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Abstract Background Sepsis is a life-threatening condition triggered by uncontrolled immune responses to infection, leading to widespread inflammation, tissue damage, organ dysfunction, and potentially death. The liver plays a crucial role in the immune response during sepsis, serving as a major site for immune cell activation and cytokine production. Liver type 1 innate lymphoid cells (ILCs) consist of NK cells and ILC1s. They maintain the local immune microenvironment by directly eliminating target cells and secreting cytokines. However, the specific roles and pathological changes of liver-resident NK cells and ILC1s during sepsis remain poorly understood. Results This study aims to investigate the pathological changes of NK cells and ILC1s, which might contribute the dysfunction of liver. Sepsis mouse model was established by cecal ligation and puncture (CLP). Mouse immune cells from liver were isolated, and the surface makers, gene expression profiles, cytokine response and secretion, and mitochondrial function of NK (Natural Killer) cells and ILC1s (Innate Lymphoid Cell 1) were analyzed. A significant decrease in the number of mature NK cells was observed in the liver after CLP. Furthermore, the secretion of interferon-gamma (IFN-γ) was found to be reduced in spleen and liver NK cells when stimulated by IL-18. Mitochondrial activities in both liver NK cells and ILC1 were found to be increased during sepsis, suggesting an enhanced metabolic response in these cells to combat the infection. However, despite this heightened activity, liver NK cells exhibited a decreased level of cytotoxicity, which might impact their ability to target infected cells effectively. RNA sequencing supported and provided the potential mechanisms for the proinflammatory effects and exhaustion like phenotypes of liver NK cells. Conclusions Sepsis induces dysfunction and exhaustion-like phenotypes in liver NK cells and ILC1, which might further impair other immune cells and represent a potential therapeutic target for sepsis.

Aimed at the problems of difficult drilling construction of blast penetration, undeveloped fractures produced by blast penetration, and the fractures is easy to recompact in the soft coal seam, the blasting operations carried out in the floor was proposed to achieve the purpose of increasing the penetration of soft coal seams and thus improve the effectiveness of gas extraction. In order to monitor the cross-interface stress wave propagation pattern and the damage state of the coal seam, a physical model was constructed in the laboratory and a similar simulation test of coal seam floor blasting was carried out. Concurrently, the numerical simulation research method was employed to supplement the evolution of damage and fractures within the coal and rock during the blasting process of the coal seam floor. The results shown that, the blast cracks expanded along the blast hole to the surrounding rock mass in soft coal seam floor, causing more serious damage at the location of blast hole, the coal-rock interface of the floor, and within the coal seam, producing cross-interfacial damage cracks. When the explosive stress wave propagated from the soft coal seam base rock layer to the soft coal seam, the interface between the rock and the soft coal generated transmitted compressive stress wave and reflected tensile stress wave. Transmission waves acted on the soft coal to increase the fractures in the coal seam. Meanwhile, the reflected waves reacted on the rock, forming cross-cracks in the coal-rock interface, making the fractures of the rock floor and the soft coal seam penetrated, which was conducive to the vertical transport flow of gas in the soft coal seam and the extraction of pressure-relief gas. Field application at Pan Yidong coal mine shown that, the pure volume of gas extraction and its concentration increased rapidly after blasting the coal seam floor to improve the penetration. The pure volume of gas extraction increased from 0.06 m3/min to 1.46 m3/min, an increase of 23.33 times. Gas concentration surged from 10.46% before blasting to approximately 45.5%, an increase of 3.34 times, and remained at a high level for a long time. The research results can provide theoretical basis and technical support for efficient gas extraction from deep soft coal seams.

Abstract Background This study aimed investigate the impact of intergenerational support on the mental health of older adults in urban China. It also sought to evaluate the chain mediation effect of attitudes toward younger people and willingness to interact with younger people within a non-familial context between intergenerational support and mental health. Methods Data were derived from a community survey that adopted quota sampling in mainland China in 2022 (N = 780). Structural equation modeling was used to analyze the data, and the bootstrap technique was used to test the mediation effect. Results A significant positive association was found between intergenerational support and the mental health of older adults in urban China (B = 0.852, 95% confidence interval CI [0.157,1.617]). Intergenerational support had a specific indirect effect on mental health through older adults’ attitudes toward younger people within a non-familial context (B = 0.665, 95% CI [0.443,1.046]). There was a chain mediation effect (B = 0.126, 95% CI [0.069,0.224]) in relation to attitudes toward younger people and the willingness to interact with younger people between intergenerational support and mental health. Mediation accounted for 44.44% of the total effects in the model. Conclusion These findings help identify modifiable factors that can improve the mental health of older adults. In line with the proposed serial multiple mediation model, this study provides theoretical and practical insights concerning the synergistic effect of intergenerational support at the family level and intergenerational interaction at the community level. Policy and social service implications are also discussed.

Group 1 innate lymphoid cells (ILCs) comprise conventional natural killer (cNK) cells and type 1 innate lymphoid cells (ILC1s). The main functions of liver cNK cells and ILC1s not only include directly killing target cells but also regulating local immune microenvironment of the liver through the secretion of cytokines. Uncovering the intricate mechanisms by which transcriptional factors regulate and influence the functions of liver cNK cells and ILC1s, particularly within the context of liver tumors, presents a significant opportunity to amplify the effectiveness of immunotherapies against liver malignancies. Using Ncr1-drived conditional knockout mouse model, our study reveals the regulatory role of Prdm1 in shaping the composition and maturation of cNK cells. Although Prdm1 did not affect the killing function of cNK cells in an in vivo cytotoxicity model, a significant increase in cancer metastasis was observed in Prdm1 knockout mice. Interferon-gamma (IFN-γ), granzyme B, and perforin secretion decreased significantly in Prdm1-deficient cNK cells and liver ILC1s. Single-cell RNA sequencing (scRNA-seq) data also provided evidences that Prdm1 maintains functional subsets of cNK cells and liver ILC1s and facilitates communications between cNK cells, liver ILC1s, and macrophages. The present study unveiled a novel regulatory mechanism of Prdm1 in cNK cells and liver ILC1s, showing promising potential for developing innovative immune therapy strategies against liver cancer.

Abstract The ventilation rate of cigarettes is an important indicator that affects the internal quality of cigarettes. When producing cigarettes, the unit may experience unstable ventilation rates, which can lead to a decrease in cigarette quality and pose certain risks to smokers. By establishing the ventilation rate prediction model, guide the design of unit parameters in advance, to achieve the goal of stabilizing unit ventilation rate, improve the stability of cigarette ventilation rate, and enhance the quality of cigarettes. This paper used multiple linear regression networks (MLR), backpropagation neural networks (BPNN), and genetic algorithm-optimized backpropagation (GABP) to construct a model for the prediction of cigarette ventilation rate. The model results indicated that the total ventilation rate was significantly positively correlated with weight (P

Objective: This research aims at clarifying the action and mechanisms of action of TP53TG1 in cancer-associated fibroblasts (CAF)-derived exosomes (EXs) on colorectal carcinoma (CRC) cells. Methods: CAF and CAF-EXs isolated from CRC tissues were incubated with CRC SW480 cells to determine alterations in biological behavior, epithelial-mesenchymal transition (EMT) capacity, and TP53TG1 and miR-330-3p expression. In addition, a dual luciferase reporter (DLR) assay was conducted to verify the connection between TP53TG1 and miR-330-3p, and the impacts of the two genes on CRC cells were analyzed. Results: CRC-CAF-EXs extracted from CRC tissues were successfully identified and were able to promote SW480 multiplication, invasiveness, migration, and EMT ability while inhibiting apoptosis (P 0.05). Conclusion: By targeting miR-330-3p, TP53TG1 in CRC-CAF-EXs can enhance CRC cell activity and EMT capacity and inhibit apoptosis.

Abstract Background Antimicrobial resistance in gonorrhea has become a growing global public health burden. Neisseria gonorrhoeae isolates with resistance to ceftriaxone, the last remaining first-line option, represent an emerging threat of untreatable gonorrhea. Methods A total of ten ceftriaxone-resistant N. gonorrhoeae FC428 isolates and two isolates harboring a novel mosaic penA-232.001 allele from 160 gonococcal isolates in Chengdu in 2019–2020 was described in the present study. Multilocus sequence typing (MLST) and N. gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) were performed to characterize the isolates. Whole genome sequencing and maximum-likelihood method were performed to infer how the genetic phylogenetic tree of these isolates looks like. Recombination analysis was performed using the RDP4 software. This study was registered in the Chinese Clinical Trial Registry (ChiCTR2100048771, registration date: 20210716). Results The genetic phylogeny showed that the ten FC428 isolates sporadically clustered into different phylogenetic clades, suggesting different introductions and local transmission of FC428. Two isolates showed close genetic relatedness to ceftriaxone-resistant clone A8806, which was only reported from Australia in 2013. Homologous recombination events were detected in penA between Neisseria gonorrhoeae and commensal Neisseria species (N. perflava and N. polysaccharea), providing evidence of commensal Neisseria species might serve as reservoirs of ceftriaxone resistance-mediating penA sequences in clinical gonococcal strains. Conclusions Our results demonstrate further dissemination of FC428 in China and resurgence risks of sporadic ceftriaxone-resistant A8806 to become the next clone to spread.

Abstract The identification of railway safety risk is important in ensuring continuous and stable railway operations. Most works fail to consider the important relation between detected objects. In addition, poor domain semantics directly degrades the final performance due to difficulty in understanding railway text. To solve these challenging issues, we introduce the triple knowledge from knowledge graph to model the railway safety risk with the knowledge interconnection mode. Afterward, we recast the identification of railway safety risk as the relation extraction task, and propose a novel and effective Domain Semantics-Enhanced Relation Extraction (DSERE) model. Specifically, we design a domain semantics-enhanced transformer mechanism that automatically enhances the railway semantics from a dedicated railway lexicon. We further introduce piece-wise convolution neural networks to explore the fine-grained features contained in the structure of triple knowledge. With the domain semantics and fine-grained features, our model can fully understand the domain text and thus improve the performance of relation classification. Finally, the DSERE model is used to identify the railway safety risk of south zone of China Railway, and achieves 81.84% AUC and 76.00% F1 scores on the real-world dataset showing the superiority of our proposed model.

The advent of Induced Pluripotent Stem Cells (iPSCs) has revolutionized neuroscience research. This groundbreaking innovation has facilitated the development of three-dimensional (3D) neural organoids, which closely mimicked the intricate structure and diverse functions of the human brain, providing an unprecedented platform for the in-depth study and understanding of neurological phenomena. However, these organoids lack key components of the neural microenvironment, particularly immune cells like microglia, thereby limiting their applicability in neuroinflammation research. Recent advancements focused on addressing this gap by integrating iPSC-derived microglia into neural organoids, thereby creating an immunized microenvironment that more accurately reflects human central neural tissue. This review explores the latest developments in this field, emphasizing the interaction between microglia and neurons within immunized neural organoids and highlights how this integrated approach not only enhances our understanding of neuroinflammatory processes but also opens new avenues in regenerative medicine.

Abstract Background This study explored the association between oral health and depression occurs via daily dietary satisfaction as a mediator, and that body mass index could moderate the path between daily dietary satisfaction and depression. Methods Data for this research were derived from a community survey adopting quota sampling in the cities of Tianjin and Shijiazhuang in mainland China in 2020 (N = 781). The moderated mediation model was tested by using bootstrapping with resampling strategies, and the Johnson-Neyman technique was used to visualize the moderating effect of body mass index. Results A significant negative association between oral health and depression has been indicated (B = −0.22, SE = 0.11, 95%CI [− 0.44, − 0.01]), and dietary satisfaction partially mediated the relationship between oral health and depression (B = −0.04, SE = 0.02, 95%CI [− 0.09, − 0.002]). The path was moderated by body mass index, and the effect of dietary satisfaction on depression was much greater in people with relatively low body mass index. Conclusions This study present evidence for policymakers and researchers that strategies to enhance oral health and daily dietary satisfaction could be important for preventing depression in Chinese older adults, and especially for the relatively fitter older groups with lower body mass index.

Abstract Novel promising strategies for combination with sorafenib are urgently needed to enhance its clinical benefit and overcome toxicity in hepatocellular carcinoma (HCC). the molecular and immunomodulatory antitumor effects of sorafenib alone and in combination with the new immunotherapeutic agent R848 are presented. Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage‐to‐FTH1high M1 macrophage transition. The close interaction between neutrophils/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8+ T cell‐mediated antitumor immunity. Additionally, low‐dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low‐dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment.

Monitoring ferroptosis-related miRNAs is crucial for the treatment and prognosis of patients with intracerebral hemorrhage. In this work, a novel hydrophobic paper (h-paper)-based plasmonic substrate was produced by dropping DS Au nanorods with a narrow range of sizes and morphologies onto h-paper. Raman reporter molecules were adsorbed to the array surface, and surface-enhanced Raman scattering spectra at randomly selected points reveal uniform and significant SERS enhancement. Hairpin DNAs labelled with Raman reporters and hybridized with placeholder DNAs were decorated on SERS substrate to fabricate SERS biosensor. Target miRNAs initiated the “inverse Molecular Sentinel” process. During the process, PHs were removed and the conformation of HPs changed toward the hairpin structure, thus eliciting the proximity of Raman reporter to substrate and a stronger SERS signal. The proposed SERS biosensor performs well in terms of stability, reproducibility, and selectivity. The limits of detection of miR-122-5p and miR-140-5p in serum were 4.17 aM and 4.49 aM, respectively. Finally, the fabricated SERS biosensor was applied to detect miR-122-5p and miR-140-5p in ICH patients and healthy subjects, and the results obtained by SERS were consistent with the results from quantitative real-time polymerase chain reaction, revealing the accuracy of the method. This simple, rapid approach offers great potential for the simultaneous detection of miRNAs in practical clinical applications.

Telomerase has been considered as a biomarker for early diagnosis and prognosis assessment of hepatocellular carcinoma (HCC), while the highly sensitive and specific methods remain challenging. To detect telomerase, a novel surface-enhanced Raman scattering (SERS) biosensor was constructed using the dual DNA-catalyzed amplification strategy composed of strand displacement amplification (SDA) and catalytic hairpin assembly (CHA). This strategy relies on the extension reaction of telomerase primer induced by telomerase, forming long-stranded DNAs with repetitive sequence to catalyze the follow-up SDA event. Subsequently, the SDA products can trigger the CHA reaction between the SERS probes (Au-Ag nanocages (Au-AgNCs) modified with hairpin DNA1 and Raman reporters) and capture substrate (Au@SiO2 array labeled with hairpin DNA2), resulting in the formation of numerous “hot spots” to significantly enhance the SERS signal. Results are promising that the established biosensor presented excellent reproducibility, specificity and sensitivity. Moreover, ELISA was applied as the golden standard to verify the application of the proposed biosensor in real samples and the results confirmed the satisfactory accuracy of our method. Therefore, the proposed SERS biosensor has the potential to be an ideal tool for the early screening of HCC.

Abstract Background While depressive symptoms are recognized as major mental health problems in later life, there is a lack of study in examining potential moderators in the association between intergenerational support and depressive symptoms, especially in social contexts with low socioeconomic status and inadequate formal public support. This study set out to examine the association between intergenerational support and depressive symptoms among older adults in rural Northeast China, and the potential moderating roles of age, living alone, and number of chronic diseases on this link. Methods A quota sampling approach was used to recruit 448 respondents aged 60 and above from rural Chinese communities. Depressive symptoms were the dependent variable. Intergenerational emotional, instrumental, and financial support were the main independent variables. Age, living alone, and number of chronic diseases were the moderators. Multiple linear regression models with interaction terms were conducted to test the proposed model. Results The results showed that intergenerational emotional support was significantly associated with depressive symptoms in older adults when instrumental and financial support and covariates were controlled (β = -0.196, p < .001). Age was found to have a significant moderating effect on the relationship between intergenerational instrumental support and depressive symptoms (β = -0.118, p < .05). Among older respondents aged 74.51 years and older, instrumental support was positively associated with depressive symptoms, but this association was not significant for younger respondents. Furthermore, living alone and number of chronic diseases suffered moderated the association between intergenerational financial support and depressive symptoms, which was statistically significant only for those living alone and with more chronic diseases (interaction term between living alone and intergenerational financial support: β = -0.082, p < .05; interaction term between number of chronic diseases and intergenerational financial support: β = -0.088, p < .05. Conclusions The findings not only highlight the important role of intergenerational support in promoting mental health in later life in rural Chinese contexts, but also identify within-population heterogeneity in the identified associations. Policy and intervention implications are discussed.

Fluopicolide is a new benzamide fungicide with a unique mechanism of action and is toxic to some non-target organisms. However, there is a lack of research on the chronic toxicity of fluopicolide to earthworms. In this study, in order to evaluate the chronic toxicity of fluopicolide to earthworms, the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST), and DNA oxidative damage (8-hyoxy-2-deoxyguanosine content) in earthworms were measured at 7, 14, 21, and 28 days after exposure to different concentrations (0, 0.1, 0.5, 1, 2.5, 5, and 10 mg/kg) of fluopicolide. In most treatment groups, the ROS levels increased significantly 7 days after exposure and then decreased gradually with an increase in exposure time, a certain dose–effect relationship. The antioxidant enzymes’ activities (SOD and CAT) in most treatment groups were activated, showing an increasing trend at first and then a decreasing trend; however, the CAT activity in the high-concentration treatment group was inhibited 21 days after exposure. The GST activity and MDA content showed an increasing trend at first and then a decreasing trend, which was dependent on the dose. As a biomarker of DNA damage, the 8-OHdG content was positively correlated with the concentration of fluopicolide. The results showed that a low dose of fluopicolide could cause oxidative stress and DNA damage in earthworms.

The risk assessment and resistance mechanisms of insecticide resistance are critical for resistance management strategy before a new insecticide is widely used. Triflumezopyrim (TFM) is the first commercialized mesoionic insecticide, which can inhibit nicotinic acetylcholine receptor with high-performance against the small brown planthopper (SBPH), Laodelphax striatellus (Fallén). In our study, the resistance of SBPH to TFM increased 26.29-fold, and the actual heritability of resistance was 0.09 after 21 generations of continuous selection by TFM. After five generations of constant feeding under insecticide-free conditions from F16 generation, the resistance level decreased 2.05-fold, and the average resistance decline rate per generation was 0.01, but there were no statistical decline. The TFM resistant strains had no cross-resistance to imidacloprid, nitenpyram, thiamethoxam, dinotefuran, flonicamid, pymetrozine, and chlorfenapyr. The third and fifth nymphal stage duration, pre-adult stage, adult preoviposition period, longevity, emergence rate, and hatchability of the resistant strain were significantly lower than those of the susceptible strain, while the female-male ratio was considerably increased. The fitness cost was 0.89. Further, cytochrome P450 monooxygenase (P450) and carboxylesterase (CarE) activities were markedly increased, but only the enzyme inhibitor piperonyl butoxide (PBO) had a significant synergistic effect on the resistant strain. The expression of CYP303A1, CYP4CE2, and CYP419A1v2 of P450 genes was significantly increased. SBPH has a certain risk of resistance to TFM with continuous application. The TFM resistance may be due to the increased activity of P450 enzyme regulated by the overexpression of P450 genes.

Spontaneous bursts in neuronal networks with propagation involving a large number of synchronously firing neurons are considered to be a crucial feature of these networks both in vivo and in vitro. Recently, learning has been shown to improve the association and synchronization of spontaneous events in neuronal networks by promoting the firing of spontaneous bursts. However, little is known about the relationship between the learning phase and spontaneous bursts. By combining high-resolution measurement with a 4,096-channel complementary metal-oxide-semiconductor (CMOS) microelectrode array (MEA) and graph theory, we studied how the learning phase influenced the initiation of spontaneous bursts in cultured networks of rat cortical neurons in vitro. We found that a small number of selected populations carried most of the stimulus information and contributed to learning. Moreover, several new burst propagation patterns appeared in spontaneous firing after learning. Importantly, these “learning populations” had more hubs in the functional network that governed the initiation of spontaneous burst activity. These results suggest that changes in the functional structure of learning populations may be the key mechanism underlying increased bursts after learning. Our findings could increase understanding of the important role that synaptic plasticity plays in the regulation of spontaneous activity.

Abstract Background With the worldwide spread of the 2019 novel coronavirus, scarce knowledge is available on the clinical features of more than two passages of patients. Further, in China, early intervention policy has been enacted since February. Whether early intervention contributes to swift recovery is still unknown. Hence, in this study, we focused on the patients from an isolated area, investigated the epidemiological and clinical characteristics of four serial passages of the virus. Methods From January 25 to February 29, 2020, all patient data on the SARS-CoV-2 passages in this isolated area were traced, and the patients were grouped according to the passaging of SARS-CoV-2. Clinical characteristics of patients, including laboratory, radiology, treatment and outcomes, were collected and analyzed. Results A total of 78 patients with four passages of virus transmission were included in this study. One patient transmitted SARS-CoV-2 to 8 patients (passage 2, P2), who next infected 23 patients (passage 3, P3), and then 46 patients (passage 4, P4). P2 received antiviral treatment when they had symptom, whereas P4 received antiviral treatment during their asymptomatic period. The incubation periods for P2, P3 and P4 patients were 7 days (IQR:2–12), 8 days (IQR:4–13) and 10 days (IQR:7–15), respectively. P2 patients showed lymphocytopenia (0.79 × 109/L), decreased lymphocyte percentages (12.15%), increased white blood cell count (6.51 × 109/L), increased total bilirubin levels (25% of P2 patients), increased C-reactive protein levels (100% of P2 patients) and abnormal liver function. By chest CT scans, all P2 patients (100%), 15 of P3 patients (65.22%) and 16 of P4 patients (34.78%) showed abnormality with typical feature of ground glass opacity. All of P2 patients (100%) received oxygen therapy, and in contrast, 19 of P4 patients (41.3%) received oxygen therapy. Further, significant decreased nucleic acid positive periods was found in P4 group (16 days, IQR: 10–23), compared with that of P2 group (22 days, IQR: 16–27). Moreover, the severity ratios were sharply decreased from 50% (P2 patients) to 4.35% (P4 patients), and the case fatality rate is zero. Conclusions Judged from four passages of patients, early intervention contributes to the early recovery of COVID-19 patients.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a low survival rate (9%). Epidemiologic studies show that healthy dietary patterns enriched of fruits and vegetables lower the risk of PDAC. We previously showed that supplementing black raspberries (BRBs) to patients with colorectal cancer increased tumor‐infiltrating NK cells and their cytotoxicity. We aimed to determine whether BRBs combat PDAC by modulating cancer immunity. NOD.SCID mice lacking T and B cells were injected with human Panc‐1‐Luc cells orthotopically, and immunocompetent KrasLSL.G12D/+‐Trp53LSL.R172H/+‐Pdx‐1‐Cre mice were fed BRBs. Peripheral blood mononuclear cells (PBMCs) from PDAC patients were treated with butyrate, a microbial metabolite of BRBs. The absence of T and B cells did not dampen BRBs’ antitumor effects in the NOD.SCID mice. In the KrasLSL.G12D/+‐Trp53LSL.R172H/+‐Pdx‐1‐Cre mice, BRBs significantly prolonged survival (189 days vs. 154 days). In both models, BRBs decreased tumor‐infiltrating CD11b+ cells and the expression of IL‐1β, sEH, and Ki67. BRBs also increased tumor‐infiltrating NKp46+ cells and the expression of CD107a, a functional marker of cytolytic NK and CD8+ T cells. In KrasLSL.G12D/+‐Trp53LSL.R172H/+‐Pdx‐1‐Cre mice, tumor infiltration of CD8+ T cells was increased by BRBs. Further using the PBMCs from PDAC patients, we show that butyrate decreased the population of myeloid‐derived suppressor cells (MDSCs). Butyrate also reversed CD11b+ cell‐mediated suppression on CD8+ T cells. Interestingly, there is a negative association between MDSC changes and patients’ survival, suggesting that the more decrease in MDSC population induced by butyrate treatment, the longer the patient had survived. Our study suggests the immune‐modulating potentials of BRBs in PDAC.

Abstract Background Yigan mingmu oral liquid (YGMM) is a herbal medicine based on a famous Chinese herbal formula that has been used for sore eyes for more than 400 years. Eye health is closely associated with the liver based on TCM. This study aimed to investigate the hepatoprotective effect of YGMM against acute liver injury induced by alcohol in rats. Methods Experimental rats were administered with silymarin and YGMM through the gastric gavage during the entire experiment. Starting from the 11th day, the rats were administered orally with 14 ml/kg Red Star Erguotou Liquor, a popular brand, at 4 h after the dose of silymarin (100 mg/kg) and YGMM (1, 2.5 and 5 ml/kg in low, middle and high dosage group, respectively) once a day for 4 weeks except for the rats in the normal group. Biochemical parameters, including ALT, AST, TB, TG, T-SOD, GSH, and MDA were detected to evaluate the protective effect of YGMM. Pathological changes were observed through histopathological examination. Results Treatment with YGMM exhibited a significant protective effect by reversing the biochemical parameters (ALT, AST, TB, TG, and GSH) and histopathological changes. Histopathological examination by Oil Red O Staining Solution showed that lipid droplets were significantly reduced in the silymarin and YGMM groups (p

Adaboost is a typical ensemble learning algorithm and has been studied and widely used in classification tasks. In order to improve the classification performance of existing Adaboost algorithms effectively, a noise confidence degree and weighted feature selection based Adaboost algorithm (called NW_Ada) is proposed. Firstly, in order to decrease the impact of sample set density on noise detection results, the conceptions of clustering degree and deviated degree are introduced, and a new method of evaluating the noise confidence is proposed. Then, based on the traditional feature selections of filters, a weighted feature selection method is proposed to select the features which can effectively distinguish the samples those are misclassified. Finally, based on the traditional error rate calculation method, the category recall based classifier error rate calculation method is proposed to solve the problem that the traditional methods ignore the distribution of misclassified samples when dealing with the unbalanced datasets. The experimental results show that the proposed method comprehensively considers the influences of sample density, sample weight and dataset size on classification results, and obtains significant improvement on classification performance compared to traditional Adaboost algorithms when different datasets especially the unbalanced datasets are used.

Moxidectin (MXD) is an antiparasitic drug used extensively in veterinary clinics. In this study, to develop a new formulation of MXD, a thermosensitive gel of MXD (MXD-TG) was prepared based on poloxamer 407/188. Furthermore, the gelation temperature, the stability, in vitro release kinetics and in vivo pharmacokinetics of MXD-TG were evaluated. The results showed that the gelation temperature was approximately 27 °C. MXD-TG was physically stable and can be released continuously for more than 96 h in vitro. The Korsmeyer–Peppas model provided the best fit to the release kinetics, and the release mechanism followed a diffusive erosion style. MXD-TG was released persistently for over 70 days in sheep. Part of pharmacokinetic parameters had a difference in female and male sheep (p < 0.05). It was concluded that MXD-TG had a good stability, and its release followed the characteristics of a diffusive erosion style in vitro and a sustained release pattern in vivo.

(1) Background: Abnormal repair after alveolar epithelial injury drives the progression of idiopathic pulmonary fibrosis (IPF). The maintenance of epithelial integrity is based on the self-renewal and differentiation of alveolar type 2 (AT2) cells, which require sufficient energy. However, the role of glutamine metabolism in the maintenance of the alveolar epithelium remains unclear. In this study, we investigated the role of glutamine metabolism in AT2 cells of patients with IPF and in mice with bleomycin-induced fibrosis. (2) Methods: Single-cell RNA sequencing (scRNA-seq), transcriptome, and metabolomics analyses were conducted to investigate the changes in the glutamine metabolic pathway during pulmonary fibrosis. Metabolic inhibitors were used to stimulate AT2 cells to block glutamine metabolism. Regeneration of AT2 cells was detected using bleomycin-induced mouse lung fibrosis and organoid models. (3) Results: Single-cell analysis showed that the expression levels of catalytic enzymes responsible for glutamine catabolism were downregulated (p < 0.001) in AT2 cells of patients with IPF, suggesting the accumulation of unusable glutamine. Combined analysis of the transcriptome (p < 0.05) and metabolome (p < 0.001) revealed similar changes in glutamine metabolism in bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inhibition of the key enzymes involved in glucose metabolism, glutaminase-1 (GLS1) and glutamic-pyruvate transaminase-2 (GPT2) leads to reduced proliferation (p < 0.01) and differentiation (p < 0.01) of AT2 cells. (4) Conclusions: Glutamine metabolism is required for alveolar epithelial regeneration during lung injury.

Detecting microRNA (miRNA) biomarkers expression is of great significance for the diagnosis and treatment of lung cancer. Surface-enhanced Raman scattering (SERS) has achieved microRNA sensing for the diagnosis of primary liver cancers. In this work, we developed a SERS technology for the rapid detection of lung cancers-related miRNA (miR-196a) using bimetallic Au-Ag nanowire (AgNW@AuNPs) substrates coupled with the target hairpin DNA. The finite-difference time-domain simulation proved that a large number of “hot spots” were generated between the AgNW and AuNPs, which resulted in a huge enhancement of the signal of Raman reporters. Filter paper treated by hexadecenyl succinic anhydride hydrophobic and modified with AgNWs@AuNPs was used as capturing substrate. The detection limits of miR-196a in PBS and serum were as low as 96.58 aM and 130 aM, respectively. Studies on nonspecific sequence and single-base mismatch of miRNA demonstrated that SERS-based platform was highly selective, excellent uniform, and reproducible. Finally, the platform was used to show that the miR-196a expression in the serum of lung cancer patients was much higher than that in healthy people. The detection results indicated that the SERS platform had potential applications in cancer diagnosis and might be a viable alternative to the conventional miRNA detection method, the real-time polymerase chain reaction (RT-PCR) technology.

Li-ion batteries are a key technology for addressing the global challenge of clean renewable energy and environment pollution. Their contemporary applications, for portable electronic devices, electric vehicles, and large-scale power grids, stimulate the development of high-performance battery materials with high energy density, high power, good safety, and long lifetime. High-throughput calculations provide a practical strategy to discover new battery materials and optimize currently known material performances. Most cathode materials screened by the previous high-throughput calculations cannot meet the requirement of practical applications because only capacity, voltage and volume change of bulk were considered. It is important to include more structure–property relationships, such as point defects, surface and interface, doping and metal-mixture and nanosize effects, in high-throughput calculations. In this review, we established quantitative description of structure–property relationships in Li-ion battery materials by the intrinsic bulk parameters, which can be applied in future high-throughput calculations to screen Li-ion battery materials. Based on these parameterized structure–property relationships, a possible high-throughput computational screening flow path is proposed to obtain high-performance battery materials.

Coptis chinensis inflorescence is rich in isoquinoline alkaloids, especially berberine; these alkaloids comprise a chemical group with anti-hyperglycaemic effect. This study mainly investigated the α-amylase and α-glucosidase inhibitory activities of C. chinensis inflorescence extract (CE). The effect of CE was similar to that of acarbose. Results of 3T3-L1 preadipocyte assay showed that CE can increase glucose consumption. In addition, CE and its main alkaloids (jatrorrhizine, columbamine, epiberberine, coptisine, palmatine, and berberine) were used to ameliorate streptozotocin-induced diabetic mice. Anti-hyperglycaemic activity was realised by reducing the blood glucose level and increasing the insulin content. Furthermore, CE and its main alkaloids can relieve liver injury and lipid metabolic disturbance. Therefore, CE exerts anti-hyperglycaemic activity, and alkaloids may be an active compound group. Overall, the results provide scientific foundation for C. chinensis inflorescence as functional food to ameliorate hyperglycaemia.

Natural killer (NK) cells are an essential component of innate immunity against cancer development. Many studies have been conducted to evaluate immune-modulating effects using dietary compounds. Our laboratory has been investigating the chemopreventive potential of black raspberries (BRBs) and previously demonstrated their beneficial modulation of genetic and epigenetic biomarkers in patients with colorectal cancer (CRC). The current study investigated their potential on modulating NK cells. To avoid the excessive inflammation caused by the dextran sulfate sodium (DSS) treatment that leads to colitis, we treated the mice with overnight DSS so that it would slightly irritate the colon but still promote colon carcinogenesis with 100% incidence in both the ApcMin/+ mice and azoxymethane (AOM)-treated mice. A significant decrease of tissue-infiltrating NK cells along the progression of microadenoma-to-adenoma and adenoma-to-adenocarcinoma was observed in the ApcMin/+/DSS and AOM/DSS mice, respectively. Depletion of NK cells significantly promoted the development of CRC, suggesting a critical role of NK cells in combating CRC progression. BRBs significantly suppressed the CRC progression and increased the number of tissue-infiltrating NK cells in both mouse models. Moreover, we further determined BRBs’ effects on NK cells in the human biopsy specimens collected from our previously completed clinical trial, in which CRC patients consumed BRBs for an average of 4 weeks during a presurgical window. We observed an increased number and an enhanced cytotoxicity of NK cells by BRB intervention. The current study provides evidence that BRBs have the potential to enhance the tumor immunesurveillance of NK cells that can be beneficial in the setting of CRC prevention and treatment.

Neovasculogenesis induced by stem cell therapy is an innovative approach to improve critical limb ischemia (CLI) in diabetes. Mesenchymal stem cells (MSCs) are ideal candidates due to their angiogenic and immunomodulatory features. The aim of this study is to determine the therapeutic effects of human placenta-derived MSCs (P-MSCs) on diabetic CLI, with or without exogenous insulin administration, and the underlying mechanism of any effect. A series of in vitro experiments were performed to assess the stemness and vasculogenic activity of P-MSCs. P-MSCs were intramuscularly injected at two different doses with and without the administration of insulin. The efficacy of P-MSC transplantation was evaluated by ischemia damage score, ambulatory score, laser Doppler perfusion image (LDPI), capillary, and vascular density. In vivo imaging was applied to track the implanted P-MSCs. In vivo differentiation and in situ secretion of angiogenic cytokines were determined. In vitro experimental outcomes showed the differentiation potential and potent paracrine effect of P-MSCs. P-MSCs survived in vivo for at least 3 weeks and led to the acceleration of ischemia recovery, due to newly formed capillaries, increased arterioles, and secretion of various proangiogenic factors. P-MSCs participate in angiogenesis and vascularization directly through differentiation and cytokine expression.

The protective properties of the Coptis chinensis inflorescence ethanolic extracts (CE) and its main alkaloid components against ultraviolet-B-induced oxidative damage were investigated. The content of berberine, jatrorrhizine, coptisine, epiberberine, and palmatine of CE were determined by HPLC. Results showed that the mixture of five alkaloids contributed to the protective properties of CE in vitro and that berberine had better antioxidant effects than coptisine. Furthermore, the protective properties of CE were investigated in vivo. The skin tissues of UVB-irradiated animals exhibited a significant decrease in glutathione peroxidase, catalase, superoxide dismutase, and hydroxyproline. Additionally, these tissues exhibited a significant increase in the formation of thiobarbituric acid-reactive substances (TBARS). These changes were significantly reversed in a dose-dependent manner after treatment with CE and the standard treatment with gallic acid. Thus, CE and its main alkaloids possess potent protective properties against oxidative damage and may have valuable applications as a kind of tea in the functional food industry.

Background: CD151 is highly expressed in breast cancer cells and has been shown to accelerate breast cancer by enhancing cell growth and motility, but its regulation is poorly understood. To explore post-translation regulation of CD151, for example microRNAs, will be of great importance to claim the mechanism. Methods: A luciferase reporter assay was used to determine whether CD151 was a target of miR-124. The levels of CD151 mRNA were detected by real-time PCR and CD151 protein expression was measured by western blot and flow cytometry. The effects of miR-124 expression on growth, apoptosis, cell cycle and motility of breast cancer cells were determined. Results: We discovered that miR-124 directly targets the 3' untranslated region (3'-UTR) of CD151 mRNAs and suppresses its mRNA expression and protein translation. Both siRNA of CD151 and miR-124 mimics could significantly inhibit proliferation of breast cancer cell lines via cell cycle arrest but does not induce apoptosis. Meanwhile, miR-124 mimics significantly inhibited the motility of breast cancer cells. Conclusion: miR-124 plays a critical role in inhibiting the invasive and metastatic potential of breast cancer cells, probably by directly targeting the CD151 genes. Our findings highlight an important role of miR-124 in the regulation of invasion and metastasis by breast cancer cells and suggest a potential application for miR-124 in breast cancer treatment.

Marine environments are a rich source of significant bioactive compounds. The Hawaiian archipelago, located in the middle of the Pacific Ocean, hosts diverse microorganisms, including many endemic species. Thirty-eight microbial extracts from Hawaiian coastal waters were evaluated for their antiviral activity against four mammalian viruses including herpes simplex virus type one (HSV-1), vesicular stomatitis virus (VSV), vaccinia virus and poliovirus type one (poliovirus-1) using in vitro cell culture assay. Nine of the 38 microbial crude extracts showed antiviral potencies and three of these nine microbial extracts exhibited significant activity against the enveloped viruses. A secosteroid, 5α(H),17α(H),(20R)-beta-acetoxyergost-8(14)-ene was putatively identified and confirmed to be the active compound in these marine microbial extracts. These results warrant future in-depth tests on the isolation of these active elements in order to explore and validate their antiviral potential as important therapeutic remedies.

This study aimed to evaluate the inhibitory effects of dill (Anethum graveolens L.) seed essential oil against Sclerotinia sclerotiorum and its mechanism of action. The antifungal activities of the two main constituents, namely carvone and limonene, were also measured. Mycelial growth and sclerotial germination were thoroughly inhibited by dill seed essential oil at the 1.00 μL/mL under contact condition and 0.125μL/mL air under vapor condition. Carvone also contributed more than limonene in inhibiting the growth of S. sclerotiorum. Carvone and limonene synergistically inhibited the growth of the fungus. In vivo experiments, the essential oil remarkably suppressed S. sclerotiorum, and considerable morphological alterations were observed in the hyphae and sclerotia. Inhibition of ergosterol synthesis, malate dehydrogenase, succinate dehydrogenase activities, and external medium acidification were investigated to elucidate the antifungal mechanism of the essential oil. The seed essential oil of A. graveolens can be extensively used in agriculture for preventing the oilseed crops fungal disease.

Konjac is one of the most important glucomannan crops worldwide. The breeding and genomic researches are largely limited by the genetic basis of Amorphophallus. In this study, the transcriptomes of A. konjac and A. bulbifer were constructed using a high-throughput Illumina sequencing platform. All 108,651 unigenes with average lengths of 430 nt in A. konjac and 119,678 unigenes with average lengths of 439 nt were generated from 54,986,020 reads and 52,334,098 reads after filtering and assembly, respectively. A total of 54,453 transcripts in A. konjac and 55,525 in A. bulbifier were annotated by comparison with Nr, Swiss-Prot, KEGG, and COG databases after removing exogenous contaminated sequences. A total of 80,332 transcripts differentially expressed between A. konjac and A. bulbifer. The majority of the genes that are associated with konjac glucomannan biosynthetic pathway were identified. Besides, the small RNAs in A. konjac leaves were also obtained by deep sequencing technology. All of 5,499,903 sequences of small RNAs were obtained with the length range between 18 and 30 nt. The potential targets for the miRNAs were also predicted according to the konjac transcripts. Our study provides a systematic overview of the konjac glucomannan biosynthesis genes that are involved in konjac leaves and should facilitate further understanding of the crucial roles of carbohydrate synthesis and other important metabolism pathways in Amorphophallus.

HIV-1 associated dementia remains a significant public health burden. Clinical and experimental research has shown that reduced levels of brain-derived neurotrophic factor (BDNF) may be a risk factor for neurological complications associated with HIV-1 infection. We are actively testing genetically modified macrophages for their possible use as the cell-based gene delivery vehicle for the central nervous system (CNS). It can be an advantage to use the natural homing/migratory properties of monocyte-derived macrophages to deliver potentially neuroprotective BDNF into the CNS, as a non-invasive manner. Lentiviral-mediated gene transfer of human (h)BDNF plasmid was constructed and characterized. Defective lentiviral stocks were generated by transient transfection of 293T cells with lentiviral transfer plasmid together with packaging and envelope plasmids. High titer lentiviral vector stocks were harvested and used to transduce human neuronal cell lines, primary cultures of human peripheral mononocyte-derived macrophages (hMDM) and murine myeloid monocyte-derived macrophages (mMDM). These transduced cells were tested for hBDNF expression, stability, and neuroprotective activity. The GenomeLab GeXP Genetic Analysis System was used to evaluate transduced cells for any adverse effects by assessing gene profiles of 24 reference genes. High titer vectors were prepared for efficient transduction of neuronal cell lines, hMDM, and mMDM. Stable secretion of high levels of hBDNF was detected in supernatants of transduced cells using western blot and ELISA. The conditioned media containing hBDNF were shown to be protective to neuronal and monocytic cell lines from TNF-α and HIV-1 Tat mediated cytotoxicity. Lentiviral vector-mediated gene transduction of hMDM and mMDM resulted in high-level, stable expression of the neuroprotective factorBDNF in vitro. These findings form the basis for future research on the potential use of BDNF as a novel therapy for neuroAIDS.

A great deal of interest has arisen recently with respect to human mesenchymal stem cells (MSCs), due to their broad therapeutic potential. However, the safety and efficacy of MSCs expanded ex vivo for clinical applications remain a concern. In this article, we establish a standardized process for manufacture of human umbilical cord-derived MSCs (UC-MSCs), which encompasses donor screening and testing, recovery, two-stage expansion, and administration. The biological properties and safety of UC-MSCs were then characterized and tested. The safety data from use in human patients have also been reported. After clinical-scale expansion, a yield of 1.03–3.78 × 10 8 MSCs was achieved in 10 batch manufacturing runs. The biological properties, such as plastic adherence, morphology, specific surface antigen (CD105, CD73, CD90, positive ≥ 95%; CD45, CD34, CD31, CD11b, CD19, HLA-DR, negative ≤2%), and multipotent differentiation potential (osteogenesis and adipogenesis) were retained. Bacterial and mycoplasma tests were negative and endotoxin levels were lower than 2 EU/ml. No adverse events were noted in two patients treated with intravenously and/or intrathecally administered MSCs. The data obtained indicate that banking UC-MSCs for clinical use is feasible.

Mesenchymal stem cells (MSCs) hold great promise as therapeutic agents in regenerative medicine and autoimmune diseases, based on their differentiation abilities and immunosuppressive properties. However, the therapeutic applications raise a series of questions about the safety of culture-expanded MSCs for human use. This paper summarized recent findings about safety issues of MSCs, in particular their genetic stability in long-term in vitro expansion, their cryopreservation, banking, and the role of serum in the preparation of MSCs.

The essential oil extracted from the seeds of dill (Anethum graveolens L.) was demonstrated in this study as a potential source of an eco-friendly antifungal agent. To elucidate the mechanism of the antifungal action further, the effect of the essential oil on the plasma membrane and mitochondria of Aspergillus flavus was investigated. The lesion in the plasma membrane was detected through flow cytometry and further verified through the inhibition of ergosterol synthesis. The essential oil caused morphological changes in the cells of A. flavus and a reduction in the ergosterol quantity. Moreover, mitochondrial membrane potential (MMP), acidification of external medium, and mitochondrial ATPase and dehydrogenase activities were detected. The reactive oxygen species (ROS) accumulation was also examined through fluorometric assay. Exposure to dill oil resulted in an elevation of MMP, and in the suppression of the glucose-induced decrease in external pH at 4 µl/ml. Decreased ATPase and dehydrogenase activities in A. flavus cells were also observed in a dose-dependent manner. The above dysfunctions of the mitochondria caused ROS accumulation in A. flavus. A reduction in cell viability was prevented through the addition of L-cysteine, which indicates that ROS is an important mediator of the antifungal action of dill oil. In summary, the antifungal activity of dill oil results from its ability to disrupt the permeability barrier of the plasma membrane and from the mitochondrial dysfunction-induced ROS accumulation in A. flavus.