CCN1 Is a Therapeutic Target for Reperfused Ischemic Brain Injury.

Ischemic stroke can lead to systemic inflammation, which can activate peripheral immune cells, causing neuroinflammation and brain injury. Meningeal lymphatics play a crucial role in transporting solutes and immune cells out of the brain and draining them into cervical lymph nodes (CLNs). However, the role of meningeal lymphatics in regulating systemic inflammation during the reperfusion stage after ischemia is not well understood. In this study, we demonstrated that brain infarct size, neuronal loss, and the effector function of inflammatory macrophage subsets were reduced after ischemia-reperfusion and disruption of meningeal lymphatics. Spatial memory function was improved in the late stage of ischemic stroke following meningeal lymphatic disruption. Brain-infiltrating immune cells, including neutrophils, monocytes, and T and natural killer cells, were reduced after cerebral ischemia-reperfusion and meningeal lymphatic disruption. Single-cell RNA sequencing analysis revealed that meningeal lymphatic disruption reprogrammed the transcriptome profile related to chemotaxis and leukocyte migration in CLN lymphatic endothelial cells (LECs), and it also decreased chemotactic CCN1 expression in floor LECs. Replenishment of CCN1 through intraventricular injection increased brain infarct size and neuronal loss, while restoring numbers of macrophages/microglia in the brains of meningeal lymphatic-disrupted mice after ischemic stroke. Blocking CCN1 in cerebrospinal fluid reduced brain infarcts and improves spatial memory function after ischemia-reperfusion injury. In summary, this study indicates that CCN1-mediated detrimental inflammation was alleviated after cerebral ischemia-reperfusion injury and meningeal lymphatic disruption. CCN1 represents a novel therapeutic target for inhibiting systemic inflammation in the brain-CLN axis after ischemia-reperfusion injury.

Stretchable Iontronic Tactile Sensing Fabric.

The iontronic tactile sensing modality has garnered significant attention due to its exceptional sensitivity, immunity to noise, and versatility in materials. Recently, various formats of iontronic tactile sensors have been developed, including droplets, polymer films, paper, ionic gels, and fabrics. However, the stretchability of the current iontronic pressure sensing fabric is inadequate, hindered by the limited stretchiness of the ionic functional fabric. Incorporating a stretchable tactile sensing implement could enhance the wear comfortability by preventing relative movement and ensuring intimate contact between the sensor and the skin. The research focuses on the development of a stretchable iontronic pressure sensing (SIPS) fabric for monitoring diverse aspects of body health and movement in wearable applications. The tactile sensing structure is generated at the iontronic interface between highly stretchable ionic and conductive fabrics. In particular, the ionic fabric is prepared by coating a layer of polyurethane/ionic liquid gel onto a Spandex fabric. To showcase its remarkable sensitivity, stretchability, and ability to detect diverse body information, several application scenarios have been demonstrated including an elastic wristband for precise pulse wave detection, a flexible belt with multitactile sensing channels for respiration and motion tracking purposes, and a stretchable fabric cuff equipped with a high-resolution sensing array comprising 32 × 32 units for accurate gesture recognition.

Dietary magnesium supplementation in cats with chronic kidney disease: A prospective double-blind randomized controlled trial.

BACKGROUND: Plasma total magnesium concentration (tMg) is a prognostic indicator in cats with chronic kidney disease (CKD), shorter survival time being associated with hypomagnesemia. Whether this risk factor is modifiable with dietary magnesium supplementation remains unexplored. OBJECTIVES: Evaluate effects of a magnesium-enriched phosphate-restricted diet (PRD) on CKD-mineral bone disorder (CKD-MBD) variables. ANIMALS: Sixty euthyroid client-owned cats with azotemic CKD, with 27 and 33 allocated to magnesium-enriched PRD or control PRD, respectively. METHODS: Prospective double-blind, parallel-group randomized trial. Cats with CKD, stabilized on a PRD, without hypermagnesemia (tMg >2.43 mg/dL) or hypercalcemia (plasma ionized calcium concentration, (iCa) >6 mg/dL), were recruited. Both intention-to-treat and per-protocol (eating ≥50% of study diet) analyses were performed; effects of dietary magnesium supplementation on clinicopathological variables were evaluated using linear mixed effects models. RESULTS: In the per-protocol analysis, tMg increased in cats consuming a magnesium-enriched PRD (ß, 0.25 ± .07 mg/dL/month; P < .001). Five magnesium supplemented cats had tMg >2.92 mg/dL, but none experienced adverse effects. Rate of change in iCa differed between groups (P = .01), with decreasing and increasing trends observed in cats fed magnesium-enriched PRD and control PRD, respectively. Four control cats developed ionized hypercalcemia versus none in the magnesium supplemented group. Log-transformed plasma fibroblast growth factor-23 concentration (FGF23) increased significantly in controls (ß, 0.14 ± .05 pg/mL/month; P = .01), but remained stable in the magnesium supplemented group (ß, 0.05±.06 pg/mL/month; P =.37). CONCLUSIONS AND CLINICAL IMPORTANCE: Magnesium-enriched PRD is a novel therapeutic strategy for managing feline CKD-MBD in cats, further stabilizing plasma FGF23 and preventing hypercalcemia.

Lonicera japonica Thunb. Ethanol Extract Exerts a Protective Effect on Normal Human Gastric Epithelial Cells by Modulating the Activity of Tumor-Necrosis-Factor-α-Induced Inflammatory Cyclooxygenase 2/Prostaglandin E2 and Matrix Metalloproteinase 9.

Gastric inflammation-related disorders are commonly observed digestive system illnesses characterized by the activation of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α). This results in the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PEG2) and matrix metallopeptidase-9 (MMP-9). These factors contribute to the pathogenesis of gastric inflammation disorders. We examined the preventive effects of Lonicera japonica Thunb. ethanol extract (Lj-EtOH) on gastric inflammation induced by TNF-α in normal human gastric mucosa epithelial cells (GES-1). The GES-1 cell line was used to establish a model that simulated the overexpression of COX-2/PGE2 and MMP-9 proteins induced by TNF-α to examine the anti-inflammatory properties of Lj extracts. The results indicated that Lj-EtOH exhibits significant inhibitory effects on COX-2/PEG2 and MMP-9 activity, attenuates cell migration, and provides protection against TNF-α-induced gastric inflammation. The protective effects of Lj-EtOH are associated with the modulation of COX-2/PEG2 and MMP-9 through the activation of TNFR-ERK 1/2 signaling pathways as well as the involvement of c-Fos and nuclear factor kappa B (NF-κB) signaling pathways. Based on our findings, Lj-EtOH exhibits a preventive effect on human gastric epithelial cells. Consequently, it may represent a novel treatment for the management of gastric inflammation.

Biological-equivalent-dose-based integrated optimization framework for fast-energy-switching Bragg peak FLASH-RT using single-beam-per-fraction.

BACKGROUNDS: When comparing the delivery of all beams per fraction (ABPF) to single beam per fraction (SBPF), it is observed that SBPF not only helps meet the FLASH dose threshold but also mitigates the uncertainty with beam switching in the FLASH effect. However, SBPF might lead to a higher biological equivalent dose in 2 Gy (EQD2) for normal tissues. PURPOSE: This study aims to develop an EQD2-based integrated optimization framework (EQD2-IOF), encompassing robust dose, delivery efficiency, and beam orientation optimization (BOO) for Bragg peak FLASH plans using the SBPF treatment schedule. The EQD2-IOF aims to enhance both dose sparing and the FLASH effect. METHODS: A superconducting gantry was employed for fast energy switching within 27 ms, while universal range shifters were utilized to improve beam current in the implementation of FLASH plans with five Bragg peak beams. To enhance dose delivery efficiency while maintaining plan quality, a simultaneous dose and spot map optimization (SDSMO) algorithm for single field optimization was incorporated into a Bayesian optimization-based auto-planning algorithm. Subsequently, a BOO algorithm based on Tabu search was developed to select beam angle combinations (BACs) for 10 lung cases. To simultaneously consider dose sparing and FLASH effect, a quantitative model based on dose-dependent dose modification factor (DMF) was used to calculate FLASH-enhanced dose distribution. The EQD2-IOF plan was compared to the plan optimized without SDSMO using BAC selected by a medical physicist (Manual plan) in the SBPF treatment schedule. Meanwhile, the mean EQD2 in the normal tissue was evaluated for the EQD2-IOF plan in both SBPF and ABPF treatment schedules. RESULTS: No significant difference was found in D2% and D98% of the target between EQD2-IOF plans and Manual Plans. When using a minimum DMF of 0.67 and a dose threshold of 4 Gy, EQD2-IOF plans showed a significant reduction in FLASH-enhanced EQD2mean of the ipsilateral lung and normal tissue by 10.5% and 11.5%, respectively, compared to Manual plans. For normal tissues that received a dose greater than 70% of the prescription dose, using a minimum DMF of 0.7 for FLASH sparing compensated for the increase in EQD2mean resulting from replacing ABPF with SBPF schedules. CONCLUSIONS: The EQD2-IOF can automatically optimize SBPF FLASH-RT plans to achieve optimal sparing of normal tissues. With an energy switching time of 27 ms, the loss of fractionate repairing using SBPF schedules in high-dose regions can be compensated for by the FLASH effect. However, when an energy switching time of 500 ms is utilized, the SBPF schedule needs careful consideration, as the FLASH effect diminishes with longer irradiation time.

Extracellular Vesicle Surface Display Enhances the Therapeutic Efficacy and Safety Profile of Cancer Immunotherapy.

Immunotherapy has emerged as a mainstay in cancer therapy, yet its efficacy is constrained by the risk of immune-related adverse events. In this study, we present a nanoparticle-based delivery system that enhances the therapeutic efficacy of immunomodulatory ligands while concurrently limiting systemic toxicity. We demonstrate that extracellular vesicles (EVs), lipid bilayer enclosed particles released by cells, can be efficiently engineered via iEDDA-mediated conjugation to display multiple immunomodulatory ligands on their surface. Display of immunomodulatory ligands on the EV surface conferred substantial enhancements in signaling efficacy, particularly for tumor necrosis factor receptor superfamily (TNFRSF) agonists, where EV surface display served as an alternative FcγR-independent approach to induce ligand multimerization and efficient receptor crosslinking. EVs displaying a complementary combination of immunotherapeutic ligands were able to shift the tumor immune milieu towards an anti-tumorigenic phenotype and significantly suppress tumor burden and increase survival in multiple models of metastatic cancer to a greater extent than an equivalent dose of free ligands. In summary, we present an EV-based delivery platform for cancer immunotherapeutic ligands that facilitates superior anti-tumor responses at significantly lower doses with less side-effects than is possible with conventional delivery approaches.

Discovery of differentially expressed proteins for CAR-T therapy of ovarian cancers with a bioinformatics analysis.

Target antigens are crucial for developing chimeric antigen receptor (CAR)-T cells, but their application to ovarian cancers is limited. This study aimed to identify potential genes as CAR-T-cell antigen candidates for ovarian cancers. A differential gene expression analysis was performed on ovarian cancer samples from four datasets obtained from the GEO datasets. Functional annotation, pathway analysis, protein localization, and gene expression analysis were conducted using various datasets and tools. An oncogenicity analysis and network analysis were also performed. In total, 153 differentially expressed genes were identified in ovarian cancer samples, with 60 differentially expressed genes expressing plasma membrane proteins suitable for CAR-T-cell antigens. Among them, 21 plasma membrane proteins were predicted to be oncogenes in ovarian cancers, with nine proteins playing crucial roles in the network. Key genes identified in the oncogenic pathways of ovarian cancers included MUC1, CXCR4, EPCAM, RACGAP1, UBE2C, PRAME, SORT1, JUP, and CLDN3, suggesting them as recommended antigens for CAR-T-cell therapy for ovarian cancers. This study sheds light on potential targets for immunotherapy in ovarian cancers.

Glutathione determines chronic myeloid leukemia vulnerability to an inhibitor of CMPK and TMPK.

Bcr-Abl transformation leads to chronic myeloid leukemia (CML). The acquirement of T315I mutation causes tyrosine kinase inhibitors (TKI) resistance. This study develops a compound, JMF4073, inhibiting thymidylate (TMP) and cytidylate (CMP) kinases, aiming for a new therapy against TKI-resistant CML. In vitro and in vivo treatment of JMF4073 eliminates WT-Bcr-Abl-32D CML cells. However, T315I-Bcr-Abl-32D cells are less vulnerable to JMF4073. Evidence is presented that ATF4-mediated upregulation of GSH causes T315I-Bcr-Abl-32D cells to be less sensitive to JMF4073. Reducing GSH biosynthesis generates replication stress in T315I-Bcr-Abl-32D cells that require dTTP/dCTP synthesis for survival, thus enabling JMF4073 susceptibility. It further shows that the levels of ATF4 and GSH in several human CML blast-crisis cell lines are inversely correlated with JMF4073 sensitivity, and the combinatory treatment of JMF4073 with GSH reducing agent leads to synthetic lethality in these CML blast-crisis lines. Altogether, the investigation indicates an alternative option in CML therapy.

Association of volatile organic compound levels with chronic obstructive pulmonary diseases in NHANES 2013-2016.

Volatile organic compounds (VOCs) represent a significant component of air pollution. However, studies evaluating the impact of VOC exposure on chronic obstructive pulmonary disease (COPD) have predominantly focused on single pollutant models. This study aims to comprehensively assess the relationship between multiple VOC exposures and COPD. A large cross-sectional study was conducted on 4983 participants from the National Health and Nutrition Examination Survey. Four models, including weighted logistic regression, restricted cubic splines (RCS), weighted quantile sum regression (WQS), and the dual-pollution model, were used to explore the association between blood VOC levels and the prevalence of COPD in the U.S. general population. Additionally, six machine learning algorithms were employed to develop a predictive model for COPD risk, with the model's predictive capacity assessed using the area under the curve (AUC) indices. Elevated blood concentrations of benzene, toluene, ortho-xylene, and para-xylene were significantly associated with the incidence of COPD. RCS analysis further revealed a non-linear and non-monotonic relationship between blood levels of toluene and m-p-xylene with COPD prevalence. WQS regression indicated that different VOCs had varying effects on COPD, with benzene and ortho-xylene having the greatest weights. Among the six models, the Extreme Gradient Boosting (XGBoost) model demonstrated the strongest predictive power, with an AUC value of 0.781. Increased blood concentrations of benzene and toluene are significantly correlated with a higher prevalence of COPD in the U.S. population, demonstrating a non-linear relationship. Exposure to environmental VOCs may represent a new risk factor in the etiology of COPD.

The Degrees of Coronary Heart Disease and the Degrees of New-Onset Blepharitis: A Nationwide Cohort Study.

In this study, we aimed to evaluate the association between the severity of coronary heart disease (CHD) and the subsequent severity of blepharitis. This retrospective population-based cohort study was conducted using the National Health Insurance Research Database (NHIRD) of Taiwan. The participants with a CHD diagnosis were divided into mild CHD and severe CHD groups at a 1:2 ratio, according to whether percutaneous coronary intervention (PCI) was performed. The main outcomes were the development of blepharitis and severe blepharitis with the application of antibiotics. Cox proportional hazard regression was performed to obtain the adjusted hazard ratio (aHR) for blepharitis, with a 95% confidence interval (CI) between the groups. There were 22,161 and 15,369 blepharitis events plus 9597 and 4500 severe blepharitis episodes in the mild and severe CHD groups, respectively. The severe CHD group showed a significantly higher incidence of blepharitis development (aHR, 1.275; 95% CI: 1.051-1.912, p = 0.0285), whereas the incidence of severe blepharitis was not significantly different between the groups (aHR, 0.981; 95% CI: 0.945-1.020, p = 0.3453). The cumulative probability of blepharitis was significantly higher in the severe CHD group than in the mild CHD group (p < 0.001). In the subgroup analyses, the correlation between severe CHD and blepharitis was more significant in patients older than 70 years compared to the younger group (p = 0.0115). In conclusion, severe CHD is associated with a higher incidence of blepharitis than mild CHD, and this correlation is more prominent in individuals older than 70 years.

AttABseq: an attention-based deep learning prediction method for antigen-antibody binding affinity changes based on protein sequences.

The optimization of therapeutic antibodies through traditional techniques, such as candidate screening via hybridoma or phage display, is resource-intensive and time-consuming. In recent years, computational and artificial intelligence-based methods have been actively developed to accelerate and improve the development of therapeutic antibodies. In this study, we developed an end-to-end sequence-based deep learning model, termed AttABseq, for the predictions of the antigen-antibody binding affinity changes connected with antibody mutations. AttABseq is a highly efficient and generic attention-based model by utilizing diverse antigen-antibody complex sequences as the input to predict the binding affinity changes of residue mutations. The assessment on the three benchmark datasets illustrates that AttABseq is 120% more accurate than other sequence-based models in terms of the Pearson correlation coefficient between the predicted and experimental binding affinity changes. Moreover, AttABseq also either outperforms or competes favorably with the structure-based approaches. Furthermore, AttABseq consistently demonstrates robust predictive capabilities across a diverse array of conditions, underscoring its remarkable capacity for generalization across a wide spectrum of antigen-antibody complexes. It imposes no constraints on the quantity of altered residues, rendering it particularly applicable in scenarios where crystallographic structures remain unavailable. The attention-based interpretability analysis indicates that the causal effects of point mutations on antibody-antigen binding affinity changes can be visualized at the residue level, which might assist automated antibody sequence optimization. We believe that AttABseq provides a fiercely competitive answer to therapeutic antibody optimization.

A bibliometric analysis of teledentistry published in the category of dentistry, oral surgery and medicine.

Background/purpose: Telemedicine has gained the popularity during COVID-19 pandemic. "Teledentistry" as the dental application of telemedicine was also with increased attention. The bibliometric analysis was employed to examine the global research trends and the current implementation status of teledentistry. Materials and methods: Titles and subjects were searched in the Web of Science database by using the keywords "teledentistry OR oral telemedicine OR dental telemedicine OR telemedicine in dentistry" in the category of Dentistry, Oral Surgery & Medicine. Documents were collected from the establishment date up to December 31, 2023. Microsoft Excel was used for the descriptive and statistical analyses. The data were exhibited with visualization by VOSviewer. Results: A total of 146 articles were identified for bibliometric analysis. An upward trend in the number of publications was evident. The statistical analysis indicated a notable increased teledentistry publications affected by COVID-19 pandemic (P < 0.01). The applications of teledentistry were mainly related to clinical practice (89.73%), such as oral and maxillofacial surgery, orthodontics, dental caries, oral mucosal lesions, and dental emergencies. For geographic distributions, the United States lead with 46 publications (34%) by corresponding authors listed in the article. The keyword network analysis highlighted the prominent research areas and the changes influenced by the pandemic and technological development, respectively. Conclusion: This bibliometric study provided an overview of the progress, trends and current directions for teledentistry in the fields of dentistry, oral surgery and medicine.

[Effect and mechanism of Gusong Qianggu Decoction on reducing bone loss in ovariectomized mice by targeting endoplasmic reticulum stress-induced apoptosis of osteocytes].

This study aims to investigate the role and mechanism of Gusong Qianggu Decoction(GSQG) in attenuating bone loss in ovariectomized mice by targeting the endoplasmic reticulum stress(ERS)-induced apoptosis of osteocytes. After the modeling of osteoporosis in mice with bilateral ovary removal(OVX), 60 mice were randomized by the random number method into six groups: sham,model, low-, medium-, and high-dose GSQG(GSQG-L, GSQG-M, and GSQG-H, respectively), and estradiol(E_2), with 10 mice in each group. The mice in each group were administrated with corresponding drugs by gavage one month after surgery and the administration lasted for 3 months. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the serum levels of osteocalcin(OCN), procollagen type Ⅰ N-terminal propeptide(PINP), carboxy-terminal cross-linked telopeptide of type Ⅰ collagen(CTX),and anti-tartarte acid phosphatase 5b(TRAcP-5b). Micro-CT was employed to observe the changes in bone microstructure of the distal femur. Hematoxylin-eosin(HE) staining was employed to observe the morphology of the bone tissue. RT-qPCR was conducted to determine the m RNA levels of tibial stem osteogenesis-associated genes [type Ⅰ collagen(Col-Ⅰ), alkaline phosphatase(ALP), Runtrelated transcription factor-2(Runx2), bone sialoprotein(BSP), and OCN] and bone-breaking related genes [tartrate-resistant acid phosphatase(TRAP), nuclear factor-activated T cell 1(NFATc1), and cathepsin K(CATK)]. TUNEL staining and immunohistochemistry were employed to detect the apoptosis of osteoblasts. Western blot was employed to measure the expression of ERS-related proteins glucose-regulated protein 78( Grp78), protein kinase RNA-like endoplasmic reticulum kinase( PERK), phosphorylated PERK(p-PERK),eukaryotic translation initiation factor 2 alpha(eIF2α), phosphorylated e IF2α(p-eIF2α), inositol-requiring enzyme 1 alpha(IRE1α), phosphorylated IRE1α(p-IRE1α), and activating transcription factor 6(ATF6) in the proximal tibial bone tissue. The results showed that GSQG significantly recovered the levels of OCN, PINP, TRAc P-5b, and CTX in the serum of ovariectomized mice, and Micro-CT showed that GSQG improved the bone microstructure of distal femur in a dose-dependent manner. Compared with the model group, GSQG widened and increased the bone trabeculae, restored the reticular structure with neat arrangement and enlarged interstitial gaps, and reduced the number of TUNEL-positive cells(P<0. 05, P<0. 01). Furthermore, GSQG down-regulated the expression levels of cysteine aspartate protease-3( caspase-3) and factor Bcl-2-associated X protein( Bax)(P< 0. 05,P<0. 01) and up-regulated the expression level of Bcl-2(P<0. 05, P<0. 01). The GSQG groups showed up-regulated m RNA levels of Col-Ⅰ, ALP, Runx2, BSP, and OCN(P< 0. 01) and down-regulated m RNA levels of TRAP, NFATc1, and CATK(P< 0. 05,P<0. 01). In addition, GSQG, especially GSQG-H, down-regulated the protein levels of Grp78, p-PERK, p-eIF2, p-IRE1α, and ATF6(P< 0. 05, P< 0. 01). In conclusion, GSQG can inhibit the apoptosis of osteocytes by inhibiting the Grp78/PERK/e IF2α/IRE1α/ATF6 signaling pathway in the proximal tibia tissue, thus reducing bone loss in ovariectomized mice.

Acutalibacter caecimuris sp. nov., Acutalibacter intestini sp. nov. and Neglectibacter caecimuris sp. nov., three novel species of the family Oscillospiraceae isolated from caecal contents of C57BL/6J mice.

The intestines of mice are colonized by diverse, as-yet-uncultivated bacteria. In this report, we describe the isolation, culture, genotypic and phenotypic characterization, as well as taxonomic classification of three novel anaerobic bacterial strains derived from the caecal contents of C57BL/6J male mice. According to the phenotypic and genotype-based polyphasic taxonomy, we propose three novel species within the family Oscillospiraceae. They are Acutalibacter caecimuris sp. nov. (type strain M00118T=CGMCC 1.18042T=KCTC 25739T), Acutalibacter intestini sp. nov. (type strain M00204T=CGMCC 1.18044T=KCTC 25741T) and Neglectibacter caecimuris sp. nov. (type strain M00184T=CGMCC 1.18043T=KCTC 25740T).

Serum Mac-2 binding protein glycosylation isomer dynamics in patients achieving sustained virologic response for hepatitis C virus.

BACKGROUND AND AIM: Understanding the dynamics of serum Mac-2 binding protein glycosylation isomer (M2BPGi) remains pivotal for hepatitis C virus (HCV) patients' post-sustained virologic response (SVR12) through direct-acting antivirals (DAAs). METHODS: We compared areas under receiver operating characteristic curves (AUROCs) of M2BPGi, FIB-4, and APRI and assess M2BPGi cutoff levels in predicting fibrosis stages of ≥F3 and F4 utilizing transient elastography in 638 patients. Variations in M2BPGi levels from pretreatment to SVR12 and their association with pretreatment alanine transaminase (ALT) levels and fibrosis stage were investigated. RESULTS: The AUROCs of M2BPGi were comparable to FIB-4 in predicting ≥F3 (0.914 vs 0.902, P = 0.48) and F4 (0.947 vs 0.915, P = 0.05) but were superior to APRI in predicting ≥F3 (0.914 vs 0.851, P = 0.001) and F4 (0.947 vs 0.857, P < 0.001). Using M2BPGi cutoff values of 2.83 and 3.98, fibrosis stages of ≥F3 and F4 were confirmed with a positive likelihood ratio ≥10. The median M2BPGi change was -0.55. Patients with ALT levels ≥5 times ULN or ≥F3 demonstrated more pronounced median decreases in M2BPGi level compared to those with ALT levels 2-5 times ULN and <2 times ULN (-0.97 vs -0.68 and -0.44; P < 0.001) or with < F3 (-1.52 vs -0.44; P < 0.001). CONCLUSIONS: Serum M2BPGi is a reliable marker for advanced hepatic fibrosis. Following viral clearance, there is a notable M2BPGi decrease, with the extent of reduction influenced by ALT levels and fibrosis stage.

Stress-induced nuclear translocation of ONAC023 improves drought and heat tolerance through multiple processes in rice.

Drought and heat are major abiotic stresses frequently coinciding to threaten rice production. Despite hundreds of stress-related genes being identified, only a few have been confirmed to confer resistance to multiple stresses in crops. Here we report ONAC023, a hub stress regulator that integrates the regulations of both drought and heat tolerance in rice. ONAC023 positively regulates drought and heat tolerance at both seedling and reproductive stages. Notably, the functioning of ONAC023 is obliterated without stress treatment and can be triggered by drought and heat stresses at two layers. The expression of ONAC023 is induced in response to stress stimuli. We show that overexpressed ONAC23 is translocated to the nucleus under stress and evidence from protoplasts suggests that the dephosphorylation of the remorin protein OSREM1.5 can promote this translocation. Under drought or heat stress, the nuclear ONAC023 can target and promote the expression of diverse genes, such as OsPIP2;7, PGL3, OsFKBP20-1b, and OsSF3B1, which are involved in various processes including water transport, reactive oxygen species homeostasis, and alternative splicing. These results manifest that ONAC023 is fine-tuned to positively regulate drought and heat tolerance through the integration of multiple stress-responsive processes. Our findings provide not only an underlying connection between drought and heat responses, but also a promising candidate for engineering multi-stress-resilient rice.

Classification of Behaviour in Conventional and Slow-Growing Strains of Broiler Chickens Using Tri-Axial Accelerometers.

Behavioural states such as walking, sitting and standing are important in indicating welfare, including lameness in broiler chickens. However, manual behavioural observations of individuals are often limited by time constraints and small sample sizes. Three-dimensional accelerometers have the potential to collect information on animal behaviour. We applied a random forest algorithm to process accelerometer data from broiler chickens. Data from three broiler strains at a range of ages (from 25 to 49 days old) were used to train and test the algorithm, and unlike other studies, the algorithm was further tested on an unseen broiler strain. When tested on unseen birds from the three training broiler strains, the random forest model classified behaviours with very good accuracy (92%) and specificity (94%) and good sensitivity (88%) and precision (88%). With the new, unseen strain, the model classified behaviours with very good accuracy (94%), sensitivity (91%), specificity (96%) and precision (91%). We therefore successfully used a random forest model to automatically detect three broiler behaviours across four different strains and different ages using accelerometers. These findings demonstrated that accelerometers can be used to automatically record behaviours to supplement biomechanical and behavioural research and support in the reduction principle of the 3Rs.

Characterization of Functional Ingredients Extracted with Ethanol Solvents from Ponkan (Citrus reticulata) By-Products Using the Microwave Vacuum Drying Method Combined with Ultrasound-Assisted Extraction.

For this study, microwave vacuum drying (MVD) was combined with ultrasound-assisted extraction to compare the effects of different ethanol volumes on ponkan extract and to evaluate the total phenolic content (TPC), total flavonoid content (TFC), and total ascorbic acid content (TAAC). High-performance liquid chromatography with photodiode array detection (HPLC-PDA) was used to analyze the flavanone contents and antioxidant activity of ponkan (Citrus reticulata) peels. The experimental results showed that the TPC and TFC increase with ethanol volume. Ethanol extraction (75%) showed significant advantages by increasing the TPC to 17.48 mg GAE/g (DW) and the TFC to 2.96 mg QE/g (DW) of ponkan extract and also exhibited the highest antioxidant activity. The TAAC improved along with increased water content. Water extraction showed the highest content (13.07 mg VitC/100 g, DW). The hesperidin content analyzed by HPLC-PDA was 102.95-622.57 mg/100 g (DW), which was the highest among the flavanones. Then, the ethanol insoluble residue extracts were taken from the pectin with four different solvents, evaluating TPC, TFC, and antioxidant activity. The TPC, TFC, and antioxidant capacity of pectin are significantly lower than those of the peels. Combining MVD and 75% ethanol with ultrasound-assisted extraction in the pre-treatment process can effectively eliminate polyphenols, flavonoids, and other compounds, thus enabling the extraction of high-methoxyl pectin. The total dietary fiber (TDF) content of MVD ponkan by-products was 25.83%. Ponkan by-products have the potential for the future development of functional foods and supplements.