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IntroductionIn the fragrance and perfume industry, the controlled release of fragrances are crucial factors that contribute to consumer appeal and product quality enhancement. In this study, various aromatic active substances were extracted from dandelion root (DR), which was subsequently calcined to produce high-performance porous biochar material.MethodsThe dandelion root biochar (DRB) material was identified as promising adsorbents for the controlled release of fragrances. Furfuryl alcohol was chosen as the model fragrance for inclusion and controlled release studies.Results and discussionThe DRB exhibited a substantial specific surface area of 991.89 m2/g, facilitating efficient storage and controlled release capabilities. Additionally, the DRB’s high stability and porous nature facilitated rapid collection and efficient recyclability. This research significantly contributes to the development of a sustainable, zero-waste multistage utilization strategy for dandelion roots, indicating a potential applications in the food flavoring industry and environmental conservations.

Laccase (LAC), a copper-containing polyphenol oxidase, is an important pathogenic factor of pathogenic fungi, and has been identified as an important virulence factor in numerous pathogenic fungi. LAC is encoded by a gene family and belongs to the class of multicopper oxidases. The study aimed to identify the LAC genes in Athelia bombacina (Link) Pers, and their interactions with the host. The expression levels of the LAC genes were quantified using RT-qPCR. The LAC activity, level of malondialdehyde (MDA) and activities of protective enzymes in ‘Huangguan’ pears during the interaction were measured. The AbLac4 gene deletion mutant strain was constructed. Six LAC genes were identified in A. bombacina, distributed across three chromosomes. Interspecies collinearity analysis suggested that LAC genes could serve as crucial pathogenic factors in A. bombacina. The LAC gene family can be classified into three distinct subgroups. Among the subgroups, variations were observed in their characteristic sequences and conserved motifs. However, the LAC genes within the same subgroup exhibited a high degree of conservation. The genes showed diverse expression profiles, with their promoters harboring multiple stress-responsive elements. Signal peptide prediction showed that all LAC proteins, with the exception of the AbLac3 protein, possessed signal peptides, indicating that they are secretory proteins. The subcellular localization analysis showed that all LAC proteins may be localized extracellularly. RT-qPCR revealed differential expression patterns among LAC genes; specifically, AbLac1 and AbLac4 exhibited distinct expression dynamics during the infection process. The LAC activity first increased and then decreased, with the highest increase rate occurring in the early stage of culture. The MDA content and catalase (CAT) activity at the inoculated site were found to be significantly higher than the uninoculated control. In addition, the deletion of AbLac4 gene reduced the growth rate and pathogenic ability of A. bombacina. This investigation found that AbLac1 and AbLac4 may play pivotal roles in mediating host interactions, and the fruit may combat pathogen infection through increasing the activities of CAT, phenylalanine ammonia lyase and peroxidase. This study provides valuable new insights into the pathogenic mechanisms of A. bombacina, significantly contributing to the field.

Background and Objective. To explore the effect of respiratory muscle training on children with bronchiectasis. Methods. Participants underwent respiratory muscle training for 24 weeks. The main results were changes in respiratory muscle strength and pulmonary function indices (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow rate (PEF), forced expiratory flow 25–75% (FEF25–75%), and maximal midexpiratory flow 75/25 (MMEF75/25)) before, 12 weeks after, and 24 weeks after the intervention. The secondary outcomes were changes in the exercise load and work rate, exercise work, Leicester Cough Questionnaire (LCQ) scale, and Fatigue Severity Scale (FSS). Results. Compared with before the intervention, after 24 weeks of respiratory muscle training, the maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were significantly enhanced (P

Abstract Activation of regeneration upon tissue damages requires the activation of many developmental genes responsible for cell proliferation, migration, differentiation, and tissue patterning. Ample evidence revealed that the regulation of chromatin organization functions as a crucial mechanism for establishing and maintaining cellular identity through precise control of gene transcription. The alteration of chromatin organization can lead to changes in chromatin accessibility and/or enhancer-promoter interactions. Like embryogenesis, each stage of tissue regeneration is accompanied by dynamic changes of chromatin organization in regeneration-responsive cells. In the past decade, many studies have been conducted to investigate the contribution of chromatin organization during regeneration in various tissues, organs, and organisms. A collection of chromatin regulators were demonstrated to play critical roles in regeneration. In this review, we will summarize the progress in the understanding of chromatin organization during regeneration in different research organisms and discuss potential common mechanisms responsible for the activation of regeneration response program.

ABSTRACT: Pear is a fruit crop of worldwide importance and cold storage is an integral part of the production and distribution of pears. An uncharacterized fungal disease has been observed on ‘Huangguan’ pear fruit during cold storage in Hebei Province. The fungus was consistently isolated from diseased fruit by routine tissue separation method, and shown to be the causal agent according to Koch postulates. Based on its morphology, molecular characteristics, pathogenicity and ITS sequence, the fungus was identified as Rhizoctonia solani. This study recorded postharvest fruit rot caused by Rhizoctonia solani on pear fruit in China.

Stroke has a high disability rate and fatality rate. It is of great clinical significance to study the automatic recognition and segmentation of stroke lesions. Convolutional neural network can not make use of time sequence correlation of medical image data, and has the problem of low feature utilization. Therefore, a bidirectional recurrent U-Net (BIRU-Net) model was proposed for segmentation of lesions. First, a recurrent neural network is introduced to replace part of the convolutional layer in U-Net with an improved attention convolutional gate recursive unit (ACGRU), so that the segmentation model is not only suitable for small-scale annotated medical image data sets, but also has the characteristics of long-term memory. Second, a dual-channel fusion training mechanism is adopted to input the forward and reverse slice data of a single view into BIRU-Net at the same time, and realize bidirectional feature fusion in the process of model forward propagation, effectively utilizing the bidirectional dependence of slice sequence. Finally, the segmentation results of each single view are refused to effectively utilize the spatial context information of data. The experimental results of ATLAS data set show that the DSC value of the proposed method reaches 62.58%. Compared with other methods at the present stage, the proposed method can segment the lesion region more accurately.

Hepatocytes are very difficult to expand in vitro. Here the authors discover that IL6 promotes long-term expansion (>30 passages) of primary mouse hepatocytes in vitro by converting the cells into hepatic progenitor cells, which maintain full capacity of differentiation into hepatocytes.

Background Checkpoint inhibitor pneumonitis (CIP) that does not respond to corticosteroids is termed steroid-refractory CIP. We aimed to find risk factors of steroid-refractory CIP and evaluate the management strategies of immunomodulators (IMs).Methods Patients with CIP were identified between August 2019 and August 2022 retrospectively. Clinical characteristics, peripheral blood biomarkers, and radiologic images were collected.Results Among 1209 patients with solid tumor receiving programmed death (ligand)-1 antibody, 28 patients developed steroid-refractory CIP and 38 patients developed steroid-response CIP. Patients with steroid-refractory CIP had a higher proportion of previous interstitial lung disease (p=0.015) and grade 3–4 (p

Background & Aims: Hepatocyte transplantation has emerged as a possible treatment option for end-stage liver disease. However, an important obstacle to therapeutic success is the low level of engraftment and proliferation of transplanted hepatocytes, which do not survive long enough to exert therapeutic effects. Thus, we aimed to explore the mechanisms of hepatocyte proliferation in vivo and find a way to promote the growth of transplanted hepatocytes. Methods: Hepatocyte transplantation was performed in Fah-/- mice to explore the mechanisms of hepatocyte proliferation in vivo. Guided by in vivo regeneration mechanisms, we identified compounds that promote hepatocyte proliferation in vitro. The in vivo effects of these compounds on transplanted hepatocytes were then evaluated. Results: The transplanted mature hepatocytes were found to dedifferentiate into hepatic progenitor cells (HPCs), which proliferate and then convert back to a mature state at the completion of liver repopulation. The combination of two small molecules Y-27632 (Y, ROCK inhibitor) and CHIR99021 (C, Wnt agonist) could convert mouse primary hepatocytes into HPCs, which could be passaged for more than 30 passages in vitro. Moreover, YC could stimulate the proliferation of transplanted hepatocytes in Fah-/- livers by promoting their conversion into HPCs. Netarsudil (N) and LY2090314 (L), two clinically used drugs which target the same pathways as YC, could also promote hepatocyte proliferation in vitro and in vivo, by facilitating HPC conversion. Conclusions: Our work suggests drugs promoting hepatocyte dedifferentiation may facilitate the growth of transplanted hepatocytes in vivo and may facilitate the application of hepatocyte therapy. Impact and implications: Hepatocyte transplantation may be a treatment option for patients with end-stage liver disease. However, one important obstacle to hepatocyte therapy is the low level of engraftment and proliferation of the transplanted hepatocytes. Herein, we show that small molecule compounds which promote hepatocyte proliferation in vitro by facilitating dedifferentiation, could promote the growth of transplanted hepatocytes in vivo and may facilitate the application of hepatocyte therapy.

Excellent mechanical properties, including residual stress, ductility and strength, are important requirements for bone implants. In order to achieve this effect, titanium samples were manufactured by selective laser melting, and the prepared parts were subsequently subjected to three different heat treatment, which were 550 °C, 650 °C and 750 °C for 2 h, respectively. The results show that for as-built sample, relatively short lath-shaped α grains and a few needle-shaped α′ grains were present. After heat treatment, the α grains became thicker and longer, and the α′ grains became more. As the heat treatment temperature increases from 550 °C to 750 °C, the size of the lath-shaped α grains gradually decreases, and the small-sized needle-shaped α′ grains become denser. Moreover, the tensile strength, elongation and shrinkage of specimens increased as the heat treatment temperature increased. The fine microstructure of heat-treated samples also significantly promoted the improvement of tensile properties. The fracture mechanism of the specimens changed from brittle fracture to a mixed mode including ductile and brittle fracture, so that the tensile strength and ductility of the heat-treated specimens were well combined.

Abstract Background Oral administration of insulin (INS) could be absorbed into systemic circulation only if the carrier protected it from the hostile gastrointestinal conditions. However, traditional macromolecular carriers have not totally overcome challenges in addressing these biological barriers. Result In this study, inspired by small molecule natural products (SMNPs), we demonstrate the multi-functional self-assembly nanoparticles (BA-Al NPs) originating from baicalin (BA) and AlCl3 through coordination bonds and hydrogen bonds. As a novel carrier for oral insulin delivery (INS@BA-Al NPs), it displayed effective capacity in pH stimuli-responsive insulin release, intestinal mucoadhesion and transepithelial absorption enhance. Meanwhile, BA improved the paracellular permeability for insulin absorption, because of its downregulation at both mRNA and protein level on internal tight junction proteins. In vivo experiments exhibited remarkable bioavailability of INS and an ideal glucose homeostasis in the type I diabetic rat model. Conclusion This study offers a novel frontier of multi-functional carriers based on SMNPs with self-assembly character and bioactivity, which could be a promising strategy for diabetes therapy. Graphical Abstract

The main objective of this work was to study the effects of carbon nanotubes (CNTs) on the strength and electrical properties of cement mortar. Molecular dynamic simulations (MDSs) were carried out to determine the mechanical and electrical properties of a cementitious composite and its associated mechanisms. To model the atomic structure of a calcium silicate hydrate (C-S-H) gel, tobermorite 11Å was chosen. Single-walled carbon nanotubes (SWCNTs) embedded in a tobermorite structure were tested numerically. In particular, it was concluded that a piezoelectric effect can be effectively simulated by varying the concentration levels of carbon nanotubes. The deformation characteristics were analyzed by subjecting a sample to an electrical field of 250 MV/m in the z-direction in a simulation box. The results indicated a progressively stronger converse piezoelectric response with an increasing proportion of carbon nanotubes. Additionally, it was observed that the piezoelectric constant in the z-direction, denoted by d33, also increased correspondingly, thereby validating the potential for generating an electrical current during sample deformation. An innovative experiment was developed for the electrical characterization of a cementitious composite of carbon nanotubes. The results showed that the electrostatic current measurements exhibited a higher electric sensitivity for samples with a higher concentration of CNTs.

Abstract Background Immune‐based combination therapies have revolutionized the first‐line treatment for advanced non‐small cell lung cancer (NSCLC). However, for the efficacy and safety, the best treatment option is still uncertain. Methods We conducted a Bayesian network meta‐analysis of randomized controlled trials (RCTs) to evaluate first‐line immune‐based combination therapies for advanced NSCLC. Results Fourteen trials involving 8467 patients were included. For the programmed cell death‐ligand 1 (PD‐L1) expression non‐selective patients, there were no significant differences among all the treatment modes for overall survival (OS), but the ranking profiles indicated that Immunotherapy + Immunotherapy + Chemotherapy (IO + IO + Chemo) was most likely to be the best mode (probability = 68%). Immunotherapy + Immunotherapy + Anti‐angiogenic therapy + Chemotherapy (IO + Anti‐angio + Chemo) was significantly better than most other treatment modes for progression‐free survival (PFS) with better objective response rate (ORR) and more obvious grade ≥3 treatment‐related adverse events (TRAEs). In PD‐L1‐high cohort, IO + Anti‐angio + Chemo seemed to be the best mode for OS, PFS, and ORR according to the ranking profiles. In PD‐L1‐intermediate and PD‐L1‐negative cohort, IO + IO + Chemo was inclined to be ranked first for prolonging OS (probability = 78%; 37%) and IO + Anti‐angio + Chemo was most likely to provide best PFS (probability = 96%; 100%). Conclusion IO + IO + Chemo has great potential to improve the OS regardless of histology type, especially in PD‐L1‐intermediate and PD‐L1‐negative cohort. IO + Anti‐angio + Chemo shows great superiority in improving the short‐term survival accompanied by increasing grade ≥3 TRAEs.

ObjectiveBesides breast and gastric cancer, HER2 amplification/mutation are also found in lung adenocarcinoma (LUAD). However, the correlation between HER2 variations and the phenotype of immunogenicity and tumor immune microenvironment (TIME) in LUAD compared with breast and gastric cancer has yet to be fully elucidated.MethodsWe integrated public databases (discovery set) and internal data (validated set) of 288 patients representing three distinct HER2-altered tumors. Genomic data were used to identify somatic mutations, copy number variations, and calculate tumor mutational burden (TMB) and microsatellite instability score. RNA sequencing was conducted to estimate immune gene signatures and contents of tumor-infiltrating immune cell populations. Finally, IHC was used to determine PD-L1 expression and the tumoral-infiltration of immune cells in 50 HER2-variant tumor specimens with no prior therapeutic regimens.ResultsCompared with HER2-amplified breast and gastric cancers, patients with HER2-amplified LUAD showed higher immunogenicity, mainly manifested in immune checkpoints expression and tissue/blood TMB. Additionally, HER2-amplified LUAD exhibited an inflamed TIME with remarkably increased genes encoding HLAs, T-cell activity and immune cell-type, and accompanied with tumor‐infiltrating lymphocytes. In LUAD, patients with HER2 amplification possessed higher tissue TMB than HER2 mutation, whereas no difference was observed in PD-L1 expression. HER2 amplification (primary) was associated with significantly higher PD-L1 expression and TMB than acquired HER2 amplification after resistance to EGFR-TKIs.ConclusionPatients with HER2-amplified LUAD have better immunogenicity and/or an inflamed TIME among HER2-aberrant tumors. Our study may provide clues for establishing the benefits and uses of ICIs for patients with this disease.

IntroductionCheckpoint inhibitor pneumonitis (CIP) is a common serious adverse event caused by immune checkpoint inhibitors (ICIs), and severe CIP can be life-threatening. We aimed to investigate the role of peripheral blood cells in diagnosis, prediction, and prognosis evaluation for all and severe CIP.Materials and methodsPatients with lung cancer receiving ICIs were enrolled in this retrospective study. Baseline was defined as the time of ICI initiation, endpoint was defined as the time of clinical diagnosis of CIP or the last ICI treatment, and follow-up point was defined as 1 week after CIP. Eosinophil percentages at baseline, endpoint, and follow-up point were shortened to “Ebas”, “Eend and “Efol”, respectively.ResultsAmong 430 patients included, the incidence of CIP was 15.6%, and severe CIP was 3.7%. The Eend/Ebas value was lower in patients with CIP (p = 0.001), especially severe CIP (p = 0.036). Receiver operating characteristic curves revealed that Eend/Ebas could serve as a biomarker to diagnose CIP (p = 0.004) and severe CIP (p < 0.001). For severe CIP, the eosinophil percentage declined before the symptoms appeared and CT diagnosis. The eosinophil percentage significantly elevated at the follow-up point in the recovery group but not in the non-recovery group. The CIP patients with Efol/Ebas ≥1.0 had significantly prolonged overall survival (p = 0.024) and after-CIP survival (AS) (p = 0.043). The same results were found in severe CIP but without a statistical difference.ConclusionsEosinophil percentage was associated with the diagnosis, prediction, and prognosis of CIP and severe CIP.

BackgroundDrug–drug interactions (DDIs) pose new challenges beyond traditional pharmacodynamics in the context of optimizing the treatment options with immune checkpoint inhibitors (ICIs). To alleviate cancer-related pain, analgesics are of absolute vital importance as chronic medications used by cancer patients. However, the possible outcome of ICI treatment concomitant with analgesics remains unclear.MethodsOriginal articles describing the possible influence of analgesics use on ICI treatment published before December 1, 2021 were retrieved from PubMed, Embase, and the Cochrane Library. Odds ratio (OR) with 95% confidence interval (CI) for objective response rate (ORR), hazard ratio (HR) with 95% CI for progression-free survival (PFS), and overall survival (OS) were calculated using the random-effects or fixed-effects model, and heterogeneity was assessed using the χ2-based Q-test. Publication bias was examined by funnel plot analysis.ResultsA total of 11 studies involving 4,404 patients were included. The pooled OR showed that opioid use decreased the response of opioid users to ICIs compared to non-opioid users (OR = 0.49, 95% CI = 0.37–0.65, p < 0.001). Compared to patients who did not receive opioids, opioid users had an increased risk of progression and mortality (HR = 1.61, 95% CI = 1.37–1.89, p < 0.001; HR = 1.67, 95% CI =1.30–2.14, p < 0.001, respectively). Furthermore, the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) was not significantly associated with differences in ORR, PFS, and OS in patients treated with ICIs (OR = 1.40, 95% CI = 0.84–2.32, p = 0.190; HR = 0.90, 95% CI = 0.77–1.06, p = 0.186; HR = 0.90, 95% CI = 0.71–1.14, p = 0.384, respectively).ConclusionThe concomitant use of opioids during ICI treatment has an adverse effect on patient prognosis, while the use of NSAIDs is not significantly associated with the prognosis in patients treated with ICIs.

In order to obtain and analyze the operator's intention comprehensively and accurately in human-robot interaction, an array-type flexible tactile sensor was designed. The sensor was encapsulated into a tactile handle to sense the grasping state of the human hand in real time. According to the analysis of different operators' grasping posture and grasping habits, the grasping state was defined as 5 modes. Based on Harris feature point positioning and extraction, a method of grasping posture conversion was proposed to ensure the completeness and standard of the extracted grasping features. A set of Convolutional Neural Networks (CNN) suitable for the real-time classification of the grasping intention was built to distinguish the grasping state sensed by the handle in real time, accurately determine the operator's intention, and complete the interaction with the robot. Using a UR collaborative robot as the experimental platform and the haptic handle as the intent sensing device, the intent-behaviour mapping relationship was constructed to control the motion of the UR collaborative robot. The experimental results show that the classification accuracy of operation intention is as high as 97.87%.

The application of nanotechnology for antimicrobial delivery has capacity to improve antibacterial efficacy. Currently, the usage of various inorganic and organic carriers, such as metal ions, nano-silicon and surfactants, might increase the potential toxicity of nanoparticles and make their clinical transformation more difficult. Herein, a nano-delivery system was constructed by direct self-assembly of antibacterial phytochemicals (berberine and rhein) originated from traditional Chinese medicine Coptis chinensis Franch. and Rheum palmatum L., respectively. Combining X-ray single crystal diffraction, nuclear magnetic resonance and other spectra characterizations, the stacked structure of nanoparticles was profoundly demonstrated. Briefly, rhein acted as the layered backbone and berberine embedded in it. In vitro bacteriostasis experiment showed the minimum bactericidal concentration of nanoparticles was 0.1 μmol/mL, which was lower than that of berberine and rhein. The results of confocal laser scanning microscope, biofilm quantitive assay and scanning electron microscopy indicated that nanoparticles had strong inhibitory effects on Staphylococcus aureus biofilm. More importantly, transmission electron microscopy and mass spectra indicated the further bacteriostatic mechanism of nanoparticles. Meanwhile, the nanoparticles had well biocompatibility and safety. Current study will open up new prospect that the design of self-assemblies between active phytochemicals can be originated from traditional Chinese medicine combination.

BackgroundNivolumab + ipilimumab + two cycles chemotherapy (N-I + chemo, intensive immunotherapy but chemo-light) and pembrolizumab + chemotherapy (Pem + chemo) were both recommended as first-line treatment for metastatic non-small cell lung carcinoma (NSCLC) patients. We conducted this indirect comparison to compare the efficacy of and safety between these two treatments for providing reference for decision making.MethodsRelevant databases were searched for eligible trials. A well-accepted adjusted indirect treatment comparison (ITC) approach was selected to pool efficacy results and safety outcomes. Subgroup analyses were stratified according to PD-L1 expression and clinical characteristics.ResultsFour eligible randomized trials (CheckMate9LA, KEYNOTE-021G, KEYNOTE 189, KEYNOTE 407) involving 2017 patients were available to analyze. The ITC results suggested that N-I + chemo is comparable to Pem + chemo in OS (HR 1.03, 95% CI 0.82-1.30) and ORR (RR 0.81, 95% CI 0.62-1.06), but tended to yield inferior PFS (HR 1.28, 95% CI 1.04-1.59) than did Pem + chemo. As for safety profiles, N-I + chemo showed no significant difference relative to Pem + chemo in any grade adverse events: (RR 1.03, 95% CI 0.99-1.10), but demonstrated reduced toxicity in chemo-related adverse events, such as anemia (RR 0.63, 95% CI 0.49-0.81), neutropenia (RR0.51, 95% CI 0.33-0.79), and thrombocytopenia (RR 0.38, 95% CI 0.21-0.69).ConclusionsN-I + chemo is a promising treatment option for providing comparable OS related to Pem + chemo. However, for never smoker female patients, Pem + chemo is preferable to choose for demonstrating favorable OS benefit than N-I + chemo.

Objective: This study was conducted to identify the characteristics and prognosis of rapidly progressive interstitial lung disease (RP-ILD) in idiopathic inflammatory myopathy (IIM) and to assess the predictors for poor survival of RP-ILD in IIM.Methods: A total of 474 patients with IIM were enrolled retrospectively according to medical records from Peking University People's Hospital. Clinical and laboratory characteristics recorded at the diagnosis of patients with RP-ILD and chronic ILD (C-ILD) were compared. The Kaplan–Meier estimator and univariate and multivariate analyses were used for data analysis.Results: ILD was identified in 65% (308/474) of patients with IIM. Patients with ILD were classified into two groups based on lung features: RP-ILD (38%, 117/308) and C-ILD (62%, 191/308). RP-ILD resulted in significantly higher mortality in IIM compared with C-ILD (27.4 vs. 7.9%, P < 0.05). In this study, by comparing IIM patients with and without RP-ILD, a list of initial predictors for RP-ILD development were identified, which included older age at onset, decreased peripheral lymphocytes, skin involvement (periungual erythema, skin ulceration, and subcutaneous/mediastinal emphysema), presence of anti-MDA5 antibody, serum tumor markers, etc. Further multivariate Cox proportional hazards model analysis identified that anti-MDA5 positivity was an independent risk factor for mortality due to RP-ILD (P < 0.05), and lymphocytes

Considering the heavy losses caused by pear ring rot (Botryosphaeria berengeriana) disease, the potential biocontrol agent against B. berengeriana was isolated and characterized in this work. Bacteria, isolated from pear orchard rhizosphere soil, were screened for the biological control of pear ring rot caused by B. berengeriana. Among them, strain L-1 showed noticeable inhibitory activities against B. berengeriana and six other commonly occurring postharvest pathogens. Molecular methods indicated strain L-1 was Bacillus amyloliquefaciens. The potential of strain L-1 as an effective biocontrol agent was further estimated. Results showed strain L-1 could successfully colonize in pear wounds, its colonies reached 142.35 folds on 4 days post inoculation, and maintained at a high level during storage. In addition, strain L-1 caused abnormal hyphae growth of B. berengeriana, and its inhibitory percentage against pear ring rot reached 76.55% in vivo on 11 days post inoculation. Strain L-1 significantly induced the peroxidase (POD) and catalase (CAT) activities and delayed the accumulation of malondialdehyde (MDA) in pears. What's more, strain L-1 did not impair the fruit quality. All these results suggest that B. berengeriana L-1 is a promising agent for the biocontrol of pear ring rot.

Andrographolide sulfonate (Andro-S), a sulfonation derivative of andrographolide, is known to be effective in treating inflammation-related diseases, while the underlying mechanisms and global protein alterations in response to Andro-S remain unknown. This study aimed to investigate the pharmacological effects and potential targets of Andro-S in a murine model of acute lung injury (ALI). ALI was induced by aerosolized lipopolysaccharide (LPS) exposure before treatment with Andro-S. Inflammatory state of each treatment group was determined by histological analysis and quantification of inflammatory markers. Differentially expressed proteins in lung tissues were identified by an iTRAQ-based quantitative proteomic approach and further confirmed by immunohistochemistry analysis. Administration of Andro-S alleviated LPS-induced histological changes in the lung and reduced the expression of inflammatory markers in serum, bronchoalveolar fluid and lung tissues. Proteomic analysis identified 31 differentially expressed proteins from a total of 2,234 quantified proteins in the lung. According to bioinformatics analysis, neutrophil elastase (ELANE), cathepsin G (CTSG) and myeloperoxidase (MPO), three neutrophil-derived proteases related to immune system process and defense responses to fungi were chosen as potential targets of Andro-S. Further immunohistochemistry analysis confirmed the inhibitory effects of Andro-S on LPS-induced ELANE, CTSG and MPO up-regulation. These results indicate that Andro-S suppressed the severity of LPS-induced ALI, possibly by attenuating the expression of and neutrophil-derived proteases.

Diosgenin, a natural product with steroidal structure, has a wide range of clinical applications in China. It also shows great potential in the treatment of blood clots and nerve damage. To enhance the bioavailability as well as efficacy of diosgenin, eighteen diosgenin-amino acid derivatives were designed and synthesized. The neuroprotective effects of these compounds were evaluated by SH-SY5Y cell line and the biosafety was evaluated by H9c2 cell line. The results displayed that part of the derivatives’ activities (EC50 < 20 μM) were higher than positive control edaravone (EC50 = 21.60 ± 3.04 μM), among which, DG-15 (EC50 = 6.86 ± 0.69 μM) exhibited the best neuroprotection. Meanwhile, biosafety evaluation showed that DG-15 had no cytotoxicity on H9c2 cell lines. Interestingly, combined neuroprotective and cytotoxic results, part of the derivatives without their protecting group were superior to compounds with protecting group. Subsequently, Giemsa staining and DAPI (4′,6-diamidino-2-phenylindole) staining indicated that DG-15 had a protective effect on damaged SH-SY5Y cells by reducing apoptosis. Moreover, DG-15 showed a higher role in promoting angiogenesis at high concentrations (4 mg/mL) on the chorioallantoic membrane model. This finding displayed that DG-15 had dual functions of neuroprotection and angiogenesis, which provided further insight into designing agent for the application in treatment of ischemic stroke.

Baicalein, a famously effective component of the traditional Chinese medicine Rhizoma Huang Qin (Scutellaria altissima L.), has been proved to have potent neuroprotection and anti-platelet aggregation effects with few side effects. Meanwhile, recent studies have revealed that the introduction of amino acid to baicalein could improve its neuroprotective activity. In the present study, a series of novel baicalein amino acid derivatives were designed, synthesized, and screened for their neuroprotective effect against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells and toxicity on the normal H9C2 cell line by standard methylthiazol tetrazolium (MTT) assay. In addition, all of the newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, and high resolution mass spectrometry (HR-MS). The results showed that most of the compounds provided more potent neuroprotection than baicalein, and were equivalent to the positive drug edaravin. They showed no obvious cytotoxicity on normal H9C2 cells. Notably, the most active compound 8 displayed the highest protective effect (50% effective concentration (EC50) = 4.31 μM) against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells, which was much better than the baicalein (EC50 = 24.77 μM) and edaravin (EC50 = 5.62 μM). Further research on the chick chorioallantoic membrane (CAM) model indicated that compound 8 could significantly increase angiogenesis, which might promote neurovascular proliferation. The detection of apoptosis analysis showed that compound 8 could dramatically alleviate morphological manifestations of cell damage. Moreover, the benzyloxycarbonyl (cbz)-protected baicalein amino acid derivatives showed better neuroprotective activity than the t-Butyloxy carbonyl (boc)-protected derivatives.

Chlamydiae are Gram-negative obligate intracellular bacteria that cause diseases with significant medical and economic impacts. Like other chlamydial species, Chlamydia pneumoniae possesses a unique developmental cycle, the infectious elementary body gains access to the susceptible host cell, where it transforms into the replicative reticulate body. The cytoplasmic vacuole where Chlamydia pneumoniae replicates is called an inclusion, which is extensively modified by the insertion of chlamydial effectors known as inclusion membrane proteins (Incs). The C. pneumoniae-specific inclusion membrane protein (Inc) Cpn0147 contains domains that are predicted to be exposed to the host cytoplasm. To map host cell binding partners of Cpn0147, a yeast two-hybrid system was used to screen Cpn0147 against a HeLa cell cDNA library, which led to the finding that Cpn0147 interacted with the host cell protein cyclic adenosine monophosphate (cAMP)-responsive element (CRE)-binding protein (CREB3). The interaction was validated by co-immunoprecipitation of Cpn0147 with CREB3 from HeLa cells ectopically expressing both. Furthermore, Cpn0147 and CREB3 were co-localised in HeLa cells under confocal fluorescence microscopy. The above observations suggest that CREB3 may directly bind to the cytoplasmic domain of Cpn0147 to mediate the interactions of chlamydial inclusions with host cell endoplasmic reticulum.

From the perspective of the interactive cooperation among subjects, this paper portrays the process of cooperative innovation in industrial cluster, in order to capture the correlated equilibrium relationship among them. Through the utilization of two key tools, evolutionary stable strategy and replicator dynamics equations, this paper considers the cost and gains of cooperative innovation and the amount of government support as well as other factors to build and analyze a classic evolutionary game model. On this basis, the subject’s own adaptability is introduced, which is regarded as the system noise in the stochastic evolutionary game model so as to analyze the impact of adaptability on the game strategy selection. The results show that, in the first place, without considering subjects’ adaptability, their cooperation in industrial clusters depends on the cost and gains of innovative cooperation, the amount of government support, and some conditions that can promote cooperation, namely, game steady state. In the second place after the introduction of subjects’ adaptability, it will affect both game theory selection process and time, which means that the process becomes more complex, presents the nonlinear characteristics, and helps them to make faster decisions in their favor, but the final steady state remains unchanged.

Clinically, many candidates for islet transplantation are already immunized, which increases their risk of graft rejection. Encapsulation of pancreatic islets using the TheraCyte™ device has been shown to protect against allograft rejection in nonimmunized recipients. However, the capacity of the TheraCyte™ device to prevent rejection in immunized recipients has not yet been studied. In this study, the protective capacity of the TheraCyte™ device was evaluated in an allogeneic rat model. Lewis rats were used as islet donors, and nonimmunized (control) and alloimmunized, diabetic Wistar–Furth (WF) rats were used as recipients. Graft survival was shorter in immunized recipients than in nonimmunized recipients (mean survival, 5.3 ± 2.7 and 9.3 ± 1.6 days, respectively, p < 0.01) when nonencapsulated islets were transplanted under the kidney capsule. When islets were transplanted into the TheraCyte™ device, graft function was maintained during the 6-month study period in both immunized and nonimmunized rats. In oral glucose tolerance tests performed at 1 month after transplantation, both groups had similar insulin and blood glucose levels indicating similar metabolic functions. Volume densities and absolute volumes of tissue inside the devices 6 months after transplantation were also comparable between the two groups, indicating that both groups maintained similar amounts of endocrine tissue. A higher number of IFN-γ-producing CD8 + T-cells were detected in immunized WF rats compared to control WF rats transplanted with encapsulated islets. This suggests that donor-specific alloreactivity in recipient rats was sustained throughout the study period. This study suggests that the TheraCyte™ device protects islet allografts also in immunized recipients. Our results further highlight the potential for using macroencapsulation to avoid immunosuppressive therapy in clinical islet transplantation.

In this study, we evaluated the effects of exendin-4 on free and encapsulated islet grafts in a rodent model. We also investigated the role of a transcription factor, hypoxia-inducible factor-1 (HIF-1), in mediating the beneficial effects of exendin-4. Diabetic athymic mice were transplanted with free rat islets under the kidney capsule or with macroencapsulated rat islets SC with or without exendin-4, islet preculture (exendin-4 0.1 nM for 20 h), and/or recipient treatment (IP 100 ng/day, day 0–7). The mice were followed for 4 weeks and the graft function and β-cell volume were evaluated. The effects of exendin-4 on islet HIF-1α mRNA and protein expression and on ATP content in a rat insulinoma cell line (INS-1E) were also examined. Preculture with exendin-4 followed by recipient treatment improved the outcome of both free (73% graft function vs. 26% in controls, p = 0.03) and macroencapsulated islet grafts (100% vs. 25% in controls, p = 0.02). In macroencapsulated grafts, the exendin-4-treated group had significantly larger endocrine volume, less graft necrosis, and more blood vessels around the capsule. In rat islets cultured with exendin-4, HIF-1α mRNA and protein expression were significantly enhanced. ATP content was increased in exendin-4-treated INS-1E cells under hypoxic conditions. The improved functional outcome after transplantation of a marginal islet mass with a brief initial treatment with exendin-4 is related to a larger surviving endocrine cell volume. Exendin-4 may improve islet graft resistance to hypoxia during the peritransplant period by increasing the expression of HIF-1α.

Abstract The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies.