Search

Abstract Background Immune checkpoint inhibitors (ICIs) have emerged as a novel and effective treatment strategy, yet their effectiveness is limited to a subset of patients. The gut microbiota, recognized as a promising anticancer adjuvant, is being increasingly suggested to augment the efficacy of ICIs. Despite this, the causal link between the gut microbiota and the success of immunotherapy is not well understood. This gap in knowledge has driven us to identify beneficial microbiota and explore the underlying molecular mechanisms. Methods Through 16S rDNA sequencing, we identified distinct gut microbiota in patients undergoing treatment with ICIs. Following this, we assessed the impact of probiotics on anti-PD-1 therapy in bladder cancer using mouse models, employing a multi-omics strategy. Subsequently, we uncovered the mechanisms through which Blautia-produced metabolites enhance antitumor immunity, utilizing untargeted metabolomics and a range of molecular biology techniques. Results In our research, the LEfSe analysis revealed a significant enrichment of the Blautia genus in the gut microbiota of patients who responded to immunotherapy. We discovered that the external addition of Blautia coccoides hampers tumor growth in a bladder cancer mouse model by enhancing the infiltration of CD8+ T cells within the tumor microenvironment (TME). Further investigations through untargeted metabolomics and molecular biology experiments showed that oral administration of Blautia coccoides elevated trigonelline levels. This, in turn, suppresses the β-catenin expression both in vitro and in vivo, thereby augmenting the cancer-killing activity of CD8+ T cells. Conclusions This research provided valuable insights into enhancing the efficacy of PD-1 inhibitors in clinical settings. It was suggested that applying Blautia coccoides and its metabolic product, trigonelline, could serve as a synergistic treatment method with PD-1 inhibitors in clinical applications. Graphical Abstract

Abstract Objective Bladder cancer(BCa) was a disease that seriously affects patients’ quality of life and prognosis. To address this issue, many researches suggested that the gut microbiota modulated tumor response to treatment; however, this had not been well-characterized in bladder cancer. In this study, our objective was to determine whether the diversity and composition of the gut microbiota or the density of specific bacterial genera influence the prognosis of patients with bladder cancer. Methods We collected fecal samples from a total of 50 bladder cancer patients and 22 matched non-cancer individuals for 16S rDNA sequencing to investigate the distribution of Parabacteroides in these two groups. Further we conducted follow-up with cancer patients to access the impact of different genera of microorganisms on patients survival. We conducted a Fecal Microbiota Transplantation (FMT) and mono-colonization experiment with Parabacteroides distasonis to explore its potential enhancement of the efficacy of anti-PD-1 immunotherapy in MB49 tumor-bearing mice. Immunohistochemistry, transcriptomics and molecular experiment analyses were employed to uncover the underlying mechanisms. Results The 16S rDNA showed that abundance of the genus Parabacteroides was elevated in the non-cancer control group compared to bladder cancer group. The results of tumor growth curves showed that a combination therapy of P. distasonis and ICIs treatment significantly delayed tumor growth and increased the intratumoral densities of both CD4+T and CD8+T cells. The results of transcriptome analysis demonstrated that the pathways associated with antitumoral immune response were remarkably upregulated in the P. distasonis gavage group. Conclusion P. distasonis delivery combined with α-PD-1 mAb could be a new strategy to enhance the effect of anti-PD-1 immunotherapy. This effect might be achieved by activating immune and antitumor related pathways.

ABSTRACT Aims This research aimed to investigate the specific mechanism of methyltransferase like 3 (METTL3) in the progression of diabetic kidney disease (DKD). Materials and Methods The model of diabetic kidney disease was established with HK‐2 cells and mice in vitro and in vivo. The N6 methyladenosine (m6A) contents in the cells and tissues were detected with a commercial kit and the m6A levels of PTEN induced putative kinase 1 (PINK2) were detected with a MeRIP kit. The mRNA and protein levels were determined with RT‐qPCR and western blot. The ROS, TNF‐α, and IL‐6 levels were assessed with ELISA. The cell proliferative ability was measured by a CCK‐8 assay and cell apoptosis was determined with TUNEL staining. The HE and Masson staining was performed to observe the renal morphology. The RIP assay was conducted to detect the interaction between METTL3/YTHDF2 and PINK1. Results The m6A content and METTL3 levels were prominently elevated in diabetic kidney disease. METTL3 silencing promoted the cell growth and the expression of LC3 II, PINK1, and Parkin, while inhibiting the cell apoptosis and the expression of LC3 I and p62 in the high glucose (HG) stimulated HK‐2 cells. METTL3 silencing also decreased the ROS, TNF‐α, and IL‐6 levels in diabetic kidney disease. PINK1 silencing neutralized the function of sh‐METTL3 in the HG stimulated HK‐2 cells. The HE and Masson staining showed that METTL3 silencing alleviated the kidney injury induced by DKD. METTL3 silencing decreased the m6A levels of PINK1, while increased the mRNA levels of PINK1 which depended on YTHDF2. Conclusions METTL3 silencing could inhibit the progression of diabetic nephropathy in vivo and in vitro by regulating the m6A modification of PINK1, which depends on YTHDF2. Our research lays the theoretical foundation for the precise treatment of diabetic kidney disease and the development of targeted drugs in the future.

Peptide stapling, by employing a stable, preformed alpha-helical conformation, results in the production of peptides with improved membrane permeability and enhanced proteolytic stability, compared to the original peptides, and provides an effective solution to accelerate the rapid development of peptide drugs. Various reviews present peptide stapling chemistries, anchoring residues and one- or two-component cyclization, however, therapeutic stapled peptides have not been systematically summarized, especially focusing on various disease-related targets. This review highlights the latest advances in therapeutic peptide drug development facilitated by the application of stapling technology, including different stapling techniques, synthetic accessibility, applicability to biological targets, potential for solving biological problems, as well as the current status of development. Stapled peptides as therapeutic drug candidates have been classified and analysed mainly by receptor- and ligand-based stapled peptide design against various diseases, including cancer, infectious diseases, inflammation, and diabetes. This review is expected to provide a comprehensive reference for the rational design of stapled peptides for different diseases and targets to facilitate the development of therapeutic peptides with enhanced pharmacokinetic and biological properties.

Background: The roots and rhizomes of Nardostachys jatamansi DC. are reported to be useful for the treatment of Parkinson's disease (PD). Previous research has also shown that Nardosinone, the main active component isolated from Nardostachys jatamansi DC., exhibits the potential to treat PD. Aim of the study: To investigate how the effects of Nardosinone could assist levodopa in the treatment of PD, how this process changes the intestinal flora, and to explore the effective forms of Nardosinone in the intestinal flora. Material and methods: We used behavioral experiments, and hematoxylin-eosin staining and immunohistochemical staining, to investigate the effects of a combination of Nardosinone and levodopa on rotenone-induced PD rats. In addition, we used LC/MS-MS to determine the levels of levodopa, 5-hydroxytryptamine, dopamine and its metabolite 3, 4-dihydroxyphenylacetic acid, and homovanillic acid, to investigate the effect of the intestinal flora on co-administration in the treatment of PD. LC/MS-MS was also used to detect the metabolites of Nardosinone on the gastrointestinal tract and intestinal flora. Results: The behavioral disorders and neuronal damage associated with PD were significantly improved following the co-administration. Analysis also revealed that the co-administration increased the levels of five neurotransmitters in the striatum, plasma and feces. In vitro experiments further demonstrated that the levels of dopamine and levodopa were increased in the intestinal flora. In total, five metabolites of Nardosinone were identified. Conclusion: Our findings indicate that Nardosinone and its metabolites might act as a potential adjutant to enhance the efficacy of levodopa via the intestinal flora, thus expanding the therapeutic potential of the combination of Chinese and Western medicine as a treatment method for PD.

Prostate cancer (PCa) is initially sensitive to androgen deprivation therapy (ADT) but ultimately develops resistance and progresses to castration-resistant prostate cancer (CRPC) with a poor prognosis. This study indicated that some PCa patients and mice were more sensitive to ADT and entered CRPC later, which was related to the gut microbiota, especially the enrichment of Akkermansia muciniphila (AKK). Untargeted metabolomics analysis found that serum inosine level was upregulated in the treatment-sensitive group and significantly correlated with AKK. Furthermore, we revealed that intestinal permeability and serum lipopolysaccharide (LPS) levels increased in treatment-resistant mice. LPS stimulated the upregulation of p-NF-κB p65 and AR in tumors. Supplementing AKK metabolite inosine could alleviate intestinal barrier damage and reduce serum LPS level, ultimately inhibiting castration resistance via the LPS/NF-κB/AR axis. Finally, we constructed a predictive model for CRPC combining gut microbiota and clinical information (AUC = 0.729). This study revealed the potential mechanism of gut microbiota on CRPC and provided potential therapeutic targets and prognostic indicators.

Over the past few decades, there has been a notable surge in interest in green stormwater infrastructure (GSI). This trend is a result of the need to effectively address issues related to runoff, pollution, and the adverse effects of urbanization and impervious surfaces on waterways. Concurrently, umanned aerial vehicles (UAVs) have gained prominence across applications, including photogrammetry, military applications, precision farming, agricultural land, forestry, environmental surveillance, remote-sensing, and infrastructure maintenance. Despite the widespread use of GSI and UAV technologies, there remains a glaring gap in research focused on the evaluation and maintenance of the GSIs using UAV-based imagery. This study aimed to develop an integrated framework to evaluate plant density and health within GSIs using UAV-based imagery. This integrated framework incorporated the UAV (commonly known as a drone), WebOpenDroneMap (WebDOM), ArcMap, PyCharm, and the Canopeo application. The UAV-based images of GSI components, encompassing trees, grass, soil, and unhealthy trees, as well as entire GSIs (e.g., bioretention and green roofs) within the Morgan State University (MSU) campus were collected, processed, and analyzed using this integrated framework. Results indicated that the framework yielded highly accurate predictions of plant density with a high R2 value of 95.8% and lower estimation errors of between 3.9% and 9.7%. Plant density was observed to vary between 63.63% and 75.30% in the GSIs at the MSU campus, potentially attributable to the different types of GSI, varying facility ages, and inadequate maintenance. Normalized difference vegetation index (NDVI) maps and scales of two GSIs were also generated to evaluate plant health. The NDVI and plant density results can be used to suggest where new plants can be added and to provide proper maintenance to achieve proper functions within the GSIs. This study provides a framework for evaluating plant performance within the GSIs using the collected UAV-based imagery.

Co-infection of Marek’s disease virus (MDV) and reticuloendotheliosis virus (REV) synergistically drives disease progression, yet little is known about the mechanism of the synergism. Here, we found that co-infection of REV and MDV increased their replication via the RIOK3-Akt pathway. Initially, we noticed that the viral titres of MDV and REV significantly increased in REV and MDV co-infected cells compared with single-infected cells. Furthermore, tandem mass tag peptide labelling coupled with LC/MS analysis showed that Akt was upregulated in REV and MDV co-infected cells. Overexpression of Akt promoted synergistic replication of MDV and REV. Conversely, inhibition of Akt suppressed synergistic replication of MDV and REV. However, PI3K inhibition did not affect synergistic replication of MDV and REV, suggesting that the PI3K/Akt pathway is not involved in the synergism of MDV and REV. In addition, we revealed that RIOK3 was recruited to regulate Akt in REV and MDV co-infected cells. Moreover, wild-type RIOK3, but not kinase-dead RIOK3, mediated Akt phosphorylation and promoted synergistic replication of MDV and REV. Our results illustrate that MDV and REV activated a novel RIOK3-Akt signalling pathway to facilitate their synergistic replication.

Abstract Background Co-infection with the avian leukosis virus subgroup J (ALV-J) and the reticuloendotheliosis virus (REV) increases mutual viral replication, causing a more serious pathogenic effect by accelerating the progression of neoplasia and extending the tumor spectrum. However, the molecular mechanism underlying the synergistic replication of ALV-J and REV remains unclear. Results Here, we performed this study to compare the differentially expressed proteins among CEF cells infected with ALV-J, REV or both at the optimal synergistic infection time using TMT-based quantitative proteomics. We identified a total of 719 (292 upregulated and 427 downregulated) and 64 (35 upregulated and 29 downregulated) proteins by comparing co-infecting both viruses with monoinfecting ALV-J and REV, respectively. GO annotation and KEGG pathway analysis showed the differentially expressed proteins participated in virus-vector interaction, biological adhesion and immune response pathways in the synergistic actions of ALV-J and REV at the protein levels. Among the differentially expressed proteins, a large number of integrins were inhibited or increased in the co-infection group. Further, eight integrins, including ITGα1, ITGα3, ITGα5, ITGα6, ITGα8, ITGα9, ITGα11 and ITGβ3, were validated in CEF cells by qRT-PCR or western blot. Conclusions These findings proved that integrins may be key regulators in the mechanism of synergistic infection of REV and ALV-J, which will provide more insight into the pathogenesis of synergism of REV and ALV-J at protein level.

Abstract The occurrence of gene duplication/amplification (GDA) provide potential material for adaptive evolution with environmental stress. Several molecular models have been proposed to explain GDA, recombination via short stretches of sequence similarity plays a crucial role. By screening genomes for such events, we propose a “SRS (short repeated sequence) *N + unit + SRS*N” amplified unit under USCE (unequal sister-chromatid exchange) for tandem amplification mediated by SRS with different repeat numbers in eukaryotes. The amplified units identified from 2131 well-organized amplification events that generate multi gene/element copy amplified with subsequent adaptive evolution in the respective species. Genomic data we analyzed showed dynamic changes among related species or subspecies or plants from different ecotypes/strains. This study clarifies the characteristics of variable copy number SRS on both sides of amplified unit under USCE mechanism, to explain well-organized gene tandem amplification under environmental stress mediated by SRS in all eukaryotes.

ObjectiveOveractive bladder (OAB) is a disease that seriously affects patients’ quality of life and mental health. To address this issue, more and more researchers are examining the relationship between OAB treatment and urinary microecology. In this study, we sought to determine whether differences in treatment efficacy were related to microbiome diversity and composition as well as the abundance of specific genera. Machine learning algorithms were used to construct predictive models for urine microbiota-based treatment of OAB.MethodsUrine samples were obtained from 64 adult female OAB patients for 16S rRNA gene sequencing. Patients’ overactive bladder symptom scores (OABSS) were collected before and after mirabegron treatment and patients were divided into effective and ineffective groups. The relationship between the relative abundance of certain genera and OABSS were analyzed. Three machine learning algorithms, including random forest (RF), supporting vector machine (SVM) and eXtreme gradient boosting (XGBoost) were utilized to predict the therapeutic effect of mirabegron based on the relative abundance of certain genera in OAB patients’ urine microbiome.ResultsThe species composition of the two groups differed. For one, the relative abundance of Lactobacillus was significantly higher in the effective group than in the ineffective group. In addition, the relative abundance of Gardnerella and Prevotella in the effective group was significantly lower than in the ineffective group. Alpha-diversity and beta-diversity differed significantly between the two groups. LEfSe analysis revealed that Lactobacillus abundance increased while Prevotella and Gardnerella abundance decreased in the effective group. The Lactobacillus abundance ROC curve had high predictive accuracy. The OABSS after treatment was negatively correlated with the abundance of Lactobacillus, whereas the relationship between OABSS and Prevotella and Gardnerella showed the opposite trend. In addition, RF, SVM and XGBoost models demonstrated high predictive ability to assess the effect of mirabegron in OAB patients in the test cohort.ConclusionsThe results of this study indicate that urinary microbiota might influence the efficacy of mirabegron, and that Lactobacillus might be a potential marker for evaluating the therapeutic efficacy of mirabegron in OAB patients.

Neohesperidin dihydrochalcone (NHDC) is a kind of sweetener widely used in food processing. Some artificial sweeteners induce food allergy by breaking oral tolerance (OT). The relationship between NHDC and oral tolerance are important in food safety. We explored the possible effects of NHDC on OT via network pharmacology combined with vivo and vitro experiments. NHDC was predicted to have effects on OT. It was focus on immunoglobulin production, inflammation and immunity. Then, OT mouse model and mast cell degranulation were applied to further explore the mechanism. NHDC could affect the Th2 response by suppressing the sIgG1 level in the serum and GATA-3 expression in the colon. NHDC could inhibit RBL-2H3 cells degranulation by suppressing the Ca2+ influx and MAPK signaling pathways. Results showed that NHDC can be safely applied in food processing and had promotional effects on oral tolerance.

Coinfection with Marek's disease virus (MDV) and reticuloendotheliosis virus (REV) causes synergistic pathogenic effects and serious losses to the poultry industry. However, whether there is a synergism between the two viruses in viral replication and the roles of host factors in regulating MDV and REV coinfection remains elusive. In this study, we found that MDV and REV coinfection increased viral replication in coinfected cells as compared to a single infection in a limited period. Further, we explore the host cell responses to MDV and REV coinfection using tandem mass tag (TMT) peptide labeling coupled with liquid chromatography–tandem mass spectrometry (LC-MS/MS). Compared with MDV/REV-infected cells, 38 proteins increased (fold change > 1.2) and 60 decreased (fold change < 0.83) their abundance in MDV and REV coinfected cells. Differentially accumulated proteins (DAPs) were involved in important biological processes involved in the immune system process, cell adhesion and migration, cellular processes, and multicellular organismal systems. STRING analysis found that IRF7, MX1, TIMP3, and AKT1 may be associated with MDV and REV synergistic replication in chicken embryo fibroblasts (CEFs). Western blotting analysis showed that the selected DAPs were identical to the quantitative proteomics data. Taken together, we verified that MDV and REV can synergistically replicate in coinfected cells and revealed the host molecules involved in it. However, the synergistic pathogenesis of MDV and REV needs to be further studied.

Synergism between avian leukosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV) has been reported frequently in co-infected chicken flocks. Although significant progress has been made in understanding the tumorigenesis mechanisms of ALV and REV, how these two simple oncogenic retroviruses induce synergistic oncogenicity remains unclear. In this study, we found that ALV-J and REV synergistically promoted mutual replication, suppressed cellular senescence, and activated epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, structural proteins from ALV-J and REV synergistically activated the expression of Musashi-1(MSI1), which directly targeted pri-miR-147 through its RNA binding site. This inhibited the maturation of miR-147, which relieved the inhibition of NF-κB/KIAA1199/EGFR signaling, thereby suppressing cellular senescence and activating EMT. We revealed a synergistic oncogenicity mechanism induced by ALV-J and REV in vitro. The elucidation of the synergistic oncogenicity of these two simple retroviruses could help in understanding the mechanism of tumorigenesis in ALV-J and REV co-infection and help identify promising molecular targets and key obstacles for the joint control of ALV-J and REV and the development of clinical technologies.

A printed circuit heat exchanger (PCHE) is utilized to cool the compressor inlet air to increase the compression efficiency in a liquid air energy storage and liquid natural gas (LNG) coupled system, which can offer large-scale energy storage with significantly improved exergy efficiency and round-trip efficiency. In this work, the effect of pressure of air, incline angle, and hydraulic diameter on the performance of a compressed air–water PCHE with a semicircle cross-section was studied. The results show that PCHE can realize the intermediate cooling of air compression in the liquid air energy storage system, and the pressure variation of air shows a limited effect on the heat transfer of PCHE; however, the hydraulic diameter and the incline angle both affect the heat transfer and the flow resistance of PCHE, and the best incline angle is 15°.

Tectonic interpretation is critical to a coal mine’s safe production, and fault interpretation is an essential component of seismic tectonic interpretation. With the increasing necessity for accuracy in fault interpretation in coal mines, it is increasingly challenging to achieve greater accuracy only through traditional fault interpretation. The convolutional neural network (CNN) is a machine learning method established in recent years and it has been widely applied in coal mine fault interpretation because of its powerful feature-learning and classification capabilities. To improve the accuracy and efficiency of fault interpretation in coal mines, an automatic seismic fault identification method based on the convolutional neural network has been developed. Taking a mining area in eastern Yunnan province as an example, the CNN model realized automatic identification of faults with eight seismic attributes as feature inputs, and the model-training parameters were optimized and compared. Ten faults in the area were selected to analyze the prediction effect, and a comparative experiment was done with model structure parameters and training sets. The experimental results indicate that the training parameters have a significant influence on the training time and testing accuracy of the model, while structural parameters and training sets affect the actual prediction effect of the model. By comparison, the fault results predicted by the convolutional neural network are in good agreement with the manual interpretation, and the accuracy of the model is more than 85%, which proves that this method has certain feasibility and provides a new way to shorten the fault interpretation period and improve the interpretation accuracy.

Collagen triple helix repeat containing-1 (CTHRC1) has recently been identified as avian leukosis virus subgroup J (ALV-J) replication-dependent factor that remarkably facilitates ALV-J replication via interaction with the envelope glycoprotein (SU) of ALV-J. However, the dynamic distribution and localization of CTHRC1 in various tissues upon ALV-J infection are still unknown. In this study, data revealed that the levels of CTHRC1 were significantly increased in various tissues and that the protein was mainly located in the cytoplasm and nucleus of parenchymal cells in tissues of chickens that were infected by ALV-J naturally and experimentally. Interestingly, CTHRC1 was also observed in leukocytes other than erythrocytes in congested veins of ALV-J-infected tissues. Consequently, the positive cells in these veins were confirmed as lymphocytes by laser confocal microscopy. Taken together, these results conclude that the CTHRC1 is an inducible protein and exhibited ubiquitous expression in ALV-J-infected chickens, which may provide basic information for in-depth study of ALV-J infection and replication mechanisms.

Salicylhydroxamic acid is an excellent collector of oxidizing ore, and it has an efficient collection performance for tungsten molybdenum ore. However, the utilization ratio of salicylhydroxamic acid is relatively low in the flotation process, and a large amount of flotation wastewater discharged might cause damage to the water environment. This study mainly compared the effects of natural sunlight degradation, ozonation, and Fenton oxidation processes on the treatment of salicylchydroxamic acid wastewater from W–Mo mineral processing. The results showed after 30 hours degradation by natural sunlight, the CODcr removal rate of wastewater was only 25.99%. When the initial pH was 8, the dosage of O3 was 1.3 mg/L and the reaction time was 60 minutes; O3 oxidation could remove 40.37% CODcr from wastewater, and the BOD5/CODcr value increased to higher than 0.3 after 15 min reaction. Under the Fenton oxidation conditions such as initial pH 3, H2O2 dosage 0.96 g/L, and the molar ratio of H2O2 to Fe2+ 2 : 1, 90.43% CODcr could be removed from flotation wastewater after 90 min reaction, and the BOD5/CODcr value was obviously improved. Fenton oxidation was a high efficient processing technology for salicylhydroxamic acid wastewater, and the effluent could meet the discharge and reuse emission standard requirements in China.

Abstract Background Co-infection with avian leukosis virus subgroup J and reticuloendotheliosis virus induces synergistic pathogenic effects and increases mortality. However, the role of exosomal miRNAs in the molecular mechanism of the synergistic infection of the two viruses remains unknown. Results In this study, exosomal RNAs from CEF cells infected with ALV-J, REV or both at the optimal synergistic infection time were analysed by Illumina RNA deep sequencing. A total of 54 (23 upregulated and 31 downregulated) and 16 (7 upregulated and 9 downregulated) miRNAs were identified by comparing co-infection with two viruses, single-infected ALV-J and REV, respectively. Moreover, five key miRNAs, including miR-184-3p, miR-146a-3p, miR-146a-5p, miR-3538 and miR-155, were validated in both exosomes and CEF cells by qRT-PCR. GO annotation and KEGG pathway analysis of the miRNA target genes showed that the five differentially expressed miRNAs participated in virus-vector interaction, oxidative phosphorylation, energy metabolism and cell growth. Conclusions We demonstrated that REV and ALV-J synergistically increased the accumulation of exosomal miRNAs, which sheds light on the synergistic molecular mechanism of ALV-J and REV.

Bone morphogenetic protein 2 (BMP2) is an efficacious inducer for the osteogenesis of mesenchymal stem cells (MSCs). Conventional applications of BMP2 have involved either the direct incorporation of BMP2 protein or ex vivo BMP2 gene transfer into stem cells prior to their transplantation. These approaches are able to promote bone formation to some extent; however, they are hampered by either the lack of stability and sustainability of BMP2 protein or the time-consuming and cost-prohibitive in vitro cell culture procedure. To overcome these limitations, we have developed a gene-activated poly-L-lactide acid (PLLA) scaffold with the encapsulation of recombinant adeno-associated viral (AAV) vector encoding a full-length cDNA of human BMP2 using an ice-based microparticle porogenization method that was recently developed. Results showed continuous release of AAV particles from the micropores of scaffolds for up to 1 week, subsequently transducing embedded human MSCs and producing functional BMP2. MSCs within scaffolds underwent efficacious osteogenesis, on the basis of osteoinductive gene expression and osteogenic differentiation, which resulted in robust new bone formation in vivo at 4 weeks. These findings show the potential of the technology toward developing clinical applications of a rapid, cost-effective, and potentially point-of-care approach for the repair of bone defects.

The prediction and pre-evaluation of the thermal properties and combustion-related problems (e.g., emissions and ash-related problems) are critical to reducing emissions and improving combustion efficiency during the agricultural crop residues combustion process. This study integrated the higher heating value (HHV) model, specific heat model, and fuel indices as a new systematic approach to characterize the agricultural crop residues. Sixteen linear and non-linear regression models were developed from three main compositions of the ultimate analysis (e.g., C, H, and O) to predict the HHV of the agricultural crop residues. Newly developed HHV models have been validated with lower estimation errors and a higher degree of accuracy than the existing models. The specific heat of flue gas during the combustion process was estimated from the concentrations of C, H, O, S, and ash content under various excess air (EA) ratios and flue gas temperatures. The specific heat of agricultural crop residues was between 1.033 to 1.327 kJ/kg·K, while it was increased by decreasing the EA ratios and elevating the temperature of the flue gas. Combustion-related problems, namely corrosions, PM1.0 emissions, SOx, HCl, and ash-related problems were predicted using the fuel indices along with S and Cl concentrations, and ash compositions. Results showed that agricultural crop residues pose a severe corrosion risk and lower ash sintering temperature. This integrated approach can be applied to a wide range of biomass before the actual combustion process which may predict thermal-chemical properties and reduce the potential combustion-related emissions.

Sex differences in the study of the human physiological response to mental stress are often erroneously ignored. To this end, we set out to show that our understanding of the stress response is fundamentally altered once sex differences are taken into account. This is achieved by comparing the heart rate variability (HRV) signals acquired during mental maths tests from ten females and ten males of similar maths ability; all females were in the follicular phase of their menstrual cycle. For rigor, the HRV signals from this pilot study were analyzed using temporal, spectral and nonlinear signal processing techniques, which all revealed significant statistical differences between the sexes, with the stress-induced increases in the heart rates from the males being significantly larger than those from the females (p-value = 4.4 × 10−4). In addition, mental stress produced an overall increase in the power of the low frequency component of HRV in the males, but caused an overall decrease in the females. The stress-induced changes in the power of the high frequency component were even more profound; it greatly decreased in the males, but increased in the females. We also show that mental stress was followed by the expected decrease in sample entropy, a nonlinear measure of signal regularity, computed from the males' HRV signals, while overall, stress manifested in an increase in the sample entropy computed from the females' HRV signals. This finding is significant, since mental stress is commonly understood to be manifested in the decreased entropy of HRV signals. The significant difference (p-value = 2.1 × 10−9) between the changes in the entropies from the males and females highlights the pitfalls in ignoring sex in the formation of a physiological hypothesis. Furthermore, it has been argued that estrogen attenuates the effect of catecholamine stress hormones; the findings from this investigation suggest for the first time that the conventionally cited cardiac changes, attributed to the fight-or-flight stress response, are not universally applicable to females. Instead, this pilot study provides an alternative interpretation of cardiac responses to stress in females, which indicates a closer alignment to the evolutionary tend-and-befriend response.

The effect of compressive pretreatment before chemical pulping on the properties of poplar kraft and soda-AQ pulp was evaluated. Compressive pretreatment not only resulted in the dissolution of hemicellulose, but also leached extractives. Pulps made from compressive pretreated wood chips required lower beating energy than the untreated pulps to achieve the same beating degree of 45°SR, and the brightness of the handsheets was improved by 2% ISO. Compressive pretreatment allowed for efficient delignification and saved about 6% alkali consumption to achieve similar pulp screen yield. Furthermore, a higher content of fines and slightly lower mechanical properties were observed after the compressive treatment.

Nitrogen fixation of wheat straw ammonium sulfite pulping spent liquor and the chelating property of nitrogen-fixed ammonium lignosulfonate were studied. Results showed that free ammonium nitrogen in spent liquor could be fixed by formaldehyde. When the amount of formaldehyde was 10% based on the dry weight of lignosulfonate, 30% of inorganic nitrogen was converted into organic nitrogen, of which 87.4% was ammonium lignosulfonate and 12.6% was urotropine. The proper chelating condition of nitrogen-fixed ammonium lignosulfonate was as follows: pH:3, hydrogen peroxide:10%, FeSO4: 40.9%, and 50 oC for 30 min. Under this reaction condition, the chelating ratio of Fe2+ was measured as 15.1%. Chelation did not result in Fe(OH)3 precipitation under alkaline conditions. Effects of H2O2 dosage on the structure of ammonium lignosulfonate were also studied. The content of carboxyl, phenolic hydroxyl, and conjugated carbonyl groups in lignosulfonate that could be chelated with metal ions increased after ammonium lignosulfonate was oxidized. Average molecular weight and distribution were also determined with GPC. Results showed that the proportion of higher molecular weight components increased after oxidation of ammonium lignosulfonate, indicating that oxidative degradation and condensation reaction proceeded during oxidative treatment and condensation was the main reaction. The increase of molecular weight could improve the chelating ability of ammonium lignosulfonate.

Overactive bladder (OAB) is a condition characterized by an urgency to urinate, which is associated with the urodynamic observation of detrusor overexcitation. Although the etiology of OAB is currently unclear, it has been suggested that in patients with OAB, disruption of bladder epithelial barrier integrity can disturb the normal contractile function of the detrusor. Additionally, dietary preferences have been suggested to influence the severity of OAB. Therefore, the aim of the present study was to investigate the effect of a high salt diet (HSD) on the development of OAB in a murine model. Mice were fed either a HSD or standard diet for 8 weeks, following which voiding characteristics and bladder barrier function were assessed. The present study demonstrated that a HSD in mice was associated with OAB-like symptoms such as increased urinary frequency and non-voiding bladder contractions. The HSD group demonstrated a thinner bladder mucus layer and decreased expression of bladder barrier markers, tight junction protein-1 and claudin-1, which may be potentially indicative of induced bladder damage. A HSD for 8 weeks in mice and a high salt treatment at the uroepithelium cellular (SV-HUC-1s) level resulted in increased uroepithelial oxidative stress and inflammatory cell infiltration, as indicated by increased expression levels of TNF-α and IL-1β, as well as activation of the nucleotide-binding domain leucine-rich-containing family pyrin domain-containing 3 (NLRP3) and NF-κB signaling pathways in vivo and in vitro. Therefore, the present study indicated that a HSD could be a potentially important risk factor for the development of OAB, as it may be associated with overactivation of contractile function of the bladder by impairing the integrity of the bladder epithelial barrier and activation of the NLRP3 and NF-κB signaling pathways. Remodeling of the bladder barrier and reduction of the inflammatory response may be potential targets for the treatment of OAB in the future. [ABSTRACT FROM AUTHOR]

Co-infection of avian leukosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV) in poultry flocks induces synergistic replication, which worsens immunosuppression, growth inhibition, and increased mortality. However, the synergistic replication mechanism between ALV-J and REV is still not fully understood. We showed that microRNA-155 (miR-155) targets a dual pathway, PRKCI-MAPK8 and TIMP3-MMP2, which interacts with the U3 region of ALV-J and REV to promote synergistic replication between ALV-J and REV. Initially, we found that the RNA levels of ALV-J and REV increased significantly in ALV-J and REV co-infected cells and tissues compared with mono-infected cells and tissues. Next, miRNAomics showed that ALV-J and REV synergistically increased miR-155 levels. In co-infected cells, miR-155 promoted synergistic replication of ALV-J and REV. All structural proteins of the two viruses activated the expression of miR-155, especially gag proteins, rather than insertional activation. Proteomic study of cells co-infected with ALV-J and REV and transfected with miR-155 indicated that miR-155 directly suppressed PRKCI and TIMP3 and that PRKCI directly prevented MAPK8 expression, while TIMP3 directly interfered MMP2 expression. We also found that MAPK8 and MMP2 co-interacted with ALV-J and REV's U3 to enhance synergistic replication. In conclusion, ALV-J and REV synergistically activate miR-155, facilitating the synergistic replication of ALV-J and REV by PRKCI-MAPK8 and TIMP3- MMP2 dual-pathway interaction with the U3 region of ALV-J and REV. This discovery will assist in explaining how two retroviruses replicate synergistically. [ABSTRACT FROM AUTHOR]

The atmospheric chemistry of organic nitrogen compounds (ONCs) is of great importance for understanding the formation of carcinogenic nitrosamines and ONC oxidation products might influence atmospheric aerosol particle formation and growth. Indole is a polyfunctional heterocyclic secondary amine with global emission quantity almost equivalent to that of trimethylamine, the amine with the highest atmospheric emission. However, the atmospheric chemistry of indole remains unclear. Herein, the reactions of indole with ·OH/·Cl, and subsequent reactions of resulting indole-radicals with O2 under 200 ppt NO and 50 ppt HO2 conditions, were investigated by a combination of quantum chemical calculations and kinetics modeling. The results indicate that OH addition is dominant pathway for the reaction of OH with indole. However, both Cl addition and H-abstraction are feasible for the corresponding reaction with Cl. All favorably formed indole-radicals further react with O2 to produce peroxy radicals, which mainly react with NO and HO2 to form organonitrates, alkoxy radicals and hydroperoxide products. Therefore, the oxidation mechanism of indole is distinct from that of previously reported amines, which primarily form highly oxidized multifunctional compounds, imines or carcinogenic nitrosamines. In addition, the peroxy radicals from the H reaction can form N-(2-formylphenyl)formamide (C8H7NO2), for the first time providing evidence for the chemical identity of the C8H7NO2 mass peak observed in the OH + indole experiments. More importantly, this study is the first to demonstrate despite forming radicals by abstracting an H-atom at the N-site, carcinogenic nitrosamines were not produced in the indole oxidation reaction. [ABSTRACT FROM AUTHOR]

A three dimensional chitosan/vacuum-stripped graphene/polypyrrole interface with a hierarchical porous structure was fabricated as a freestanding and flexible electrochemical sensing electrode for dopamine detection, which exhibits unprecedented good selectivity, high sensitivity (632.1 µA mM[sup -1] cm[sup -2]), wide linear response range (0.1-200 µM), low detection limit (19.4 nM, S/N = 3) and good sensing performance in human serum samples, outperforming the previously reported 2D and 3D graphene and/or the PPy modified electrode, and exhibiting comparable performance with the Au modified electrode. [ABSTRACT FROM AUTHOR]

We developed a simple and novel layer-by-layer (LBL) assembly in combination with covalent connection strategy for the synthesis of multifunctional carbon nanotubes (CNTs)-based magnetic-fluorescent nanohybrids as multimodal cellular imaging agents for detecting human embryonic kidney (HEK) 293T cells viamagnetic resonance (MRI) and confocal fluorescence imaging. Superparamagnetic iron oxide nanoparticles (SPIO) and near-infrared fluorescent CdTe quantum dots (QDs) were covalently coupled on the surface of CNTs in sequence viaLBL assembly. It was indicated that the SPIO layer acted not only as a contrast agent for MRI, but also as a spacer between CdTe QDs and CNTs for prohibiting fluorescence quenching of QDs on the surface of the CNTs. The multifunctional CNT-based magnetic-fluorescent nanohybrids showed an enhanced MRI signal as contrast agent for detecting 293T cells in comparison with the pure SPIO. This is due to the magnetic coupling between the orderly arrayed SPIO, the function of CNTs for lowering the transverse relaxation and the ability of CNTs for penetrating into cells. Moreover, the multifunctional CNT-based magnetic-fluorescent nanohybrids exhibited the higher intracellular labeling efficiency due to the ability of CNTs for penetrating into cells in comparison with pure SPIO-CdTe nanoparticles. [ABSTRACT FROM AUTHOR]

Avian leukosis virus subgroup J (ALV-J) induces myelocytomas, which can metastasize to multiple organs in diseased chickens. Although metastasis is the primary cause of death in such cases, the mechanism for it remains unclear. Here, we found that interaction between ALV-J surface protein (SU) and doublecortin-like kinase 1 (DCLK1) promotes epithelial-mesenchymal transition (EMT) and cell proliferation. We found that ALV-J can activate EMT in infected cells. Subsequently, proteomics analysis revealed that DCLK1, a well-established putative tumor stem cell marker, which is highly expressed in ALV-J-infected DF-1 cells and chickens, might be a potential factor mediating EMT. Furthermore, using immunofluorescence and immunoprecipitation, we verified that SU interacts with DCLK1. Functional studies suggested that overexpression of DCLK1 increased viral replication and promoted cell proliferation by accelerating the progression of cells from the G0/G1 phase to the S phase of cell cycle, whereas RNA interference of DCLK1 reduced viral replication and arrested cell proliferation by retarding cell cycle progression from the late G1 phase into the S phase in ALV-J-infected cells. Moreover, we demonstrate that the increased accumulation of DCLK1 promotes EMT by increasing the expression of Ncadherin, vimentin, MMP2, and transcription factor Snail1 and decreasing the expression of epithelial marker E-cadherin. These results suggest that ALV-J SU interacts with DCLK1, and accelerates cell proliferation, leading to increased viral replication and ultimately activating EMT, which paves the way for tumor metastasis. [ABSTRACT FROM AUTHOR]