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. Parameters such as organ blood flows, plasma-binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate (GFR) and gastrointestinal transit rate were integrated into the simulation. The pharmacokinetic profiles of these drugs and their active metabolites were simulated for 1000 virtual individuals. The developed semi-PBPK model, after validation in healthy individuals, was extrapolated to LC patients. Most of the observations fell within the 5th and 95th percentiles of simulations from 1000 virtual patients. The estimated AUC and Cmax were within 0.5–2-fold of the observed values. The sensitivity analysis showed that the decreased plasma exposure of active metabolites due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model successfully predicted the pharmacokinetics of CES1 substrates and their metabolites in healthy individuals and LC patients, facilitating tailored dosing of CES1 substrates in LC patients.

A tenon connection structure is widely used for the blade-disk connection in turbomachinery, and its ability to resist wear influences operation life. The finite element method (FEM) has been extensively applied in predicting fretting wear due to its advantage in solving problems like the non-linearity of boundary conditions. This work proposes a model that combines a modified Archard model with FEM to simulate fretting wear in multiple pairs of contact curved surfaces of the tenon connection structure. The model considers various factors, including the direction of fretting, time, load magnitude, and the application of aerodynamic load. The results indicate that the direction of fretting has a significant effect on the wear of the tenon connection structure. The wear depth of the tenon connection structure caused by axial fretting is nearly twice that of circumferential and radial fretting, and the corresponding wear depth values are 57.22, 30.85, and 24.36 µm in this study, respectively, and the rate of change in wear depth increases over time, while the contact pressure decreases initially and then increases with continuous wear. This study provides valuable insight into the impact of fretting under different working conditions on the wear of turbine tenon connection structures, which is of great significance for their wear-resistant design and life prediction.

Zhiciweipi (Corium Erinacei Praeparaum) is one of the traditional Chinese animal medicines used to treat hematochezia and hemorrhoids. At present, there is a lack of the workflow for ingredient identification of Zhiciweipi (Corium Erinacei Praeparaum) and the studies regarding immunocompetent ingredient screening and evaluation. This study aims to screen immunopeptides in Zhiciweipi (Corium Erinacei Praeparaum) and investigate their immunity to RAW264.7 macrophages. In this study, the workflow for protein polypeptide identification and analysis of Zhiciweipi (Corium Erinacei Praeparaum) was established based on LC-MS/MS. According to Gene ontology_Biological process (GO_BP) functional and signal pathway enrichment analysis results, the identified proteins are related with vascular development, wound healing, IL2 STAT5 signal, and so on. A total of 20 immune regulatory genes were identified from the Venn diagram of protein and immune regulatory genes in Zhiciweipi (Corium Erinacei Praeparaum). The PPI network analysis demonstrated that ALB protein ranks the top in term of significance. According to analysis on physical properties and structural and safety prediction of 61 polypeptide fragments related with serum albumin in Zhiciweipi (Corium Erinacei Praeparaum) which are corresponding to ALB protein, RHPYFYAPELL and RHPYFYAPELLYF (RHP-LYF) are the most optimal. The molecular docking showed that RHPYFYAPELL and RHP-LYF can make effective bonding with IL-2 and STAT5. The molecular dynamic experiment reflected that RHP-LYF has the strongest affinity with ALB. In the present study, CCK8 method was applied to test RHP-LYF treatment of RAW264.7 cells in the mice macrophage system at different concentrations. Results showed that such treatment may not inhibit cell growth when the RHP-LYF concentration is lower than 200 ng/mL. The polypeptide fluorescence marking experiment proved that polypeptides can enter into cells and can be detected in the whole cell. Effects of RHP-LYF on IL-2, TNFα, IFNγ and IL10 levels in RAW264.7 cells and mice serum were detected by ELISA kit. Results showed that polypeptide not only can inhibit secretion of inflammatory factors in vivo and in vitro, but also promote secretion of anti-inflammatory factors, and further test effects of RAW264.7 cells on expressions of p-STAT5 and STAT5 through Western Blot. Results showed that polypeptide treatment may inhibit level of p-STAT5 and has dosage-dependent effect. Polypeptides from Zhiciweipi (Corium Erinacei Praeparaum) are safe and have immunization to RAW264.7 macrophage. All of these results can provide a meaningful method to drug quality assessment, immune bioactive peptide screening and evaluation of Zhiciweipi (Corium Erinacei Praeparaum) and other animals rich of peptides.

IntroductionViral infection, typically disregarded, has a significant role in burns. However, there is still a lack of biomarkers and immunotherapy targets related to viral infections in burns.MethodsVirus-related genes (VRGs) that were extracted from Gene Oncology (GO) database were included as hallmarks. Through unsupervised consensus clustering, we divided patients into two VRGs molecular patterns (VRGMPs). Weighted gene co-expression network analysis (WGCNA) was performed to study the relationship between burns and VRGs. Random forest (RF), least absolute shrinkage and selection operator (LASSO) regression, and logistic regression were used to select key genes, which were utilized to construct prognostic signatures by multivariate logistic regression. The risk score of the nomogram defined high- and low-risk groups. We compared immune cells, immune checkpoint-related genes, and prognosis between the two groups. Finally, we used network analysis and molecular docking to predict drugs targeting CD69 and SATB1. Expression of CD69 and SATB1 was validated by qPCR and microarray with the blood sample from the burn patient.ResultsWe established two VRGMPs, which differed in monocytes, neutrophils, dendritic cells, and T cells. In WGCNA, genes were divided into 14 modules, and the black module was correlated with VRGMPs. A total of 65 genes were selected by WGCNA, STRING, and differential expression analysis. The results of GO enrichment analysis were enriched in Th1 and Th2 cell differentiation, B cell receptor signaling pathway, alpha-beta T cell activation, and alpha-beta T cell differentiation. Then the 2-gene signature was constructed by RF, LASSO, and LOGISTIC regression. The signature was an independent prognostic factor and performed well in ROC, calibration, and decision curves. Further, the expression of immune cells and checkpoint genes differed between high- and low-risk groups. CD69 and SATB1 were differentially expressed in burns.DiscussionThis is the first VRG-based signature (including 2 key genes validated by qPCR) for predicting survival, and it could provide vital guidance to achieve optimized immunotherapy for immunosuppression in burns.

In recent years, the shape of particles has emerged as a key factor influencing their self-assembly and phase behaviors. Understanding the phase behaviors of systems containing shape anisotropic particles remains challenging. In this mini-review, we will summarize our recent experimental studies on the phase behaviors of colloidal systems in which all or part of particles have anisotropic shapes. We focus on two types of shape anisotropic particles, ellipsoids and rods. In particular, it was found that 1) in equilibrium, the anisotropic particles form a nematic phase in 2D, 2) when quenched, they can form a stable glassy state with a two-step glass transition, and 3) when they are dispersed as impurities in a 2D colloidal crystal of spheres, they can destroy the 2D crystal phase. We will discuss the current challenges in the field.

First, this study proposed a metamaterial beam model with spatially varying interval density. The interval dynamic equation of this model could be established by incorporating the decomposition results of the interval field based on Karhunen–Loeve expansion into the finite element method. An interval perturbation finite element method was developed to evaluate the bounds of the dynamic response interval vector. Then, an interval vibration transmission analysis could be performed, and the frequency range of the safe band gap could be determined. Meanwhile, Monte Carlo simulations and the vertex method are also presented to provide reference solutions. By comparison, it was found that the calculation accuracy of the interval perturbation finite element method was acceptable. The numerical results also showed that the safe band gap range was significantly smaller than that of the deterministic band gap.

BackgroundNitrogen metabolism (NM) plays a pivotal role in immune regulation and the occurrence and development of cancers. The aim of this study was to construct a prognostic model and nomogram using NM-related genes for the evaluation of patients with lung adenocarcinoma (LUAD).MethodsThe differentially expressed genes (DEGs) related to NM were acquired from The Cancer Genome Atlas (TCGA) database. Consistent clustering analysis was used to divide them into different modules, and differentially expressed genes and survival analysis were performed. The survival information of patients was combined with the expressing levels of NM-related genes that extracted from TCGA and Gene Expression Omnibus (GEO) databases. Subsequently, univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) regression were used to build a prognostic model. GO and KEGG analysis were elaborated in relation with the mechanisms of NM disorder (NMD). Meanwhile, immune cells and immune functions related to NMD were discussed. A nomogram was built according to the univariate and multivariate Cox analysis to identify independent risk factors. Finally, real-time fluorescent quantitative PCR (RT-PCR) and Western bolt (WB) were used to verify the expression level of hub genes.ResultsThere were 138 differential NM-related genes that were divided into two gene modules. Sixteen NM-related genes were used to build a prognostic model and the receiver operating characteristic curve (ROC) showed that the efficiency was reliable. GO and KEGG analysis suggested that NMD accelerated development of LUAD through the Wnt signaling pathway. The level of activated dendritic cells (aDCs) and type II interferon response in the low-risk group was higher than that of the high-risk group. A nomogram was constructed based on ABCC2, HMGA2, and TN stages, which was identified as four independent risk factors. Finally, RT-PCR and WB showed that CDH17, IGF2BP1, IGFBP1, ABCC2, and HMGA2 were differently expressed between human lung fibroblast (HLF) cells and cancer cells.ConclusionsHigh NM levels were revealed as a poor prognosis of LUAD. NMD regulates immune system through affecting aDCs and type II interferon response. The prognostic model with NM-related genes could be used to effectively evaluate the outcomes of patients.

Background: Immunosuppression is an important trigger for infection and a significant cause of death in patients with severe burns. Nevertheless, the prognostic value of immune-related genes remains unclear. This study aimed to identify the biomarkers related to immunosuppression in severe burns.Methods: The gene expression profile and clinical data of 185 burn and 75 healthy samples were obtained from the GEO database. Immune infiltration analysis and gene set variation analysis were utilized to identify the disorder of circulating immune cells. A weighted gene co-expression network analysis (WGCNA) was carried out to select immune-related gene modules. Enrichment analysis and protein–protein interaction (PPI) network were performed to select hub genes. Next, LASSO and logistic regression were utilized to construct the hazard regression model with a survival state. Finally, we investigated the correlation between high- and low-risk patients in total burn surface area (TBSA), age, and inhalation injury.Results: Gene set variation analysis (GSVA) and immune infiltration analysis showed that neutrophils increased and T cells decreased in severe burns. In WGCNA, four modular differently expressed in burns and controls were related to immune cells. Based on PPI and enrichment analysis, 210 immune-related genes were identified, mainly involved in T-cell inhibition and neutrophil activation. In LASSO and logistic regression, we screened out key genes, including LCK, SKAP1 and GZMB, and LY9. In the ROC analysis, the area under the curve (AUC) of key genes was 0.945, indicating that the key genes had excellent diagnostic value. Finally, we discovered that the key genes were related to T cells, and the regression model performed well when accompanied by TBSA and age.Conclusion: We identified LCK, SKAP1, GZMB, and LY9 as good prognostic biomarkers that may play a role in post-burn immunosuppression against T-cell dysfunction and as potential immunotherapeutic targets for transformed T-cell dysfunction.

Intended for the vibration and noise control problems faced by many engineering fields, a fresh variety of phononic crystal beam structure was constructed by attaching a one-dimensional periodic multilayer cylinder to a double-layer beam structure. Utilizing the finite element method and the Bloch theorem, the vibration modes of the band structure, the critical point of the band gap and the associated finite structure’s vibration transmission is estimated, and then the band gap characteristics of the structure are comprehensively studied. The results show that reasonable parameter design can achieve vibration and noise control in a certain frequency range. Based on the modal analysis, the mechanism of band gap opening is revealed. By comparing the single-layer beam and double-layer beam with the same parameters, the advantages of the double-layer beam in vibration reduction and noise reduction are shown. The study’s findings offer a fresh concept for ship engineering disciplines including vibration and noise reduction technology.

The immense potential of active colloids in practical applications and fundamental research calls for an efficient method to synthesize active colloids of high uniformity. Herein, a facile method is reported to synthesize uniform organic–inorganic hybrid active colloids based on the wetting effect of polystyrene (PS) with photoresponsive inorganic nanoparticles in a tetrahydrofuran/water mixture. The results show that a range of dimer active colloids can be produced by using different inorganic components, such as AgCl, ZnO, TiO2, and Fe2O3 nanoparticles. Moreover, the strategy provides a simple way to prepare dual-drive active colloids by a rational selection of the starting organic materials, such as magnetic PS particles that result in light and magnet dual-drive active colloids. The motions of these active colloids are quantified, and well-controlled movements are demonstrated.

Locally resonant phononic crystals are a kind of artificial periodic composite material/structure with an elastic wave band gap that show attractive application potential in low-frequency vibration control. For low-frequency vibration control problems of ship power systems, this paper proposes a phononic crystal board structure, and based on the Bloch theorem of periodic structure, it uses a finite element method to calculate the band structure and the displacement fields corresponding to the characteristic mode and vibration transmission curve of the corresponding finite periodic sandwich plate structure, and the band gap characteristics are studied. The mechanism of band gap formation is mainly attributed to the mode coupling of the phononic crystal plate structure. Numerical results show that the sandwich plate structure has a double periodicity, so it has a multi-stage elastic wave band gap, which can fully inhibit the transmission of flexural waves and isolate the low-frequency flexural vibration. The experimental measurements of flexural vibration transmission spectra were conducted to validate the accuracy and reliability of the numerical calculation method. On this basis, the potential application of the proposed vibration isolation method in a marine power system is discussed. A vibration isolation platform mounted on a steel plate is studied by numerical simulation, which can isolate low-frequency vibration to protect electronic equipment and precision instruments.

In plants, glycerol-3-phosphate dehydrogenase (GPDH) catalyzes the interconversion of glycerol-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP) coupled to the reduction/oxidation of the nicotinamide adenine dinucleotide (NADH) pool, and plays a central role in glycerolipid metabolism and stress response. Previous studies have focused mainly on the NAD+-dependent GPDH isoforms, neglecting the role of flavin adenine dinucleotide (FAD)-dependent GPDHs. We isolated and characterized three mitochondrial-targeted FAD-GPDHs in soybean, of which one isoform (GmGPDH12) showed a significant transcriptional response to NaCl and mannitol treatments, suggesting the existence of a major FAD-GPDH isoform acting in soybean responses to salt and osmotic stress. An enzyme kinetic assay showed that the purified GmGPDH12 protein possessed the capacity to oxidize G3P to DHAP in the presence of FAD. Overexpression and RNA interference of GmGPDH12 in soybean hairy roots resulted in elevated tolerance and sensitivity to salt and osmotic stress, respectively. G3P contents were significantly lower in GmGPDH12-overexpressing hair roots and higher in knockdown hair roots, indicating that GmGPDH12 was essential for G3P catabolism. A significant perturbation in redox status of NADH, ascorbic acid (ASA) and glutathione (GSH) pools was observed in GmGPDH12-knockdown plants under stress conditions. The impaired redox balance was manifested by higher reactive oxygen species generation and consequent cell damage or death; however, overexpressing plants showed the opposite results for these traits. GmGPDH12 overexpression contributed to maintaining constant respiration rates under salt or osmotic stress by regulating mRNA levels of key mitochondrial respiratory enzymes. This study provides new evidence for the roles of mitochondria-localized GmGPDH12 in conferring resistance to salt or osmotic stress by maintaining cellular redox homeostasis, protecting cells and respiration from oxidative injury.

We numerically demonstrated six types of pulses in an Yb-doped fiber laser, including dissipative soliton (DS), dissipative soliton resonance (DSR), multipulse, noise-like pulse (NLP), breathing soliton and soliton explosion. The influence of cavity conditions on DSR pulse properties is discussed systematically. It is found that the change of the saturation power of saturable absorber (SA) could transform DSR into various types of pulses. Saturation power of SA and injected signal affect the number and shape of multipulse. Furthermore, the influence of the saturation power of SA and intra-cavity dispersion on pulse type is diagrammed intuitively. By properly adjusting the transmission curve of SA, breathing soliton and soliton explosion can be obtained as well.

Background Burn patients are prone to infection as well as immunosuppression, which is a significant cause of death. Currently, there is a lack of prognostic biomarkers for immunosuppression in burn patients. This study was conducted to identify immune-related genes that are prognosis biomarkers in post-burn immunosuppression and potential targets for immunotherapy. Methods We downloaded the gene expression profiles and clinical data of 213 burn patients and 79 healthy samples from the Gene Expression Omnibus (GEO) database. Immune infiltration analysis was used to identify the proportion of circulating immune cells. Functional enrichment analyses were carried out to identify immune-related genes that were used to build miRNA-mRNA networks to screen key genes. Next, we carried out correlation analysis between immune cells and key genes that were then used to construct logistic regression models in GSE77791 and were validated in GSE19743. Finally, we determined the expression of key genes in burn patients using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results A total of 745 differently expressed genes were screened out: 299 were up-regulated and 446 were down-regulated. The number of Th-cells (CD4+) decreased while neutrophils increased in burn patients. The enrichment analysis showed that down-regulated genes were enriched in the T-cell activation pathway, while up-regulated genes were enriched in neutrophil activation response in burn patients. We screened out key genes (NFATC2, RORA, and CAMK4) that could be regulated by miRNA. The expression of key genes was related to the proportion of Th-cells (CD4+) and survival, and was an excellent predictor of prognosis in burns with an area under the curve (AUC) value of 0.945. Finally, we determined that NFATC2, RORA, and CAMK4 were down-regulated in burn patients. Conclusion We found that NFATC2, RORA, and CAMK4 were likely prognostic biomarkers in post-burn immunosuppression and potential immunotherapeutic targets to convert Th-cell dysfunction.

Summary: Flagellated bacteria move collectively in a swirling pattern on agar surfaces immersed in a thin layer of viscous “swarm fluid,” but the role of this fluid in mediating the cooperation of the bacterial population is not well understood. Herein, we use gold nanorods (AuNRs) as single particle tracers to explore the spatiotemporal structure of the swarm fluid. Individual AuNRs are moving in a plane of ∼2 μm above swarms, traveling for long distances in high speed without interferences from bacterial movements. The particles are lifted and transported by collective mixing of small vortices around bacteria during localized clustering and de-clustering of motile cells. Their motions fit the Lévy walk model, revealing efficient fluidic flows above the swarms. These flows provide obstacle-free highways for long-range material transportations, allow swarming bacteria to perform population-level communications, and imply the essential role of the fluid phase on the emergence of large-scale synergy. : Transport Phenomena; Biological Sciences; Biophysics; Laser Biophysics Subject Areas: Transport Phenomena, Biological Sciences, Biophysics, Laser Biophysics

The efficacy of first-and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC patients with the EGFR L861Q mutation has been studied previously. However, there is little evidence on the efficacy of osimertinib in NSCLC patients with uncommon mutations. Here, we report the case of a 68-year-old man with advanced NSCLC with concurrent EGFR L861Q mutation as well as TP53 and RB1 mutations. The patient was treated with osimertinib as first-line therapy and achieved a remarkable progression-free survival of 15 months. His symptoms were significantly alleviated and the dose was well tolerated. The findings of the present study indicate that osimertinib might be a good treatment option for NSCLC patients with the L861Q mutation.

Summary: Inspired by astonishing collective motions and tactic behaviors in nature, here we show phototactic flocking of synthetic photochemical micromotors. When enriched with hydroxyl groups, TiO2 micromotors can spontaneously gather into flocks in aqueous media through electrolyte diffusiophoresis. Under light irradiation, due to the dominant nonelectrolyte diffusiophoretic interaction resulting from the overlap of asymmetric nonelectrolyte clouds around adjacent individuals, these flocks exhibit intriguing collective behaviors, such as dilatational negative phototaxis, high collective velocity, and adaptive group reconfiguration. Consequently, the micromotor flocks can migrate along pre-designed paths and actively bypass obstacles with reversible dilatation (expansion/contraction) under pulsed light navigation. Furthermore, owing to the enhanced driving force and rapid dilatational area covering, they are able to execute cooperative tasks that single micromotors cannot achieve, such as cooperative large-cargo transport and collective microenvironment mapping. Our discovery would promote the creation of reconfigurable microrobots, active materials, and intelligent synthetic systems. : Chemistry; Catalysis; Nanoparticles Subject Areas: Chemistry, Catalysis, Nanoparticles

Single-pixel imaging (SPI) utilizes a second-order correlation of structured illumination light field and a single-pixel detector to form images. As the single-pixel detector provides no spatial resolution, a structured illumination light field generated by devices such as a spatial light modulator substitutes the role of array camera to retrieve pixel-wise spatial information. Due to its unique imaging modality, SPI has certain advantages. Meanwhile, its counterintuitive configuration and reciprocity relation to traditional array cameras have been studied to understand its fundamental principle. According to previous studies, the non-spatial detection property makes it possible for SPI to resist scattering in the detection part. In this work, we study the influence of an obstacle aperture in the detection part of SPI. We notice that such an obstacle aperture can restrict the field-of-view (FOV) of SPI, which can be diminished by a scattering process. We investigate these properties with experiment results and analysis under geometry optics. We believe that our study will be helpful in understanding the counterintuitive configuration of SPI and its reciprocity to traditional imaging.

Transmembrane transport of metformin is highly controlled by transporters including organic cation transporters (OCTs), plasma membrane monoamine transporter (PMAT), and multidrug/toxin extrusions (MATEs). Hepatic OCT1, intestinal OCT3, renal OCT2 on tubule basolateral membrane, and MATE1/2-K on tubule apical membrane coordinately work to control metformin disposition. Drug–drug interactions (DDIs) of metformin occur when co-administrated with perpetrators via inhibiting OCTs or MATEs. We aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model characterizing interplay of OCTs and MATEs in the intestine, liver, and kidney to predict metformin DDIs with cimetidine, pyrimethamine, trimethoprim, ondansetron, rabeprazole, and verapamil. Simulations showed that co-administration of perpetrators increased plasma exposures to metformin, which were consistent with clinic observations. Sensitivity analysis demonstrated that contributions of the tested factors to metformin DDI with cimetidine are gastrointestinal transit rate > inhibition of renal OCT2 ≈ inhibition of renal MATEs > inhibition of intestinal OCT3 > intestinal pH > inhibition of hepatic OCT1. Individual contributions of transporters to metformin disposition are renal OCT2 ≈ renal MATEs > intestinal OCT3 > hepatic OCT1 > intestinal PMAT. In conclusion, DDIs of metformin with perpetrators are attributed to integrated effects of inhibitions of these transporters.

Synthetic cells are designed to mimic basic life processes, but it is challenging to prepare cells that can persist and operate at non-equilibrium conditions. Here, Yin et al.show complex dynamical behaviors of protocells made by exposing polylysine and single-stranded DNA droplets to an electric field.

The glass transition, a many-body system undergoes an apparent dynamic arrest with no appearance of long-range order, is one of the most challenging problems in condensed matter physics. Recently attention has been focused on the puzzling two-step transition observed in colloidal suspensions of ellipsoids. It was observed that micro nematic domains appearing with increasing packing density suggesting that such micro domains may be the structure origin of the two-step glass transition. Here we report an experimental study of monolayers of colloidal rods which exhibits a two-step glass transition with no appearance of pseudo-nematic domains. Instead, it was found that parallel and perpendicularly packed rods form local free energy minima in configurational space, separated by an activation barrier. This barrier increases significantly when rotational glass transition is approached, thereby the rotational motion is frozen while the translational one remains diffusive. We propose that the activation barrier for rotation is the key to the two-step glass transition in suspensions of rods. Such an activation barrier between well-defined local configurations holds the key to understanding the two-step glass transition in general.

Phthalocyanine (Pc) is a type of promising sensitizer molecules for photodynamic therapy (PDT), but its hydrophobicity substantially prevents its applications. In this study, we efficiently encapsulate Pc into poly(N-isopropylacrylamide) (pNIPAM) microgel particles, without or with lipid decoration (i.e., Pc@pNIPAM or Pc@pNIPAM/lipid), to improve its water solubility and prevent aggregation in aqueous medium. The incorporation of lipid molecules significantly enhances the Pc loading efficiency of pNIPAM. These Pc@pNIPAM and Pc@pNIPAM/lipid composite microspheres show thermo-triggered release of Pc and/or lipid due to the phase transition of pNIPAM. Furthermore, in the in vitro experiments, these composite particles work as drug carriers for the hydrophobic Pc to be internalized into HeLa cells. After internalization, the particles show efficient fluorescent imaging and PDT effect. Our work demonstrates promising candidates in promoting the use of hydrophobic drugs including photosensitizers in tumor therapies.

Objective: Carcinoid syndrome (CS) commonly results from neuroendocrine tumors. While active substances are recognized as the main causes of the typical symptoms such as diarrhea and skin flush, the cause-and-effect relationship between gut microbiota abundance and CS remains unclear. Methods: The Single Nucleotide Polymorphisms (SNPs) related to gut microbiota abundance and CS were obtained from the GWAS summary data. The inverse variance weighted (IVW) method was used to assess the causal relationship between gut microbiota abundance and CS. Additionally, the MR-Egger, Weighted Median model, and Weighted model were employed as supplementary approaches. The heterogeneity function of the TwoSampleMR package was utilized to assess whether SNPs exhibit heterogeneity. The Egger intercept and Presso test were used to assess whether SNPs exhibit pleiotropy. The Leave-One-Out test was employed to evaluate the sensitivity of SNPs. The Steiger test was utilized to examine whether SNPs have a reverse causal relationship. A bidirectional mendelian randomization (MR) study was conducted to elucidate the inferred cause-and-effect relationship between gut microbiota abundance and CS. Results: The IVW results indicated a causal relationship between 6 gut microbiota taxa and CS. Among the 6 gut microbiota taxa, the genus Anaerofilum (IVW OR: 0.3606, 95%CI: 0.1554-0.8367, p-value: 0.0175) exhibited a protective effect against CS. On the other hand, the family Coriobacteriaceae (IVW OR: 3.4572, 95%CI: 1.0571-11.3066, p-value: 0.0402), the genus Enterorhabdus (IVW OR: 4.2496, 95%CI: 1.3314-13.5640, p-value: 0.0146), the genus Ruminiclostridium6 (IVW OR: 4.0116, 95%CI: 1.2711-12.6604, p-value: 0.0178), the genus Veillonella (IVW OR: 3.7023, 95%CI: 1.0155-13.4980, p-value: 0.0473) and genus Holdemanella (IVW OR: 2.2400, 95%CI: 1.0376-4.8358, p-value: 0.0400) demonstrated a detrimental effect on CS. The CS was not found to have a reverse causal relationship with the above 6 gut microbiota taxa. Conclusion: Six microbiota taxa were found to have a causal relationship with CS, and further randomized controlled trials are needed for verification. [ABSTRACT FROM AUTHOR]

In this paper, a piezoelectric phononic crystal beam at the nanoscale has been mechanically modeled by using the surface piezoelectric theory. The band gap has been calculated by the plane wave expansion method and the band gap structure picture has been analyzed. The influence of electromechanical coupling effects, surface effects and geometry on the band gap properties are discussed separately. This study contributes positively to the design and active control of nanoelectromechanical systems. [ABSTRACT FROM AUTHOR]