Development of a haematological indices-based nomogram for prognostic prediction and immunotherapy response assessment in primary pulmonary lymphoepithelioma-like carcinoma patients.

Background: Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare yet aggressive malignancy. This study aims to investigate a deep learning model based on hematological indices, referred to as haematological indices-based signature (HIBS), and propose multivariable predictive models for accurate prognosis prediction and assessment of therapeutic response to immunotherapy in PPLELC. Methods: This retrospective study included 117 patients with PPLELC who received immunotherapy and were randomly divided into a training (n=82) and a validation (n=35) cohort. A total of 41 hematological features were extracted from routine laboratory tests and the least absolute shrinkage and selection operator (LASSO) algorithm were utilized to establish the HIBS. Additionally, we developed a nomogram using the HIBS and clinical characteristics through multivariate Cox regression analysis. To evaluate the nomogram's predictive performance, we used calibration curves and calculated the time-dependent area under the curve (AUC). Kaplan-Meier survival analysis was performed to estimate progression-free survival (PFS) in both cohorts. Results: The proposed HIBS comprised 14 hematological features and showed that patients who experienced disease progression had significantly higher HIBS scores compared to those who did not progress (P<0.001). Five prognostic factors, including HIBS, tumor-node-metastasis (TNM) stage, presence of bone metastasis and the specific immunotherapy regimen, were found to be independent factors and were used to construct a nomogram, which effectively categorized PPLELC patients into a high-risk and a low-risk group, with patients in the high-risk patients demonstrating worse PFS (7.0 vs. 18.0 months, P<0.001) and lower overall response rates (22.2% vs. 52.7%, P<0.001). The nomogram showed satisfactory discrimination for PFS, with AUC values of 0.837 and 0.855 in the training and validation cohorts, respectively. Conclusions: The HIBS-based nomogram could effectively predict the PFS and response of patients with PPLELC regarding immunotherapy and serve as a valuable tool for clinical decision making.

Phospholipid Type Regulates Protein Corona Composition and In Vivo Performance of Lipid Nanodiscs.

Over the years, there has been significant interest in PEGylated lipid-based nanocarriers within the drug delivery field. The inevitable interplay between the nanocarriers and plasma protein plays a pivotal role in their in vivo biological fate. Understanding the factors influencing lipid-based nanocarrier and protein corona interactions is of paramount importance in the design and clinical translation of these nanocarriers. Herein, discoid-shaped lipid nanodiscs (sNDs) composed of different phospholipids with varied lipid tails and head groups were fabricated. We investigated the impact of phospholipid components on the interaction between sNDs and serum proteins, particle stability, and biodistribution. The results showed that all of these lipid nanodiscs remained stable over a 15 day storage period, while their stability in the blood serum demonstrated significant differences. The sND composed of POPG exhibited the least stability due to its potent complement activation capability, resulting in rapid blood clearance. Furthermore, a negative correlation between the complement activation capability and serum stability was identified. Pharmacokinetic and biodistribution experiments indicated that phospholipid composition did not influence the capability of sNDs to evade the accelerated blood clearance phenomenon. Complement deposition on the sND was inversely associated with the area under the curve. Additionally, all lipid nanodiscs exhibited dominant adsorption of apolipoprotein. Remarkably, the POPC-based lipid nanodisc displayed a significantly higher deposition of apolipoprotein E, contributing to an obvious brain distribution, which provides a promising tool for brain-targeted drug delivery.

Research on Automatic Recognition of Dairy Cow Daily Behaviors Based on Deep Learning.

Dairy cow behavior carries important health information. Timely and accurate detection of behaviors such as drinking, feeding, lying, and standing is meaningful for monitoring individual cows and herd management. In this study, a model called Res-DenseYOLO is proposed for accurately detecting the individual behavior of dairy cows living in cowsheds. Specifically, a dense module was integrated into the backbone network of YOLOv5 to strengthen feature extraction for actual cowshed environments. A CoordAtt attention mechanism and SioU loss function were added to enhance feature learning and training convergence. Multi-scale detection heads were designed to improve small target detection. The model was trained and tested on 5516 images collected from monitoring videos of a dairy cowshed. The experimental results showed that the performance of Res-DenseYOLO proposed in this paper is better than that of Fast-RCNN, SSD, YOLOv4, YOLOv7, and other detection models in terms of precision, recall, and mAP metrics. Specifically, Res-DenseYOLO achieved 94.7% precision, 91.2% recall, and 96.3% mAP, outperforming the baseline YOLOv5 model by 0.7%, 4.2%, and 3.7%, respectively. This research developed a useful solution for real-time and accurate detection of dairy cow behaviors with video monitoring only, providing valuable behavioral data for animal welfare and production management.

Corrigendum: Identification and validation of immune-related methylation clusters for predicting immune activity and prognosis in breast cancer.

[This corrects the article DOI: 10.3389/fimmu.2021.704557.].

ANKRD22 promotes M2 polarization in lung adenocarcinoma macrophages via the glycolytic pathway.

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer with a low 5-year survival rate. ANKRD22 is an ankyrin repeat protein capable of promoting tumor progression, and its mechanism in LUAD remains elusive. Our study aims to investigate the mechanisms underlying the involvement of ANKRD22 in the progression of LUAD. The expression of ANKRD22 in LUAD and its enriched pathway were analyzed by bioinformatics analysis. Meanwhile, the correlation between ANKRD22 and the expression of glycolysis-related genes and M2 macrophage marker genes was analyzed. qRT-PCR was used for determination of the expression of ANKRD22, IL-10 and CCL17, CCK-8 for cell viability, and western blot for expression of ANKRD22, LDHA, HK2, PGK1, and PKM2. Immunofluorescence and flow cytometry were utilized to examine the level of CD163, and kits were used to measure the contents of pyruvic acid, lactate, citrate, and malate. Seahorse XF96 analyzer was employed to determine extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Mitochondrial membrane potential was assessed using the JC-1 probe. Bioinformatics analysis, qRT-PCR, and western blot showed that ANKRD22 was highly expressed in LUAD, which had a positive connection with M2 marker genes. Knockdown of ANKRD22 considerably attenuated the expression of ANKRD22, IL-10, and CCL17 in M2. ANKRD22 overexpression demonstrated the opposite results. Bioinformatics analysis uncovered that ANKRD22 was enriched in the glycolytic pathway and positively correlated with glycolysis-related genes. The knockdown of ANKRD22 substantially attenuated pyruvic acid, lactate, citrate, malate, and ECAR levels and elevated OCR levels in cells. The knockdown of ANKRD22 also reduced mitochondrial membrane potential. Further, it was discovered that glycolysis-related genes had a positive correlation with M2 marker genes. It was revealed by rescue experiments that the usage of 2-DG, a glycolytic inhibitor, remarkably reversed the facilitating effect of overexpression of ANKRD22 on M2 polarization. This study demonstrates that ANKRD22 can facilitate LUAD M2 polarization through glycolysis, and targeting ANKRD22 to inhibit M2 polarization has the potential to be a new strategy for LUAD treatment.

Development of an Alternative In Vitro Rumen Fermentation Prediction Model.

The aim of this study is to identify an alternative approach for simulating the in vitro fermentation and quantifying the production of rumen methane and rumen acetic acid during the rumen fermentation process with different total mixed rations. In this experiment, dietary nutrient compositions (neutral detergent fiber (NDF), acid detergent fiber (ADF), crude protein (CP), and dry matter (DM)) were selected as input parameters to establish three prediction models for rumen fermentation parameters (methane and acetic acid): an artificial neural network model, a genetic algorithm-bp model, and a support vector machine model. The research findings show that the three models had similar simulation results that aligned with the measured data trends (R2 ≥ 0.83). Additionally, the root mean square errors (RMSEs) were ≤1.85 mL/g in the rumen methane model and ≤2.248 mmol/L in the rumen acetic acid model. Finally, this study also demonstrates the models' capacity for generalization through an independent verification experiment, as they effectively predicted outcomes even when significant trial factors were manipulated. These results suggest that machine learning-based in vitro rumen models can serve as a valuable tool for quantifying rumen fermentation parameters, guiding the optimization of dietary structures for dairy cows, rapidly screening methane-reducing feed options, and enhancing feeding efficiency.

Association between living habits, indoor humidity, ventilation and asthma among residents in the tropical regions of China.

Objective: Asthma is a major public health problem that affects both children and adults, and its prevalence varies among people with different climatic characteristics and living habits. However, few studies have investigated the prevalence and risk factors for asthma among tropical residents in China. Therefore, this study aims to investigate the correlation between individuals' living environment and daily habits in Hainan Province, and the occurrence of asthma. Methods: This cross-sectional study collected data from 1021 participants in three regions of the Hainan Province. A questionnaire derived from the European Community Respiratory Health Survey was used to collect data on demographics, living habits, self-reported asthma, and respiratory system-related symptoms. Logistic regression was used for univariate and multivariate analyses to screen for relative risk factors associated with asthma. Results: Among the 1,021 subjects investigated, the prevalence rate of self-reported asthma was 18.6%. Significant risk factors for asthma include hair dyeing, longer living time in Hainan, higher BMI, and living in a damp and musty room. Protective factors included fruit intake, years of higher education, and indoor timing of natural ventilation. Conclusion: Higher frequency of hair dyeing, higher body mass index (BMI), longer living in Hainan, lower frequency of fruit intake, fewer years of education, a damp and musty room, and no indoor timing natural ventilation were associated with an increased risk of asthma.

Effects of contralateral controlled functional electrical stimulation combined with mirror therapy on motor recovery and negative mood in stroke patients.

OBJECTIVE: To investigate the effect of contralateral controlled functional electrical stimulation (CCFES) combined with mirror therapy on motor function and negative mood in stroke patients. METHODS: Medical records of 94 stroke patients in Baoji Central Hospital admitted from April 2020 to October 2022 were retrospectively analyzed. Among them, 45 patients receiving routine rehabilitation training combined with mirror therapy were included in a control group, and 49 patients receiving CCFES combined with mirror therapy were in an observation group. Observation indexes included changes in Fugl-Meyer Assessment (FMA), Berg Balance Scale (BBS), Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), Stroke Specific Quality of Life Scale (SS-QoL) score, and Barthel Index score before and after treatment. Patients with HAMA score >14 and HAMD score ≥20 after the treatment were included in a negative mood group, and logistics regression was used to analyze the risk factors for negative mood. RESULTS: The observation group had a significantly higher overall response rate after treatment compared to the control group. In addition, the observation group exhibited significantly higher scores in the FMA and BBS after treatment, indicating better physical function (P<0.001). Furthermore, the observation group showed lower HAMA and HAMD scores after treatment, suggesting reduced anxiety and depression levels (P<0.001). The quality-of-life scores measured by the SS-QoL and the Barthel Index score were both increased in the observation group after treatment, indicating better overall well-being and functional independence (P<0.001). Logistic regression analysis revealed that age, post-treatment SS-QoL scores, and post-treatment Barthel Index were identified as influencing factors for the onset of adverse emotions in patients (P<0.05). CONCLUSION: CCFES plus mirror therapy can effectively ameliorate limb function and lessen anxiety and depression in stroke patients, exerting beneficial effects on rehabilitation.

TRIM67 Implicates in Regulating the Homeostasis and Synaptic Development of Mitral Cells in the Olfactory Bulb.

In recent years, olfactory dysfunction has attracted increasingly more attention as a hallmark symptom of neurodegenerative diseases (ND). Deeply understanding the molecular basis underlying the development of the olfactory bulb (OB) will provide important insights for ND studies and treatments. Now, with a genetic knockout mouse model, we show that TRIM67, a new member of the tripartite motif (TRIM) protein family, plays an important role in regulating the proliferation and development of mitral cells in the OB. TRIM67 is abundantly expressed in the mitral cell layer of the OB. The genetic deletion of TRIM67 in mice leads to excessive proliferation of mitral cells in the OB and defects in its synaptic development, resulting in reduced olfactory function in mice. Finally, we show that TRIM67 may achieve its effect on mitral cells by regulating the Semaphorin 7A/Plexin C1 (Sema7A/PlxnC1) signaling pathway.

A near-infrared fluorescence-enhancing plasmonic biosensing microarray identifies soluble PD-L1 and ICAM-1 as predictive checkpoint biomarkers for cancer immunotherapy.

Sensitive and accurate biomarker-driven assay guidance has been widely adopted to identify responsive patients for immune checkpoint blockade (ICB) therapy to impede disease progression and extend survival. However, most current assays are invasive, requiring surgical pathology specimens and only informing monochronic information. Here, we report a multiplexed enhanced fluorescence microarray immunoassay (eFMIA) based on a nanostructured gold nanoisland substrate (AuNIS), which macroscopically amplifies near-infrared fluorescence (NIRF) of a structurally symmetric IRDye78 fluorophore by over two orders of magnitude of 202.6-fold. Aided by non-contact piezo-driven micro-dispensing (PDMD), eFMIA simultaneously and semi-quantitatively detected intracellular and secreted programmed death-ligand 1 (PD-L1) and intercellular adhesion molecule-1 (ICAM-1) in human nasopharyngeal carcinoma (NPC) cells. The assay performance was superior to fluorescence immunoassays (FIA) and enzyme-linked immunosorbent assays (ELISA), with lower detection limits. Using eFMIA, we found significantly differential levels of soluble PD-L1 (sPD-L1) and sICAM-1 in the sera of 28 cancer patients, with different clinical outcomes following anti-PD-1 ICB therapy. With a well-characterized mechanism, the high-performance plasmonic multiplexed assay with the composite biomarkers may be a valuable tool to assist clinicians with decision-making and patient stratification to afford predictive ICB therapy responses.

Physicochemical properties and adsorption state of aluminum adjuvants with different processes in vaccines.

Aluminum salts are by far the most widely used adjuvants for human vaccines, showing acceptable safety and efficacy. Previous studies have shown that each aluminum adjuvant have different charges and morphologies, but whether the manufacturing and production processes affects the physicochemical properties of aluminum adjuvant has not yet been reported. In this study, we explored the physical and chemical properties of different aluminum adjuvants and Hib, sIPV antigens through particle size, zeta potential and morphological characteristics. The adsorption rate and efficacy were also investigated. The results showed that the preparation process had an impact on the physical and chemical properties of aluminum adjuvants, including differences in the particle size，zeta potential and morphological structure. Hib vaccine had larger particle size than sIPV vaccine with different aluminum adjuvants in the process of vaccine preparation. In addition, by measuring the adsorption rate, increasing the concentration of phosphate or Aluminum phosphate (AP) can improve the adsorption rate of Hib, but Aluminium hydroxide (AH) and amorphous aluminum hydroxyphosphate sulfate (AAHS) adjuvants are not affected. In vivo result showed that increasing the adsorption rate of Hib could enhance the Hib-IgG antibody titers. In conclusion, this study provides a reference for the application of adjuvants in vaccines by studying the physicochemical properties and adsorption conditions of different aluminum adjuvants and antigens.

Mitochondrial DNA methylation is a predictor of immunotherapy response and prognosis in breast cancer: scRNA-seq and bulk-seq data insights.

Background: Alterations in Mitochondrial DNA methylation (MTDM) exist in many tumors, but their role in breast cancer (BC) development remains unclear. Methods: We analyzed BC patient data by combining scRNA-seq and bulk sequencing. Weighted co-expression network analysis (WGCNA) of TCGA data identified mitochondrial DNA methylation (MTDM)-associated genes in BC. COX regression and LASSO regression were used to build prognostic models. The biological function of MTDM was assessed using various methods, such as signaling pathway enrichment analysis, copynumber karyotyping analysis, and quantitative analysis of the cell proliferation rate. We also evaluated MTDM-mediated alterations in the immune microenvironment using immune microenvironment, microsatellite instability, mutation, unsupervised clustering, malignant cell subtype differentiation, immune cell subtype differentiation, and cell-communication signature analyses. Finally, we performed cellular experiments to validate the role of the MTDM-associated prognostic gene NCAPD3 in BC. Results: In this study, MTDM-associated prognostic models divided BC patients into high/low MTDM groups in TCGA/GEO datasets. The difference in survival time between the two groups was statistically significant (P<0.001). We found that high MTDM status was positively correlated with tumor cell proliferation. We analyzed the immune microenvironment and found that low-MTDM group had higher immune checkpoint gene expression/immune cell infiltration, which could lead to potential benefits from immunotherapy. In contrast, the high MTDM group had higher proliferation rates and levels of CD8+T cell exhaustion, which may be related to the secretion of GDF15 by malignant breast epithelial cells with a high MTDM status. Cellular experiments validated the role of the MTDM-associated prognostic gene NCAPD3 (the gene most positively correlated with epithelial malignant cell proliferation in the model) in BC. Knockdown of NCAPD3 significantly reduced the activity and proliferation of MDA-MB-231 and BCAP-37 cells, and significantly reduced their migration ability of BCAP-37 cell line. Conclusion: This study presented a holistic evaluation of the multifaceted roles of MTDM in BC. The analysis of MTDM levels not only enables the prediction of response to immunotherapy but also serves as an accurate prognostic indicator for patients with BC. These insightful discoveries provide novel perspectives on tumor immunity and have the potentially to revolutionize the diagnosis and treatment of BC.

PFKFB2 is a favorable prognostic biomarker for colorectal cancer by suppressing metastasis and tumor glycolysis.

PURPOSE: This study was to investigate the biological effect of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) in colorectal cancer (CRC). METHODS: PFKFB2 was selected by metabolism polymerase chain reaction (PCR) array from CRC cells under alkaline culture medium (pH 7.4) and acidic culture medium (pH 6.8). The expression of PFKFB2 mRNA and protein was detected by quantitative real-time PCR and immunohistochemistry in 70 paired fresh and 268 paired paraffin-embedded human CRC tissues, respectively, and then the prognostic value of PFKFB2 was investigated. The effects of PFKFB2 on CRC cells were also verified in vitro, which were through detecting the change of migration, invasion, sphere formation, proliferation, colony formation, and extracellular acidification rate of CRC cells after PFKFB2 knockdown in alkaline culture medium (pH 7.4) and overexpression in acidic culture medium (pH 6.8). RESULTS: PFKFB2 expression was downregulated in acidic culture medium (pH 6.8). In addition, we found PFKFB2 expression decreased in human CRC tissues compared with the adjacent normal tissues. Furthermore, the OS and DFS rate of CRC patients with low PFKFB2 expression was significantly shorter than those of patients with high PFKFB2 expression. Multivariate analysis indicated that low PFKFB2 expression was an independent prognostic factor for both OS and DFS in CRC patients. Moreover, the abilities of migration, invasion, spheroidizing ability, proliferation, and colony formation of CRC cells were significantly increased after depletion of PFKFB2 in alkaline culture medium (pH 7.4) and decreased after overexpression of PFKFB2 in acidic culture medium (pH 6.8) in vitro. Epithelial-mesenchymal transition (EMT) pathway was found and verified involved in the PFKFB2-mediated regulation of metastatic function in CRC cells. Further, glycolysis of CRC cells was significantly elevated after knockdown of PFKFB2 in alkaline culture medium (pH 7.4) and decreased after overexpression of PFKFB2 in acidic culture medium (pH 6.8). CONCLUSION: PFKFB2 expression is downregulated in CRC tissues and associated with worse survival for CRC patients. PFKFB2 could inhibit metastasis and the malignant progression of CRC cells by suppressing EMT and glycolysis.

Mirror therapy combined with contralaterally controlled functional electrical stimulation for the upper limb motor function after stroke: a randomized controlled trial.

PURPOSE: In this study, we investigated the effects of mirror therapy (MT) combined with contralaterally controlled functional electrical stimulation (CCFES) on upper limb motor function, activities of daily life, and corticospinal excitability in post-stroke patients. METHODS: Sixty post-stroke patients were randomly divided into four groups: CCFES, MT, MT combined with CCFES, and control. All the patients underwent routine rehabilitation. Those in the MT, CCFES, MT combined with CCFES, and control groups received MT, CCFES, MT combined with CCFES, and routine rehabilitation alone, respectively. Upper limb motor function, activities of daily living, and corticospinal excitability were evaluated before and after a 3-week intervention period. RESULTS: MT combined with CCFES demonstrated a significantly greater therapeutic effect on motor function of the paretic wrist than CCFES, MT, or routine rehabilitation alone. However, there was no significant difference in the overall motor function of the affected upper limb, activities of daily life, or corticospinal excitability between the MT combined with CCFES group and the other three groups. CONCLUSION: MT combined with CCFES may be a potential adjuvant therapy to promote motor function in paretic wrist after stroke.

The combined therapy of mirror therapy (MT) and contralaterally controlled functional electrical stimulation (CCFES) may be a potential adjuvant therapy to promote motor function in paretic wrists after stroke.MT combined with CCFES could be incorporated into rehabilitation programs for post-stroke patients with impaired upper limb motor function.Exploring the potential benefits of combining different rehabilitation therapies could inform the development of more effective interventions.

Sustained-release nitrate combined with microbial fuel cell: A novel strategy for PAHs and odor removal from sediment.

Nitrate addition is a biostimulation technique that can improve both the oxidation of acid volatile sulfide (AVS) through autotrophic denitrification and the biodegradation of polycyclic aromatic hydrocarbons (PAHs) via heterotrophic denitrification. However, during the remediation, parts of the dissolved nitrate in the sediment migrates from the sediment to the overlying water, leading to the loss of effective electron acceptor. To overcome this limitation, a combined approached was proposed, which involved nitrocellulose addition and a microbial fuel cell (MFC). Results indicated the nitrate could be slowly released and maintained at a higher concentration over long term. In the combined system, the removal efficiencies of PAHs and AVS were 71.56% and 89.76%, respectively. Furthermore, the voltage attained for the MFC-nitrocellulose treatment was maintained at 146.1 mV on Day 70, which was 5.37 times higher than that of the MFC-calcium nitrate treatment. Sediments with nitrocellulose resulted in lower levels of nitrate and ammonium in the overlying water. Metagenomic results revealed that the combined technology improved the expression of nitrogen-cycling genes. The introduction of MFC inhibited sulfide regeneration during incubation by suppressing the enzyme activity like EC4.4.1.2. The enhanced biostimulation provided potential for in-situ bioremediation utilizing MFC coupled with slow-released nitrate (i.e., nitrocellulose) treatment.

Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy.

Aberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of Aconitum carmichaelii, shows unique efficacy in reviving Yang for resuscitation, which has been widely used in clinics. As a main cardiotonic component of Fuzi, mesaconine has been proven effective in various cardiomyopathy models. Here, we aimed to define a previously unrevealed cardioprotective mechanism of mesaconine-mediated restoration of obstructive mitophagy. The functional implications of mesaconine were evaluated in doxorubicin (DOX)-induced heart failure models. DOX-treated mice showed characteristic cardiac dysfunction, ectopic myocardial energy disorder, and impaired mitophagy in cardiomyocytes, which could be remarkably reversed by mesaconine. The cardioprotective effect of mesaconine was primarily attributed to its ability to promote the restoration of mitophagy in cardiomyocytes, as evidenced by elevated expression of PINK1, a key mediator of mitophagy induction. Silencing PINK1 or deactivating mitophagy could completely abolish the protective effects of mesaconine. Together, our findings suggest that the cardioprotective effects of mesaconine appear to be dependent on the activation of PINK1-induced mitophagy and that mesaconine may constitute a promising therapeutic agent for the treatment of heart failure.

Dealkylation in Fluid Catalytic Cracking Condition for Efficient Conversion of Heavy Aromatics to Benzene-Toluene-Xylene.

Based on the characteristics of typical C9 + aromatics in naphtha fractions, the effects of key process parameters and heavy aromatic composition on product distribution of fluid catalytic cracking (FCC) of heavy aromatics (HAs) were investigated. The results show that catalysts with large pore size and strong acid sites are favorable for the conversion of HAs to benzene-toluene-xylene (BTX) at higher reaction temperatures and moderate catalyst-oil ratios (C/O). With a Y zeolite-based catalyst which was hydrothermally pretreated for 4 h, the conversion of Feed 1 at 600 °C and C/O of 10 may reach 64.93%. Meanwhile, the yield and selectivity of BTX are 34.80 and 53.61%, respectively. The proportion of BTX can be adjusted within a certain range. The HAs from different sources show high conversion and good BTX selectivity, which provides strong support for the technological development of HAs to light aromatics in FCC operation.

Changes and transcriptome regulation of endogenous hormones during somatic embryogenesis in Ormosia henryi Prain.

Introduction: Ormosia henryi is a rare and endangered plant growing in southern China. Somatic embryo culture is an effective measure for the rapid propagation of O. henryi. It has not been reported how regulatory genes induce somatic embryogenesis by regulating endogenous hormone changes during the process of somatic embryogenesis in O. henryi. Methods: In this study, we analysed the endogenous hormone levels and transcriptome data of nonembryogenic callus (NEC), embryogenic callus (EC), globular embryo (GE) and cotyledon embryo (CE) in O. henryi. Results: The results showed that the indole-3-acetic acid (IAA) content was higher and the cytokinins (CKs) content was lower in EC than in NEC, and the gibberellins (GAs) and abscisic acid (ABA) contents were significantly higher in NEC than in EC. The contents of IAA, CKs, GAs and ABA increased significantly with EC development. The expression patterns of differentially expressed genes (DEGs) involved in the biosynthesis and signal transduction of auxin (AUX) (YUCCA and SAUR), CKs (B-ARR), GAs (GA3ox, GA20ox, GID1 and DELLA) and ABA (ZEP, ABA2, AAO3, CYP97A3, PYL and ABF) were consistent with the levels of endogenous hormones during somatic embryogenesis (SE). In this study, 316 different transcription factors (TFs) regulating phytohormones were detected during SE. AUX/IAA were downregulated in the process of EC formation and GE differentiation into CE, but other TFs were upregulated and downregulated. Conclusion: Therefore, we believe that relatively high IAA content and low CKs, GAs and ABA contents contribute to EC formation. The differential expression of AUX, CKs, GAs and ABA biosynthesis and signal transduction genes affected the endogenous hormone levels at different stages of SE in O. henryi. The downregulated expression of AUX/IAA inhibited NEC induction, promoted EC formation and GE differentiation into CE.

G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35-STARD4 axis is a promising therapeutic target for NAFLD.

Lipid-Based Nanocarriers Enabled Oral Delivery of Oleanolic Acid Derivative DKS26 for Diabetes Management.

Oleanolic acid derivative DKS26 has hypolipidemic, islet, and hepatoprotective effects. However, high lipophilicity and low water solubility led to DKS26 extremely low oral bioavailability. Herein, lipid-based nanocarriers, including lipid nanodiscs (sND/DKS26) and liposomes (sLip/DKS26), are prepared to improve DKS26 oral absorption. In comparison to free DKS26 (5.81%), the absolute oral bioavailabilities are significantly increased to 29.47% (sND/DKS26) and 37.25% (sLip/DKS26) without detectable toxicity or immunogenicity even after repeated administrations. Both sND/DKS26 and sLip/DKS26 significantly reduce the feeding glucose level and the AUC of OGTT in db/db diabetic mice. Aiding by the newly developed scFv-based nanocarrier separation methods, no intact nanocarriers are detected in blood circulation after oral administration, suggesting that both formulations are unable to penetrate the intestinal epithelium. They enhance DKS26 absorption mainly by improving intestinal cell uptake and rapid intracellular release of the payload. Since pre-existing anti-PEG is widely detected in humans, the present oral absorption pathway of both nanocarriers successfully avoids unfavorable immunological responses after interaction with anti-PEG antibodies. The application of lipid-based nanocarriers paves an efficient and safe avenue for the clinical translation and application of poorly soluble therapeutics derived from traditional Chinese medicine.