Deep learning-based 3D quantitative total tumor burden predicts early recurrence of BCLC A and B HCC after resection.

OBJECTIVES: This study aimed to evaluate the potential of deep learning (DL)-assisted automated three-dimensional quantitative tumor burden at MRI to predict postoperative early recurrence (ER) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This was a single-center retrospective study enrolling patients who underwent resection for BCLC A and B HCC and preoperative contrast-enhanced MRI. Quantitative total tumor volume (cm3) and total tumor burden (TTB, %) were obtained using a DL automated segmentation tool. Radiologists' visual assessment was used to ensure the quality control of automated segmentation. The prognostic value of clinicopathological variables and tumor burden-related parameters for ER was determined by Cox regression analyses. RESULTS: A total of 592 patients were included, with 525 and 67 patients assigned to BCLC A and B, respectively (2-year ER rate: 30.0% vs. 45.3%; hazard ratio (HR) = 1.8; p = 0.007). TTB was the most important predictor of ER (HR = 2.2; p < 0.001). Using 6.84% as the threshold of TTB, two ER risk strata were obtained in overall (p < 0.001), BCLC A (p < 0.001), and BCLC B (p = 0.027) patients, respectively. The BCLC B low-TTB patients had a similar risk for ER to BCLC A patients and thus were reassigned to a BCLC An stage; whilst the BCLC B high-TTB patients remained in a BCLC Bn stage. The 2-year ER rate was 30.5% for BCLC An patients vs. 58.1% for BCLC Bn patients (HR = 2.8; p < 0.001). CONCLUSIONS: TTB determined by DL-based automated segmentation at MRI was a predictive biomarker for postoperative ER and facilitated refined subcategorization of patients within BCLC stages A and B. CLINICAL RELEVANCE STATEMENT: Total tumor burden derived by deep learning-based automated segmentation at MRI may serve as an imaging biomarker for predicting early recurrence, thereby improving subclassification of Barcelona Clinic Liver Cancer A and B hepatocellular carcinoma patients after hepatectomy. KEY POINTS: Total tumor burden (TTB) is important for Barcelona Clinic Liver Cancer (BCLC) staging, but is heterogenous. TTB derived by deep learning-based automated segmentation was predictive of postoperative early recurrence. Incorporating TTB into the BCLC algorithm resulted in successful subcategorization of BCLC A and B patients.

Biogeography and community assembly of soil fungi from alpine meadows in southwestern China show the importance of climatic selection.

Soil fungi are pivotal in alpine and arctic ecosystems that are vulnerable to climate changes. Previous studies have shown broad connections between soil fungi in the arctic and alpine regions, but most of these studies are mainly from Europe and North America, with more sporadic studies from East Asia. Currently, little is known about the biogeographic relationships between soil fungi in alpine meadows of southwestern China (AMSC) and other regions of the world. In addition, the regional-scale spatial patterns of fungal communities in the AMSC, as well as their driving factors and ecological processes, are also poorly understood. In this study, we collected roots and surrounding soils of two dominant ectomycorrhizal plants, Bistorta vivipara and B. macrophylla from the AMSC, and performed bioinformatic and statistical analyses based on high-throughput sequencing of ITS2 amplicons. We found that: (1) fungi from the AMSC were closely related with those from boreal forests and tundra, and saprotrophic fungi had higher dispersal potential than ectomycorrhizal fungi; (2) community compositions exhibited clear divergences among geographic regions and between root and soil samples; (3) climate was the predominant factor driving regional-scale spatial patterns but had less explanatory power for saprotrophic and total fungi from roots than those from soils; (4) homogeneous selection and drift were the key ecological processes governing community assembly, but in communities of saprotrophic and total fungi from soil samples, drift contributed less and its role was partially replaced by dispersal limitation. This study highlights the importance of climatic selection and stochastic processes on fungal community assembly in alpine regions, and emphasizes the significance of simultaneously investigating fungi with different trophic modes and from both roots and soils.

Clinical features of neonatal hyperthyroidism: a retrospective analysis in southwestern China.

Purpose: This study aimed to explore the clinical characteristics and evaluate the different types of thyroid dysfunction in babies with neonatal hyperthyroidism. Methods: The clinical data of 19 neonates with hyperthyroidism admitted to the Children's Hospital of Chongqing Medical University between January 2012 and April 2021 were retrospectively analyzed. Results: Fifteen (78.9%) infants were born to mothers with Graves' disease. Eleven (57.9%) infants were premature; two babies were born at small for gestational age. The age at diagnosis ranged from 3 to 34 days, with a mean of 18.53 ± 6.85 days. The majority of the babies presented with goiter (84.2%) and tachycardia (94.7%) after birth. Nine (47.4%) of them presented with abnormal weight gain, seven (36.8%) presented with stare or ocular protrusion, six (31.6%) presented with hyperexcitability, four (21.1%) presented with jaundice and liver dysfunction, two (10.5%) presented with sweating, one (5.3%) presented with fever, and one case presented without any symptoms. Transient hyperthyroidism was the main thyroid dysfunction in our study. Overt hyperthyroidism was diagnosed in 13 (68.4%) neonates. Another three babies (15.8%) presented with hyperthyroidism with slightly elevated free triiodothyronine levels, normal thyroxine (T4) levels, and low thyroid-stimulating hormone (TSH) levels. Normal thyroid hormone levels with low TSH levels were observed in three (15.8%) neonates. Ten children were treated with antithyroid drugs. Eighteen children recovered normal thyroid function at 1-3 months of age; one baby in the study group required further levothyroxine supplementation due to primary hypothyroidism (HT). One child was found to have developmental delay at 2 years of age during follow-up. Conclusions: Our study highlights the need for prolonged monitoring of thyroid function in suspected patients. A single normal screening for hyperthyroidism or the absence of a maternal history of hyperthyroidism cannot exclude this disease.

Resting-state electroencephalography (EEG) microstates of healthy individuals following mild sleep deprivation.

Mild sleep deprivation is widespread in many societies worldwide. Electroencephalography (EEG) microstate analysis provides information on spatial and temporal characteristics of resting brain network, serving as an indicator of neurophysiological activities at rest. This study seeks to investigate potential neural markers in EEG following mild sleep deprivation of a single night using EEG microstate analysis. Six-minute resting EEG was conducted on thirty healthy adults within 6 hours of waking in the morning and after at least 18 h of sleep deprivation. Translated and validated Malay language Karolinska Sleepiness Scale was used to assess the participants' degree of sleepiness. Microstate characteristics analysis was conducted on the final 24 subjects based on four standard microstate maps. Microstate C shows a significant increase in mean duration, coverage and occurrence, while microstate D has significantly higher occurrence after sleep deprivation. This study demonstrates notable changes in resting state EEG microstates following mild sleep deprivation. Present findings deepen our understanding of the brain's spatiotemporal dynamics under this condition and suggest the potential utility of neural markers in this domain as components of composite markers for sleep deprivation.

Exploration of the mechanism of Qinglongyi-Buguzhi drug pair in treating vitiligo based on network pharmacology, molecular docking and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: The Qinglongyi-Buguzhi herbal pair (QB) is one of commonly used herbal combinations for treating vitiligo in traditional Chinese medicine, consisting of the exocarp of the immature fruit of Juglans regia L. or Juglans mandshurica Maxim., and dried, mature fruit of Psoralea corylifolia L. However, the active components and potential mechanisms of QB in the treatment of vitiligo are still unclear. AIM OF THE STUDY: The purpose of this study is to clarify the effects and mechanisms of QB on vitiligo treatment through integration of network pharmacology and empirical examinations. MATERIALS AND METHODS: The active components and targets of QB as well as the targets linked to vitiligo were obtained from network databases. Visualization networks were constructed with Cytoscape 3.9.1. GO and KEGG enrichment analysis were conducted to investigate the possible mechanism. Molecular docking was employed to evaluate the binding affinities between the primary active ingredients of QB and essential targets of the PI3K/Akt/Nrf2 pathway. In vivo and in vitro experiments were carried out to confirm the results of network pharmacology. RESULTS: We evaluated 44 active compounds and 602 genes from QB, and 107 of these genes linked to vitiligo. GO analysis suggested QB might lessen vitiligo by regulating oxidative stress. KEGG pathway analysis indicated the PI3K/Akt pathway may be crucial for treating vitiligo. Molecular docking results demonstrated the key active ingredients of QB had good binding activity with the major targets in the PI3K/Akt/Nrf2 pathway. In vivo, QB significantly ameliorated vitiligo model mouse's skin pathologies by reducing ROS, elevating CAT and SOD levels. Western blot showed that QB increased the phosphorylation of PI3K and Akt and the expressions of Nrf2 and HO-1 in the skin. In vitro, QB reversed H2O2-induced oxidative injury of melanocytes, enhanced cell survival rate, reduced ROS level, upregulated SOD and CAT activities, and raised the content of melanin. Moreover, QB upregulated the expression levels of Akt, Nrf2, HO-1 mRNA, Akt phosphorylation, HO-1, and nuclear Nrf2 proteins, and also encouraged the nuclear translocation of Nrf2. However, LY294002 treatment significantly reversed the regulatory effect of QB on oxidative damage of melanocytes. CONCLUSIONS: This study revealed that the therapeutic effect of QB on vitiligo was achieved through multiple components, targets and pathways. Experimental investigation demonstrated that QB could improve vitiligo via reducing oxidative stress, which was probably accomplished by activating the PI3K/Akt/Nrf2 signaling pathway.

[Material basis of kidney Yang deficiency rats before and after salt processing of Dipsacus asper based on spectrum-effect relationship].

This paper aims to study the spectrum-effect relationship between the fingerprints before and after salt processing of Dipsacus asper and the efficacy of warming and tonifying kidney Yang and find the main active components against kidney Yang deficiency before and after salt processing of D. asper, so as to provide the basis for clarifying the effect of salt processing on kidney Yang deficiency. The HPLC fingerprint before and after salt processing of D. asper was established by the HPLC-DAD. 15 common peaks were obtained, and 11 components were identified. The content changes of various components in rat serum were detected, and the difference in efficacy before and after salt processing was compared. The results of pharmacological experiments showed that salt processing of D. asper could enhance the kidney index. At the same dose, there was a significant difference between the raw D. asper and D. asper after salt processing groups. Compared with the model group, the contents of ACTH, cAMP, CORT, E_2, GH, Na~+-K~+-ATPase, T, and T4 in the serum of rats in the administration group increased to a certain extent, and the contents of cGMP and TNF-α decreased to a certain extent. Among them, there were significant differences in the above indexes in the serum of rats in the high-dose group of raw D. asper, middle-dose group of D. asper after salt processing, high-dose group of D. asper after salt processing, and the positive drug group. The overall results showed that D. asper after salt processing was more effective than raw D. asper in preventing kidney yang deficiency. The efficacy of D. asper was evaluated by grey correlation analysis, entropy method, and Pearson correlation analysis, and the components of D. asper after salt processing against kidney yang deficiency were screened out. According to the results of correlation degree ranking, the components with increased ranking before and after salt processing of D. asper were loganin, chlorogenic acid, dipsacoside A, asperosaponin Ⅵ, caffeic acid, and isochlorogenic acid B. It was preliminarily speculated that these compounds may be the potential pharmacodynamic components for the treatment of kidney yang deficiency before and after salt processing of D. asper. The changing components before and after the salt processing of D. asper were determined, which proved that D. asper after salt processing was superior to D. asper in the treatment of kidney yang deficiency. The spectrum-effect relationship between the efficacy of D. asper before and after salt processing and the treatment of kidney yang deficiency was established, which laid a foundation for the subsequent study on the pharmacodynamic components and molecular mechanism of salt processing of D. asper.

Colonization of microbiota derived from Macaca fascicularis, Bama miniature pigs, beagle dogs, and C57BL/6J mice alleviates DSS-induced colitis in germ-free mice.

Fecal microbiota transplantation (FMT) is an innovative and promising treatment for inflammatory bowel disease (IBD), which is related to the capability of FMT to supply functional microorganisms to improve recipient gut health. Numerous studies have highlighted considerable variability in the efficacy of FMT interventions for IBD. Several factors, including the composition of the donor microorganisms, significantly affect the efficacy of FMT in the treatment of IBD. Consequently, identifying the functional microorganisms in the donor is crucial for enhancing the efficacy of FMT. To explore potential common anti-inflammatory bacteria with therapeutic implications for IBD, germ-free (GF) BALB/c mice were pre-colonized with fecal microbiota obtained from diverse donors, including Macaca fascicularis (MCC_FMT), Bama miniature pigs (BP_FMT), beagle dogs (BD_FMT), and C57BL/6 J mice (Mice_FMT). Subsequently, mice were treated with dextran sodium sulfate (DSS). As expected, the symptoms of colitis were alleviated by MCC_FMT, BP_FMT, BD_FMT, and Mice_FMT, as demonstrated by the prevention of an elevated disease activity index in mice. Additionally, the utilization of distinct donors protected the intestinal barrier and contributed to the regulation of cytokine homeostasis. Metagenomic sequencing data showed that the microbial community structure and dominant species were significantly different among the four groups, which may be linked to variations in the anti-inflammatory efficacy observed in the respective groups. Notably, Lactobacillus reuteri and Flavonifractor plautii were consistently present in all four groups. L. reuteri exhibited a significant negative correlation with IL-1ß, and animal studies further confirmed its efficacy in alleviating IBD, suggesting the presence of common functional bacteria across different donors that exert anti-inflammatory effects. This study provides essential foundational data for the potential clinical applications of FMT.IMPORTANCEDespite variations in efficacy observed among donors, numerous studies have underscored the potential of fecal microbiota transplantation (FMT) for managing inflammatory bowel disease (IBD), indicating the presence of shared anti-IBD bacterial species. In the present study, the collective anti-inflammatory efficacy observed across all four donor groups prompted the identification of two common bacterial species using metagenomics. A significant negative correlation between Lactobacillus reuteri and IL-1ß was revealed. Furthermore, mice gavaged with L. reuteri successfully managed the colitis challenge induced by dextran sodium sulfate (DSS), suggesting that L. reuteri may act as an efficacious bacterium mediating shared anti-inflammatory effects among variable donors. This finding highlights the utilization of variable donors to screen FMT core bacteria, which may be a novel strategy for developing FMT applications.

[Effects of cortical bone thickness and jaw bone density on pain during implant surgery].

PURPOSE: To investigate the effects of different cortical bone thickness and jaw bone density at implant sites on intraoperative pain during implant surgery. METHODS: One hundred and eighty-seven patients(263 implant sites) who underwent implant placement surgery at the Fourth Affiliated Hospital of Nanchang University from August 2021 to August 2022 were selected to investigate the effects of different cortical bone thickness and jaw bone density HU values at implant sites on the anesthetic effect under local infiltration anesthesia with epinephrine in articaine. SPSS 26.0 software package was used for data analysis. RESULTS: The mean cortical bone thickness at the painful sites[(3.90±1.36) mm] was significantly greater than that at the non-painful sites [(2.24±0.66) mm], and the difference was statistically significant(P＜0.05). The differences in cortical bone thickness in the mandibular anterior, premolar, and molar regions were statistically significant in the comparison of pain and non-pain sites. The mean HU value of bone density was (764.46±239.75) for the painful sites and (612.23±235.31) for the non-painful sites, with significant difference(P＜0.05). The difference was not significant(P＞0.05) when comparing the HU values of painful sites with non-painful sites in the mandibular anterior teeth and anterior molar region, while the difference was significant(P＜0.05) when comparing the HU values of painful sites with non-painful sites in the mandibular molar region. CONCLUSIONS: Sites with large cortical bone thickness have a greater effect on blocking infiltrative anesthetic penetration and are more prone to intraoperative pain during implantation. In the mandibular anterior and premolar regions, the HU value of the implant sites had less effect on infiltrative anesthetic penetration, and the effect was greater in the mandibular molar region, and the implant sites with high HU values in the mandibular molar region were more likely to have intraoperative pain. When the cortical bone thickness in the planned implant site is greater than 3.9 mm and the mean bone density in the mandibular molar region is greater than 665 HU. If there is sufficient safe distance for hole operation, it is recommended to apply mandibular nerve block anesthesia combined with articaine infiltration anesthesia to avoid intraoperative pain and bad surgical experience for the patients.

OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN PRESUMED VETERINARY ANTHELMINTIC DRUG-INDUCED RETINAL TOXICITY: A Glimpse into Underlying Mechanism.

PURPOSE: To report optical coherence tomography findings of presumed veterinary anthelmintic drugs (VADs)-induced retinal toxicity that may aid in understanding potential pathogenic mechanisms. METHODS: This is a retrospective observational case series analysis of patients with vision abnormalities following the accidental or intentional consumption of veterinary anthelmintic drugs. All cases underwent a thorough ophthalmological examination. Moreover, medical records, as well as the initial and follow-up optical coherence tomography images, were thoroughly scrutinized. RESULTS: Four patients were identified (3 men; mean [range] age, 36.5 [22-52] years). Each patient overdosed on one or two of the following VADs: closantel, triclabendazole, praziquantel, pyrantel pamoate, and niclofolan. The most characteristic optical coherence tomography finding was diffuse, granular, hyperreflective lesions throughout the outer retina, which were initially identified in the ellipsoid zone in two cases. At follow-up, optical coherence tomography exhibited regression of hyperreflective lesions and extensive loss of the outer retinal elements in two patients. In addition, the subfoveal outer retinal layers may be partially preserved. CONCLUSION: Some veterinary anthelmintic drugs could be detrimental to the human retina if overdosed, resulting in visual disturbances. Optical coherence tomography revealed the mitochondria-enriched ellipsoid zone where outer retinal damage first appeared on, implying that these medications may harm the retina by inhibiting mitochondrial energy metabolism, as they do to eliminate parasites.

The association of back pain with physical inactivity and hypothyroidism in pregnant women.

BACKGROUND: During pregnancy, structural and functional changes usually occur in the body, which has various consequences, including lower back pain (LBP) and hypothyroidism. One of the risk factors for these problems is physical inactivity. OBJECTIVE: This study aimed to investigate the association of back pain and physical inactivity, weight gain, and hypothyroidism in pregnant women. METHODS: In this cohort study, 420 pregnant women (26.333 ± 5.820 years old) were included. At first, participants answered this question: "Do you have any plans for pregnancy in the next month?" If the answer was yes, further evaluations were performed. The physical activity and pain intensity were measured by the International Physical Activity Questionnaire Short Form (IPAQ-S) and Visual Analogue Scale. Serum TSH was measured by automated chemiluminescence and commercial kits. Measurements were conducted before, the first, second, and third trimester of pregnancy. RESULTS: Women reporting LBP were less engaged in physical activities and weight gained in the second and third trimesters of pregnancy was significantly higher than pregnant women without LBP (p< 0.05). TSH level and weight gained in pregnant women with low physical activity level was significantly higher than pregnant women with moderate and high physical activity (p< 0.05) (without significant difference in TSH and BMI). The physical inactivity (before: OR: 1.11 95% CI: 0.89 to 1.22; first trimester: OR: 1.09 95% CI: 1.02 to 1.59; second trimester: OR: 0.92 95% CI: 0.87 to 1.31; third trimester: OR: 1.12 95% CI: 1.02 to 1.39), TSH (OR: 0.85 95% CI: 0.57 to 1.29), and weight gain (second trimester: OR: 0.87 95% CI: 0.92 to 1.59; third trimester: OR: 1.44 95% CI: 1.02 to 1.98; p< 0.05) did predict increased pain intensity. CONCLUSION: Using health-oriented approaches to increase physical activity and normalize thyroid function and weight gain during pregnancy can have beneficial effects on LBP.

The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection.

PURPOSE: Vibrio vulnificus (V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. METHODS: An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. RESULTS: In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival (p = 0.014), reduced the serum creatinine (p = 0.002), urea nitrogen (p = 0.030), aspartate aminotransferase (p = 0.029), and alanine aminotransferase (p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1ß: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1ß, IL-6, TNF-α in liver (IL-1ß: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1ß: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid (p = 0.225), liver (p = 0.186), or kidney (p = 0.637). CONCLUSION: Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.

PGD: Shared gene linking polycystic ovary syndrome and endometrial cancer, influencing proliferation and migration through glycometabolism.

The relationship among polycystic ovary syndrome (PCOS), endometrial cancer (EC), and glycometabolism remains unclear. We explored shared genes between PCOS and EC, using bioinformatics to unveil their pathogenic connection and influence on EC prognosis. Gene Expression Omnibus datasets GSE226146 (PCOS) and GSE196033 (EC) were used. A protein-protein interaction (PPI) network was constructed to identify the central genes. Candidate markers were screened using dataset GSE54250. Differences in marker expression were confirmed in mouse PCOS and human EC tissues using RT-PCR and immunohistochemistry. The effect of PGD on EC proliferation and migration was explored using Ki-67 and Transwell assays. PGD's impact on the glycometabolic pathway within carbon metabolism was assessed by quantifying glucose content and lactic acid production. R software identified 31 common genes in GSE226146 and GSE196033. Gene Ontology functional classification revealed enrichment in the "purine nucleoside triphosphate metabolism process," with key Kyoto Encyclopedia of Genes and Genomes pathways related to "carbon metabolism." The PPI network identified 15 hub genes. HK2, NDUFS8, PHGDH, PGD, and SMAD3 were confirmed as candidate markers. The RT-PCR analysis validated distinct HK2 and PGD expression patterns in mouse PCOS ovarian tissue and human EC tissue, as well as in normal and EC cells. Transfection experiments with Ishikawa cells further confirmed PGD's influence on cell proliferation and migration. Suppression of PGD expression impeded glycometabolism within the carbon metabolism of EC cells, suggesting PGD as a significant PCOS risk factor impacting EC proliferation and migration through modulation of single carbon metabolism. These findings highlight PGD's pivotal role in EC onset and prognosis.

Advance on Chinese Medicine for Hypertensive Renal Damage: Focus on the Complex Molecular Mechanisms.

Hypertensive renal damage (HRD) is a major cause of end-stage renal disease. Among the causes of end-stage renal disease, HRD accounts for nearly 34% of the total number of cases. Antihypertensive treatment is primarily drug-based, but therapeutic efficacy is less effective and can have serious side effects. Chinese medicine (CM) has significant advantages in the treatment of HRD. CM is rich in various active ingredients and has the property of targeting multiple targets and channels. Therefore, the regulatory network of CM on disease is complex. A large number of CM have been employed to treat HRD, either as single applications or as part of compound formulations. The key possible mechanisms of CM for HRD include regulation of the renin-angiotensin-aldosterone system, antioxidation, anti-inflammation, rescue of endothelial function, regulation of vasoactive substance secretion and obesity-related factors, etc. This review summarized and discussed the recent advance in the basic research mechanisms of CM interventions for HRD and pointed out the challenges and future prospects.

Protein and metabolic profiles of tyrosine kinase inhibitors co-resistant liver cancer cells.

Hepatocellular Carcinoma (HCC) patients often develop resistance to tyrosine kinase inhibitors (TKIs) like sorafenib (SR) and lenvatinib (RR). We established HCC cell lines resistant to these drugs and analyzed the correlation between protein and metabolite profiles using bioinformatics. Our analysis revealed overexpression of MISP, CHMP2B, IL-18, TMSB4X, and EFEMP1, and downregulation of IFITM3, CA4, AGR2, and SLC51B in drug-resistant cells. Differential signals are mainly enriched in steroid hormone biosynthesis, cell adhesion, and immune synapses, with metabolic pathways including cytochrome P450 drug metabolism, amino acid metabolism, and glycolysis. Proteomics and metabolomics analysis showed co-enrichment signals in drug metabolism, amino acids, glucose metabolism, ferroptosis, and other biological processes. Knocking down MISP, CHMP2B, IL-18, TMSB4X, and EFEMP1 significantly reduced drug resistance, indicating their potential as therapeutic response biomarkers. This study characterizes protein and metabolic profiles of drug-resistant HCC cells, exploring metabolite-protein relationships to enhance understanding of drug resistance mechanisms and clinical treatment.

Resilience and adaptation: a mixed-methods exploration of COVID-19's influence on neonatal residency education in China.

BACKGROUND: This study aimed to assess the impact of the pandemic of the coronavirus disease 2019 (COVID-19) on neonatology residency training in a tertiary children's hospital in Chongqing, located in southwest China. Specifically, the study encompassed the effects on residents' education, lived experiences, well-being, and the quality of neonatal care delivered. As higher educational institutions adapt to the post-COVID-19 era after the pandemic disruption, it is imperative that educational designers/academics learn from their experiences and challenges in curriculum design and delivery, ensuring quality and relevance in education. METHODS: This study employed a mixed-methods approach to investigate the influence of the COVID-19 pandemic on neonatology residency training at a tertiary children's hospital in Chongqing. The first phase surveyed residents' perceptions and experiences of their clinical education and well-being during the crisis. The second phase compared the quality of neonatal care between the pre-pandemic and pandemic periods. RESULTS: The survey of 123 neonatology residents examines the effects of COVID-19 on their learning, training, and mental health. The survey showed that most residents adapted well to the situation. Still, some faced challenges in their clinical education and experiences, such as reduced clinical exposure and opportunities to see rare diseases and conditions. A retrospective analysis of clinical data revealed that 7,151 neonates were admitted to the neonatology department during the study period. There was a 27.6% decrease in neonatal admissions during COVID-19, with more premature births and transfers. Residents conducted fewer clinical procedures but managed more complex cases. During COVID, hospital stays and costs were higher, but antibiotic use was lower. Although the case-mix index (CMI) score increased during the pandemic (1.25 vs. 1.18, p < 0.05), there was no significant difference in the rates of readmission within 7 days or poor prognosis. CONCLUSIONS: Despite reduced clinical exposure, the quality of neonatal care was maintained through innovative training methods that enhanced comprehensive residency programs. The study suggested that neonatology residency education remained effective and resilient during the crisis. Exceptional health professional education is vital to train qualified physicians and enhance healthcare systems for future challenges.

WTAP participates in neuronal damage by protein translation of NLRP3 in an m6A-YTHDF1-dependent manner after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a common complication of acute and severe neurosurgery. Remodeling of N6-methyladenosine (m6A) stabilization may be an attractive treatment option for neurological dysfunction after TBI. In the present study, we explored the epigenetic methylation of RNA-mediated NLRP3 inflammasome activation after TBI. METHODS: Neurological dysfunction, histopathology, and associated molecules were examined in conditional knockout (CKO) WTAP[flox/flox, Camk2a-cre], WTAPflox/flox, and pAAV-U6-shRNA-YTHDF1-transfected mice. Primary neurons were used in vitro to further explore the molecular mechanisms of action of WTAP/YTHDF1 following neural damage. RESULTS: We found that WTAP and m6A levels were upregulated at an early stage after TBI, and conditional deletion of WTAP in neurons did not affect neurological function but promoted functional recovery after TBI. Conditional deletion of WTAP in neurons suppressed neuroinflammation at the TBI early phase: WTAP could directly act on NLRP3 mRNA, regulate NLRP3 mRNA m6A level, and promote NLRP3 expression after neuronal injury. Further investigation found that YTH domain of YTHDF1 could directly bind to NLRP3 mRNA and regulate NLRP3 protein expression. YTHDF1 mutation or silencing improved neuronal injury, inhibited Caspase-1 activation, and decreased IL-1ß levels. This effect was mediated via suppression of NLRP3 protein translation, which also reversed the stimulative effect of WTAP overexpression on NLRP3 expression and inflammation. CONCLUSION: Our results indicate that WTAP participates in neuronal damage by protein translation of NLRP3 in an m6A-YTHDF1-dependent manner after TBI and that WTAP/m6A/YTHDF1 downregulation therapeutics is a viable and promising approach for preserving neuronal function after TBI, which can provide support for targeted drug development.

Health-SigQOLM is a versatile scale for measuring various aspects of health-related quality of life.

OBJECTIVE: The "Health" element is one of the elements in Significant Quality of Life Measure (SigQOLM) that measures quality of life and well-being of people. This study aims to evaluate the Health element (Health-SigQOLM) as a generic and dynamic scale to measure health-related quality of life (HRQOL) with a broader spectrum of coverage. This study used a secondary data that developed SigQOLM. Only the "Health" element with 33 items is used for analysis. RESULTS: The construct of Health-SigQOLM has a minimum factor loading of 0.425 with excellent model fit. The health status among healthcare workers is significantly associated with the Health-SigQOLM (p < 0.001). The Health-SigQOLM score can clearly distinguish between healthy people and those who have been afflicted with some diseases but have never been hospitalized due to disease progression or other associated complications (p = 0.002). The Health-SigQOLM is a generic and dynamic tool for assessing various aspects of health-related quality of life.

Study on the photosynthetic growth characters in Cimicifuga dahurica (Turcz.) Maxim under different supplemental light environments.

Cimicifuga dahurica (C. dahurica) is an important medicinal plant in the northern region of China. The best supplemental light environment helps plant growth, development, and metabolism. In this study, we used two-year-old seedlings as experimental materials. The white light as the control (CK). The different ratios of red (R) and blue (B) combined light were supplemented (T1, 2R: 1B, 255.37 µmol m-2·s-1; T2, 3R: 1B, 279.69 µmol m-2·s-1; T3, 7R: 1B, 211.16 µmol m-2·s-1). The growth characteristics, photosynthetic pigment content, photosynthesis and chlorophyll fluorescence parameters, and primary metabolite content were studied in seedlings. The results showed that: 1) The fresh weight from shoot, root, and total fresh weight were significantly (P < 0.05) increased under T2 and T3 treatment. 2) The contents of chlorophyll a (Chl a), chlorophyll b (Chl b), and total chlorophyll (Chl) were significantly (P < 0.05) increased under T2 treatment, and carotenoid (car) content was reduced. 3) The photochemical quenching (qP), the actual photosynthetic efficiency of PSII (Y(II)), and the photosynthetic electron transfer rate (ETR) from leaves were significantly (P < 0.05) increased under T1 treatment. The Net photosynthetic rate (Pn), stomatal conductance (Gs), intercellular CO2 concentration (Ci), and transpiration rate (Tr) were significantly (P < 0.05) increased under T2 and T3 treatments. 4) A total of 52 primary metabolites were detected in C. dahurica leaves. Compared with CK, 14, 15, and 18 differential metabolites were screened under T1, T2, and T3 treatments. In addition, D-xylose, D-glucose, glycerol, glycolic acid, and succinic acid were significantly (P < 0.05) accumulated under the T2 treatment, which could regulate the TCA cycle metabolism pathway. The correlation analysis suggested that plant growth was promoted by regulating the change of D-mannose content in galactinol metabolism and amino sugar and nucleotide sugar metabolism. In summary, the growth of C. dahurica was improved under T2 treatment.

Dysfunction of Complementarity Determining Region 1 Encoded by T Cell Receptor Beta Variable Gene Is Potentially Associated with African Swine Fever Virus Infection in Pigs.

The beta T-cell receptor (TRB) expressed by beta T cells is essential for foreign antigen recognition. The TRB locus contains a TRBV family that encodes three complementarity determining regions (CDRs). CDR1 is associated with antigen recognition and interactions with MHC molecules. In contrast to domestic pigs, African suids lack a 284-bp segment spanning exons 1 and 2 of the TRBV27 gene that contains a sequence encoding CDR1. In this study, we used the African swine fever virus (ASFV) as an example to investigate the effect of deleting the TRBV27-encoded CDR1 on the resistance of domestic pigs to exotic pathogens. We first successfully generated TRBV27-edited fibroblasts with disruption of the CDR1 sequence using CRISPR/Cas9 technology and used them as donor cells to generate gene-edited pigs via somatic cell nuclear transfer. The TRBV-edited and wild-type pigs were selected for synchronous ASFV infection. White blood cells were significantly reduced in the genetically modified pigs before ASFV infection. The genetically modified and wild-type pigs were susceptible to ASFV and exhibited typical fevers (>40 °C). However, the TRBV27-edited pigs had a higher viral load than the wild-type pigs. Consistent with this, the gene-edited pigs showed more clinical signs than the wild-type pigs. In addition, both groups of pigs died within 10 days and showed similar severe lesions in organs and tissues. Future studies using lower virulence ASFV isolates are needed to determine the relationship between the TRBV27 gene and ASFV infection in pigs over a relatively long period.

Generation and transcriptomic characterization of MIR137 knockout miniature pig model for neurodevelopmental disorders.

BACKGROUND: Neurodevelopmental disorders (NDD), such as autism spectrum disorders (ASD) and intellectual disorders (ID), are highly debilitating childhood psychiatric conditions. Genetic factors are recognized as playing a major role in NDD, with a multitude of genes and genomic regions implicated. While the functional validation of NDD-associated genes has predominantly been carried out using mouse models, the significant differences in brain structure and gene function between mice and humans have limited the effectiveness of mouse models in exploring the underlying mechanisms of NDD. Therefore, it is important to establish alternative animal models that are more evolutionarily aligned with humans. RESULTS: In this study, we employed CRISPR/Cas9 and somatic cell nuclear transplantation technologies to successfully generate a knockout miniature pig model of the MIR137 gene, which encodes the neuropsychiatric disorder-associated microRNA miR-137. The homozygous knockout of MIR137 (MIR137-/-) effectively suppressed the expression of mature miR-137 and led to the birth of stillborn or short-lived piglets. Transcriptomic analysis revealed significant changes in genes associated with neurodevelopment and synaptic signaling in the brains of MIR137-/- miniature pig, mirroring findings from human ASD transcriptomic data. In comparison to miR-137-deficient mouse and human induced pluripotent stem cell (hiPSC)-derived neuron models, the miniature pig model exhibited more consistent changes in critical neuronal genes relevant to humans following the loss of miR-137. Furthermore, a comparative analysis identified differentially expressed genes associated with ASD and ID risk genes in both miniature pig and hiPSC-derived neurons. Notably, human-specific miR-137 targets, such as CAMK2A, known to be linked to cognitive impairments and NDD, exhibited dysregulation in MIR137-/- miniature pigs. These findings suggest that the loss of miR-137 in miniature pigs affects genes crucial for neurodevelopment, potentially contributing to the development of NDD. CONCLUSIONS: Our study highlights the impact of miR-137 loss on critical genes involved in neurodevelopment and related disorders in MIR137-/- miniature pigs. It establishes the miniature pig model as a valuable tool for investigating neurodevelopmental disorders, providing valuable insights for potential applications in human research.