ALYREF recruits ELAVL1 to promote colorectal tumorigenesis via facilitating RNA m5C recognition and nuclear export.

ALYREF can recognize 5-methylcytosine (m5C) decoration throughout RNAs to regulate RNA metabolism. However, its implications in cancer and precise regulatory mechanisms remain largely elusive. Here, we demonstrated that ALYREF supported colorectal cancer (CRC) growth and migration. Integrated analysis of ALYREF-RIP-Bis-seq and transcriptome profiles identified ribosomal protein S6 kinase B2 (RPS6KB2) and regulatory-associated protein of mTOR (RPTOR) as ALYREF's possible downstream effectors. Mechanistically, ALYREF formed a complex with ELAV like RNA binding protein 1 (ELAVL1) to cooperatively promote m5C recognition and nuclear export of the two mRNAs. Moreover, ALYREF protein was highly expressed in tumor tissues of CRC patients, which predicted their poor prognosis. E2F transcription factor 6 (E2F6)-mediated transactivation gave a molecular insight into ALYREF overexpression. Collectively, ALYREF recruits ELAVL1 to collaboratively facilitate m5C recognition and nuclear export of RPS6KB2 and RPTOR transcripts for colorectal tumorigenesis, providing RNA m5C methylation as promising therapeutic targets and prognostic biomarkers for CRC.

Exosomes from human bone marrow MSCs alleviate PD-1/PD-L1 inhibitor-induced myocardial injury in melanoma mice by regulating macrophage polarization and pyroptosis.

Myocarditis, which can be triggered by immune checkpoint inhibitor (ICI) treatment, represents a critical and severe adverse effect observed in cancer therapy. Thus, elucidating the underlying mechanism and developing effective strategies to mitigate its harmful impact is of utmost importance. The objective of this study is to investigate the potential role and regulatory mechanism of exosomes derived from human bone marrow mesenchymal stem cells (hBMSC-Exos) in providing protection against myocardial injury induced by ICIs. We observed that the administration of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor BMS-1 in tumor-bearing mice led to evident cardiac dysfunction and myocardial injury, which were closely associated with M1 macrophage polarization and cardiac pyroptosis. Remarkably, these adverse effects were significantly alleviated through tail-vein injection of hBMSC-Exos. Moreover, either BMS-1 or hBMSC-Exos alone demonstrated the ability to reduce tumor size, while the combination of hBMSC-Exos with BMS-1 treatment not only effectively improved the probability of tumor inhibition but also alleviated cardiac anomalies induced by BMS-1.

Yield, cell structure and physiological and biochemical characteristics of rapeseed under waterlogging stress.

Rapeseed (Brassica napus L.) is a major oilseed crop in the middle and lower reaches of the Yangtze River in China. However, it is susceptible to waterlogging stress. This study aimed to investigate the physiological characteristics, cellular changes, and gene expression patterns of rapeseed under waterlogging stress, with the goal of providing a foundation for breeding waterlogging-tolerant rapeseed. The results revealed that waterlogging-tolerant rapeseed exhibited higher levels of soluble sugars and antioxidant enzyme activity, particularly in the roots. Conversely, waterlogging-sensitive rapeseed displayed greater changes in malondialdehyde, proline, and hydrogen peroxide levels. Cellular observations showed that after experiencing waterlogging stress, the intercellular space of rapeseed leaf cells expanded, leading to disintegration of mitochondria and chloroplasts. Moreover, the area of the root xylem increased, the number of vessels grew, and there were signs of mitochondrial disintegration and vacuole shrinkage, with more pronounced changes observed in waterlogging-sensitive rapeseed. Furthermore, significant differences were found in the transcription levels of genes related to anaerobic respiration and flavonoid biosynthesis, and different varieties demonstrated varied responses to waterlogging stress. In conclusion, there are differences in the response of different varieties to waterlogging stress at the levels of morphology, physiological characteristics, cell structure, and gene transcription. Waterlogging-tolerant rapeseed responds to waterlogging stress by regulating its antioxidant defense system. This study provides valuable insights for the development of waterlogging-tolerant rapeseed varieties.

Lacticaseibacillus rhamnosus GG alleviates sleep deprivation-induced intestinal barrier dysfunction and neuroinflammation in mice.

Consuming probiotic products is a solution that people are willing to choose to augment health. As a global health hazard, sleep deprivation (SD) can cause both physical and mental diseases. The present study investigated the protective effects of Lacticaseibacillus rhamnosus GG (LGG), a widely used probiotic, on a SD mouse model. Here, it has been shown that SD induced intestinal damage in mice, while LGG supplementation attenuated disruption of the intestinal barrier and enhanced the antioxidant capacity. Microbiome analysis revealed that SD caused dysbiosis in the gut microbiota, characterized by increased levels of Clostridium XlVa, Alistipes, and Desulfovibrio, as well as decreased levels of Ruminococcus, which were partially ameliorated by LGG. Moreover, SD resulted in elevated pro-inflammatory cytokine concentrations in both the intestine and the brain, while LGG provided protection in both organs. LGG supplementation significantly improved locomotor activity in SD mice. Although heat-killed LGG showed some protective effects in SD mice, its overall efficacy was inferior to that of live LGG. In terms of mechanism, it was found that AG1478, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, could diminish the protective effects of LGG. In conclusion, LGG demonstrated the ability to alleviate SD-induced intestinal barrier dysfunction through EGFR activation and alleviate neuroinflammation.

Metabolomic and transcriptomic analyses highlight metabolic regulatory networks of Salvia miltiorrhiza in response to replant disease.

BACKGROUND: Salvia miltiorrhiza, a well-known traditional Chinese medicine, frequently suffers from replant diseases that adversely affect its quality and yield. To elucidate S. miltiorrhiza's metabolic adaptations to replant disease, we analyzed its metabolome and transcriptome, comparing normal and replant diseased plants for the first time. RESULTS: We identified 1,269 metabolites, 257 of which were differentially accumulated metabolites, and identified 217 differentially expressed genes. Integrated transcriptomic and metabolomic analyses revealed a significant up-regulation and co-expression of metabolites and genes associated with plant hormone signal transduction and flavonoid biosynthesis pathways in replant diseases. Within plant hormone signal transduction pathway, plants afflicted with replant disease markedly accumulated indole-3-acetic acid and abscisic acid, correlating with high expression of their biosynthesis-related genes (SmAmidase, SmALDH, SmNCED, and SmAAOX3). Simultaneously, changes in hormone concentrations activated plant hormone signal transduction pathways. Moreover, under replant disease, metabolites in the local flavonoid metabolite biosynthetic pathway were significantly accumulated, consistent with the up-regulated gene (SmHTC1 and SmHTC2). The qRT-PCR analysis largely aligned with the transcriptomic results, confirming the trends in gene expression. Moreover, we identified 10 transcription factors co-expressed with differentially accumulated metabolites. CONCLUSIONS: Overall, we revealed the key genes and metabolites of S. miltiorrhiza under replant disease, establishing a robust foundation for future inquiries into the molecular responses to combat replant stress.

Corneal ulcer development due to sintilimab-anlotinib combination therapy-induced dry eye: a case report.

Background: Programmed cell death-1 (PD-1) inhibitors and anti-angiogenic drugs have become a hotspot in research of anti-tumor programs; however, they can also cause some rare drug-related adverse reactions. Immune checkpoint inhibitors (ICIs) cause adverse reactions in the body, collectively known as immune-related adverse events (irAEs). Ocular side effects can occur in both targeted and immunotherapy patients, including dry eye, blurred vision, uveitis, conjunctivitis, retinopathy, or thyroid eye disease. To our knowledge, this is the first case report describing corneal ulcers secondary to dry eye in a patient treated with the combination of PD-1 inhibitor sintilimab and multi-targeted receptor tyrosine kinase inhibitor (TKI) anlotinib. Case Description: A 65-year-old woman with non-small cell lung cancer (NSCLC) and bone metastases, without pre-existing ocular conditions, experienced mild dry eye symptoms 1 month following treatment with sintilimab (200 mg q3w) in combination with anlotinib (12 mg q3w). Unrelieved dry eye symptoms occurred after the third cycle of chemotherapy, and she was diagnosed with dry eye syndrome. Subsequently, she received corneal protective lens, sodium hyaluronate eye drops, and prednisone treatment. Her corneal epithelial damage did not improve significantly, and within the following 2 months, her vision decreased in both eyes and progressed to bilateral corneal ulcers. Oral administration of sintilimab and anlotinib was interrupted, and treatments such as corticosteroids, anti-inflammatory drugs, and corneal repair were administered; however, both eyes presented with corneal subepithelial defect and corneal scarring. Due to a shortage of donors, no corneal transplantation surgery could be performed. Conclusions: The development of corneal epithelial disorders in patients receiving target therapy and immunotherapy may not be reversed by reducing its dose. Although the condition is controlled with the use of glucocorticoids, some eye side effects cannot be cured. The timely detection and intervention of adverse effects of anti-tumor drugs by oncologists and ophthalmologists is critical for rational prescription. Ophthalmologists should be aware of eye side effects in patients using immunotherapy to ensure appropriate treatment and minimize potential eye complications such as dry eye, conjunctivitis, etc.

Abnormal effective connectivity of reward network in first-episode schizophrenia with auditory verbal hallucinations.

OBJECTIVE: Auditory verbal hallucinations (AVHs) in schizophrenia is proved to be associated with dysfunction of mesolimbic-cortical circuits, especially during abnormal salient and internal verbal resource monitoring processing procedures. However, the information flow among areas involved in coordinated interaction implicated the pathophysiology of AVHs remains unclear. METHODS: We used spectral dynamic causal modeling (DCM) to quantify connections among eight critical hubs of reward network in 86 first-episode drug-naïve schizophrenia patients with AVHs (AVH), 93 patients without AVHs (NAVH), and 88 matched normal controls (NC) using resting-state functional magnetic resonance imaging. Group-level connection coefficients, between-group differences and correlation analysis between image measures and symptoms were performed. RESULT: DCM revealed weaker effective connectivity (EC) from right ventral striatum (RVS) to ventral tegmental area (VTA) in AVH compared to NAVH. AVH showed stronger EC from left anterior insula (AI) to RVS, stronger EC from RVS to anterior cingulate cortex (ACC), and stronger EC from VTA to posterior cingulate cortex (PCC) compared to NC. The correlation analysis results were mostly visible in the negative correlation between EC from right AI to ACC and positive sub-score, P1 sub-score, and P3 sub-score of PNASS in group-level. CONCLUSION: These findings suggest that neural causal interactions between the reward network associated with AVHs are disrupted, expanding the evidence for potential neurobiological mechanisms of AVHs. Particularly, dopamine-dependent salience attribution and top-down monitoring impairments and compensatory effects of enhanced excitatory afferents to ACC, which may provide evidence for a therapeutic target based on direct in vivo of AVHs in schizophrenia.

Desulfovibrio vulgaris interacts with novel gut epithelial immune receptor LRRC19 and exacerbates colitis.

BACKGROUND: The overgrowth of Desulfovibrio, an inflammation promoting flagellated bacteria, has been found in ulcerative colitis (UC) patients. However, the molecular mechanism in promoting colitis remains unestablished. METHODS: The relative abundance Desulfovibrio vulgaris (D. vulgaris) in stool samples of UC patients was detected. Mice were treated with dextran sulfate sodium to induce colitis with or without administration of D. vulgaris or D. vulgaris flagellin (DVF), and the severity of colitis and the leucine-rich repeat containing 19 (LRRC19) signaling were assessed. The interaction between DVF and LRRC19 was identified by surface plasmon resonance and intestinal organoid culture. Lrrc19-/- and Tlr5-/- mice were used to investigate the indispensable role of LRRC19. Finally, the blockade of DVF-LRRC19 interaction was selected through virtual screening and the efficacy in colitis was assessed. RESULTS: D. vulgaris was enriched in fecal samples of UC patients and was correlated with the disease severity. D. vulgaris or DVF treatment significantly exacerbated colitis in germ-free mice and conventional mice. Mechanistically, DVF could interact with LRRC19 (rather than TLR5) in colitis mice and organoids, and then induce the production of pro-inflammatory cytokines. Lrrc19 knockdown blunted the severity of colitis. Furthermore, typhaneoside, a blockade of binding interfaces, blocked DVF-LRRC19 interaction and dramatically ameliorated DVF-induced colitis. CONCLUSIONS: D. vulgaris could promote colitis through DVF-LRRC19 interaction. Targeting DVF-LRRC19 interaction might be a new therapeutic strategy for UC therapy. Video Abstract.

Risk prediction models for postoperative delirium in elderly patients with fragility hip fracture: A systematic review and critical appraisal.

BACKGROUND: Elderly patients with fragility hip fracture continue to experience a high rate of postoperative delirium (POD), which has a significant negative impact on prognosis and imposes a huge economic burden. A number of risk prediction models have been developed to detect POD early. However, the risk of bias and clinical applicability of the models remain unclear. The aim of this study was to systematically evaluate risk prediction models for POD. METHODS: CNKI, WanFang DATA, Vip Database, SinoMed, PubMed, Web of Science, Embase, and the Cochrane Library were searched for studies published by July 2023. The literature was screened independently by two investigators. The Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS) and the Prediction Model Risk of Bias Assessment Tool (PROBAST) were respectively used for data extraction, risk of bias, and applicability assessment. RESULTS: A total of 16 studies on the construction of POD risk prediction models were included. The area under the ROC curve of the models ranges from 0.670 to 0.957. The most common predictors of POD included age, history of dementia, history of delirium, ASA classification, preoperative waiting time, and preoperative albumin level. All models had a high risk of bias, mainly due to inadequate sample size, inappropriate handling of missing data, a lack of model performance evaluation, and overfitting of the models. CONCLUSIONS: Overall, risk prediction models for POD in fragility hip fracture patients are still in the development stage. The majority of POD prediction models have substantial bias risks, attributable primarily to poor reporting of analysis and evaluation of model performance. In future research, it is recommended to conduct validation of the models or develop localized prediction models with demonstrated high performance, with the aim of benefiting POD screening. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023449153.

Gray matter atrophy is constrained by normal structural brain network architecture in depression.

BACKGROUND: There is growing evidence that gray matter atrophy is constrained by normal brain network (or connectome) architecture in neuropsychiatric disorders. However, whether this finding holds true in individuals with depression remains unknown. In this study, we aimed to investigate the association between gray matter atrophy and normal connectome architecture at individual level in depression. METHODS: In this study, 297 patients with depression and 256 healthy controls (HCs) from two independent Chinese dataset were included: a discovery dataset (105 never-treated first-episode patients and matched 130 HCs) and a replication dataset (106 patients and matched 126 HCs). For each patient, individualized regional atrophy was assessed using normative model and brain regions whose structural connectome profiles in HCs most resembled the atrophy patterns were identified as putative epicenters using a backfoward stepwise regression analysis. RESULTS: In general, the structural connectome architecture of the identified disease epicenters significantly explained 44% (±16%) variance of gray matter atrophy. While patients with depression demonstrated tremendous interindividual variations in the number and distribution of disease epicenters, several disease epicenters with higher participation coefficient than randomly selected regions, including the hippocampus, thalamus, and medial frontal gyrus were significantly shared by depression. Other brain regions with strong structural connections to the disease epicenters exhibited greater vulnerability. In addition, the association between connectome and gray matter atrophy uncovered two distinct subgroups with different ages of onset. CONCLUSIONS: These results suggest that gray matter atrophy is constrained by structural brain connectome and elucidate the possible pathological progression in depression.

Decreased intrinsic neural timescale in treatment-naïve adolescent depression.

BACKGROUND: Major depressive disorder (MDD) is mainly characterized by its core dysfunction in higher-order brain cortices involved in emotional and cognitive processes, whose neurobiological basis remains unclear. In this study, we applied a relatively new developed resting-state functional magnetic resonance imaging (rs-fMRI) method of intrinsic neural timescale (INT), which reflects how long neural information is stored in a local brain area and reflects an ability of information integration, to investigate the local intrinsic neural dynamics using univariate and multivariate analyses in adolescent depression. METHOD: Based on the rs-fMRI data of sixty-six treatment-naïve adolescents with MDD and fifty-two well-matched healthy controls (HCs), we calculated an INT by assessing the magnitude of autocorrelation of the resting-state brain activity, and then compared the difference of INT between the two groups. Correlation between abnormal INT and clinical features was performed. We also utilized multivariate pattern analysis to determine whether INT could differentiate MDD patients from HCs at the individual level. RESULT: Compared with HCs, patients with MDD showed shorter INT widely distributed in cortical and partial subcortical regions. Interestingly, the decreased INT in the left hippocampus was related to disease severity of MDD. Furthermore, INT can distinguish MDD patients from HCs with the most discriminative regions located in the dorsolateral prefrontal cortex, angular, middle occipital gyrus, and cerebellar posterior lobe. CONCLUSION: Our research aids in advancing understanding the brain abnormalities of treatment-naïve adolescents with MDD from the perspective of the local neural dynamics, highlighting the significant role of INT in understanding neurophysiological mechanisms. This study shows that the altered intrinsic timescales of local neural signals widely distributed in higher-order brain cortices regions may be the neurodynamic basis of cognitive and emotional disturbances in MDD patients, and provides preliminary support for the suggestion that these could be used to aid the identification of MDD patients in clinical practice.

Clustering of lifestyle behaviours and analysis of their associations with MAFLD: a cross-sectional study of 196,515 individuals in China.

BACKGROUND: The aggregation of lifestyle behaviours and their association with metabolic-associated fatty liver disease (MAFLD) remain unclear. We identified lifestyle patterns and investigated their association with the risk of developing MAFLD in a sample of Chinese adults who underwent annual physical examinations. METHODS: Annual physical examination data of Chinese adults from January 2016 to December 2020 were used in this study. We created a scoring system for lifestyle items combining a statistical method (multivariate analysis of variance) and clinical expertise (Delphi method). Subsequently, principal component analysis and two-step cluster analysis were implemented to derive the lifestyle patterns of men and women. Binary logistic regression analysis was used to explore the prevalence risk of MAFLD among lifestyle patterns stratified by sex. RESULTS: A total of 196,515 subjects were included in the analysis. Based on the defined lifestyle scoring system, nine and four lifestyle patterns were identified for men and women, respectively, which included "healthy or unhealthy" patterns and mixed patterns containing a combination of healthy and risky lifestyle behaviours. This study showed that subjects with an unhealthy or mixed pattern had a significantly higher risk of developing MAFLD than subjects with a relatively healthy pattern, especially among men. CONCLUSIONS: Clusters of unfavourable behaviours are more prominent in men than in women. Lifestyle patterns, as important factors influencing the development of MAFLD, show significant sex differences in the risk of MAFLD. There is a strong need for future research to develop targeted MAFLD interventions based on the identified behavioural clusters by sex stratification.

Development of a Real-Time Quantitative PCR Based on a TaqMan-MGB Probe for the Rapid Detection of Theileria haneyi.

Equine piroplasmosis (EP) is a parasitic disease caused by Theileria equi (T. equi), Babesia caballi (B. caballi) and Theileria haneyi (T. haneyi). This disease is considered to be reportable by the World Organization for Animal Health (WOAH). Real-time quantitative PCR (qPCR) is regarded as a straightforward, rapid and sensitive diagnostic method to detect pathogens. However, qPCR has not been employed in the various epidemiological investigations of T. haneyi. In this study, we developed a new qPCR method to detect T. haneyi based on the chr1sco (chromosome 1 single-copy open reading frame (ORF)) gene, which has no detectable orthologs in T. equi or B. caballi. A TaqMan MGB probe was used in the development of the qPCR assay. A plasmid containing the chr1sco gene was constructed and used to establish the standard curves. The novel qPCR technique demonstrated great specificity for detecting additional frequent equine infectious pathogens and sensitivity for detecting diluted standard plasmids. This qPCR was further validated by comparison with an optimized nested PCR (nPCR) assay in the analysis of 96 clinical samples. The agreement between the nPCR assay and the established qPCR assay was 85.42%. The newly established method could contribute to the accurate diagnosis of T. haneyi infections in horses.

Study on the metabolic process of phthalic acid driven proliferation of Rhizoctonia solani.

Introduction: Continuous cropping obstacle seriously affects the quality and yield of Salvia miltiorrhiza, and the synergistic effect of root exudates and rhizosphere pathogenic microorganisms may be an important cause of continuous cropping obstacle. This study aimed to explore the effects of representative organic acids on the growth and metabolism of specific microorganisms in the S. miltiorrhiza rhizosphere soil under continuous cropping, and clarify its mechanism. Methods: The effect of phthalic acid (PA) on the growth and metabolism of Rhizoctonia solani was evaluated by mycelial growth inhibition method. Ultra-high performance liquid chromatography and tandem mass spectrometry were used to identify the differential metabolites of R. solani induced by exogenous PA. Results: PA exerted a concentration-dependent effect on mycelial growth, biomass, intracellular polysaccharides con-tent, and total protein content in R. solani. A total of 1773 metabolites and 1040 differential metabolites were identified in the blank medium (CK), Fungi (CK + fungi), and PA-Fungi (CK + fungi + acid) groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the differential metabolites were mainly involved in the sugar, lipid, and protein metabolic pathways related to stable membrane structure and cell growth. Discussion: The proliferation and metabolism network of R. solani induced by PA was proposed, and the enhancement of sugar, lipid, and amino acid metabolism was presumed to be related to the active resistance of cells to organic acid stress. These results offer new in-sights into the effects of PA metabolism on promoting R. solani proliferation, and provide theoretical support for further optimizing the rhizosphere microecological environment of Salvia miltiorrhiza continuous cropping soil and reducing continuous cropping obstacle.

Upconversion-Luminescent Fiber Microchannel Sensors for Temperature Monitoring at High Spatial Resolution in the Brains of Freely Moving Animals.

Brain temperature is a critical factor affecting neural activity and function, whose fluctuations may result in acute life-threatening health complications and chronic neuropathology. To monitor brain temperature, luminescent nanothermometry (LN) based on upconversion nanoparticles (UCNPs) with low autofluorescence has received extensive attention for its advantages in high temperature sensitivity and high response speed. However, most of current the LNs are based on optical imaging, which fails in temperature monitoring in deep brain regions at high spatial resolution. Here, the fiber microchannel sensor (FMS) loaded with UCNPs (UCNP-FMS) is presented for temperature monitoring at high spatial resolution in the deep brains of freely moving animals. The UCNP-FMS is fabricated by incorporating UCNPs in microchannels of optical fibers, whose diameter is ∼50 µm processed by femtosecond laser micromachining for spatially resolved sensing. The UCNPs provide thermal-sensitive upconversion emissions at dual wavelengths for ratiometric temperature sensing, ensuring a detection accuracy of ± 0.3 °C at 37 °C. Superior performances of UCNP-FMS are demonstrated by real-time temperature monitoring in different brain regions of freely moving animals under various conditions such as taking food, undergoing anesthesia/wakefulness, and suffering external temperature changes. Moreover, this study shows the capability of UCNP-FMS in distributed temperature sensing in mammalian brains in vivo.

Impact renaming non-alcoholic fatty liver disease to metabolic associated fatty liver disease in prevalence, characteristics and risk factors.

BACKGROUND: Recently, a group of hepatologists proposed to rename non-alcoholic fatty liver disease (NAFLD) as metabolic associated fatty liver disease (MAFLD) with modified diagnostic criteria. It is important to note, however, that there are some differences between the diagnostic criteria used for NAFLD and MAFLD. Since the research on MAFLD is just beginning, however, evidence on its incidence and prevalence in the general population and in specific subpopulations remains limited. AIM: To assess epidemiology of fatty liver in new definition and compare MAFLD with NAFLD. Exploring risk factors of MAFLD individuals. METHODS: This was a retrospective, cross-sectional study. A total of 85242 adults were selected from the Chinese health management database in 2017-2022. The data of general information, laboratory indicators, lifestyle management and psychological status were obtained. MAFLD was diagnosed as ultrasound diagnosis of fatty liver and at least one between these three conditions: Overweight/obesity, type 2 diabetes mellitus (T2DM) or metabolic dysregulation. Metabolic factors were not considered in NAFLD diagnosis standard. The clinical characteristics of MAFLD and NAFLD were analysed using descriptive statistics. Continuous variables normally distributed were expressed as means ± SD. Categorical variables were expressed as frequencies and proportions. Binary logistic regression was used to determine risk factors of the MAFLD. RESULTS: The prevalence of MAFLD and NAFLD was 40.5% and 31.0%, respectively. The MAFLD or NAFLD population is more likely to be older (M: 47.19 ± 10.82 vs 43.43 ± 11.96; N: 47.72 ± 11.17 vs 43.71 ± 11.66), male (M: 77.21% vs 44.43%; N: 67.90% vs 53.12%) and high body mass index (M: 26.79 ± 2.69 vs 22.44 ± 2.48; N: 26.29 ± 2.84 vs 23.29 ± 3.12) than the non-MAFLD or non-MAFLD population. In multivariate analysis, general information (e.g., ≥ 2 metabolic abnormalities OR = 3.38, (95%CI: 2.99-3.81), P < 0.001; diastolic blood pressure OR = 1.01, (95%CI: 1.00-1.01), P = 0.002), laboratory results [e.g.,total bilirubin (TBIL) OR = 0.98, (95%CI: 0.98-0.99), P < 0.001; serum uric acid(SUA) OR = 1.01, (95%CI: 1.01-1.01), P < 0.001], and lifestyle factors [e.g., drink beverage OR = 0.32, (95%CI: 0.17-0.63), P = 0.001] were influence factors for MAFLD. Our study results offer new insight into potential risk factors associated with fatty liver disease, including SUA, TBIL and creatinine, all of which are related to chronic renal disease (CKD). CONCLUSION: MAFLD is more prevalent than NAFLD, with two-fifths of individuals meeting the diagnosis criteria. MAFLD and NAFLD populations have different clinical characteristics. CKD may be related with MAFLD.

A Gellan Gum/Sodium Alginate-based gastric-protective hydrogel loaded with a combined herbal extract consisting of Panax notoginseng, Bletilla striata and Dendrobium officinale.

One Chinese herbal combination consisting of Panax notoginseng, Bletilla striata and Dendrobium officinale (PBD) is an effective Traditional Chinese Medicine (TCM) prescription and is widely used in clinics to treat gastric ulcers due to their safety and effectiveness compared with chemical agents, such as aspirin and omeprazole. Herein, an in situ forming gel (ISFG) based on Gellan Gum (GG) and Sodium Alginate (SA) was designed to deliver extracts of PBD prescription (EPBDP). The central composite design optimized prescription dosage was 0.1 % w/v of GG and 0.5 % w/v of SA. Gels prepared with this formulation demonstrated outstanding fluidity and instantaneous gel formation. In vitro release data showed that sustained drug release occurred in the gel, and the gel was pH-sensitive. The rheological tests confirmed the formation of stable gel, which exhibited strong viscosity and elasticity. In vitro adhesion assays revealed that the gel had strong gastric mucosal adhesion, while in vivo residual rate experiments of active ingredients revealed that the gel might greatly improve the gastric retention of active ingredients. Animal studies demonstrated that the gel was effective in treating gastric ulcers. Hence, the results of the study show that EPBDP-ISFG, a highly pH-sensitive sustained-release system, is effective.

Prmt5 deficiency inhibits CD4+ T-cell Klf2/S1pr1 expression and ameliorates EAE disease.

BACKGROUND: Protein arginine methyltransferase 5 (Prmt5) is the main type II methyltransferase, catalyzes protein arginine residue symmetric dimethylation, and modulates normal cellular physiology and disease progression. Prmt5 inhibition or deletion in CD4+ T cells has been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), but the detailed molecular mechanisms have not yet been elucidated. METHODS: EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35-55) in T cells Prmt5 conditional knockout (CD4-cre-Prmt5fl/fl, Prmt5cko) and Prmt5fl/fl (WT) mice. Flow cytometry, single-cell RNA sequencing, ATAC sequencing and chromatin immunoprecipitation assay (ChIP) approaches were used to explore the detail mechanisms. RESULTS: We find that Prmt5cko mice are resistant to EAE; infiltrating inflammatory CD4+ T cells in the central nervous system (CNS) are greatly reduced. However, in Prmt5cko mice, T cells in the spleen show much more proliferation and activation properties, the total number of CD4+ T cells in the spleen is not reduced, and the percentage of Rora+ CD4+ T cells is elevated. Also, CD4+ T cells express lower levels of S1pr1 and Klf2 than WT mice, which may influence pathogenic CD4+ T-cell egress from the spleen and migration to the CNS. Moreover, the single-cell ATAC sequence and ChIP assay reveal that the transcription factor Klf2 is enriched at the S1pr1 promoter and that Klf2 motif activity is reduced in Prmt5cko mice. CONCLUSIONS: Our study delineates the undiscovered role of Prmt5 in T-cell biology in which Prmt5 may inhibit Klf2-S1pr1 pathway to ameliorate EAE disease. Controlling T-cell Prmt5 expression may be helpful for the treatment of autoimmune diseases.

Parsing altered gray matter morphology of depression using a framework integrating the normative model and non-negative matrix factorization.

The high inter-individual heterogeneity in individuals with depression limits neuroimaging studies with case-control approaches to identify promising biomarkers for individualized clinical decision-making. We put forward a framework integrating the normative model and non-negative matrix factorization (NMF) to quantitatively assess altered gray matter morphology in depression from a dimensional perspective. The proposed framework parses altered gray matter morphology into overlapping latent disease factors, and assigns patients distinct factor compositions, thus preserving inter-individual variability. We identified four robust disease factors with distinct clinical symptoms and cognitive processes in depression. In addition, we showed the quantitative relationship between the group-level gray matter morphological differences and disease factors. Furthermore, this framework significantly predicted factor compositions of patients in an independent dataset. The framework provides an approach to resolve neuroanatomical heterogeneity in depression.