Genetic and phenotypic analysis of 225 Chinese children with developmental delay and/or intellectual disability using whole-exome sequencing.

Developmental delay (DD), or intellectual disability (ID) is a very large group of early onset disorders that affects 1-2% of children worldwide, which have diverse genetic causes that should be identified. Genetic studies can elucidate the pathogenesis underlying DD/ID. In this study, whole-exome sequencing (WES) was performed on 225 Chinese DD/ID children (208 cases were sequenced as proband-parent trio) who were classified into seven phenotype subgroups. The phenotype and genomic data of patients with DD/ID were further retrospectively analyzed. There were 96/225 (42.67%; 95% confidence interval [CI] 36.15-49.18%) patients were found to have causative single nucleotide variants (SNVs) and small insertions/deletions (Indels) associated with DD/ID based on WES data. The diagnostic yields among the seven subgroups ranged from 31.25 to 71.43%. Three specific clinical features, hearing loss, visual loss, and facial dysmorphism, can significantly increase the diagnostic yield of WES in patients with DD/ID (P = 0.005, P = 0.005, and P = 0.039, respectively). Of note, hearing loss (odds ratio [OR] = 1.86%; 95% CI = 1.00-3.46, P = 0.046) or abnormal brainstem auditory evoked potential (BAEP) (OR = 1.91, 95% CI = 1.02-3.50, P = 0.042) was independently associated with causative genetic variants in DD/ID children. Our findings enrich the variation spectrums of SNVs/Indels associated with DD/ID, highlight the value genetic testing for DD/ID children, stress the importance of BAEP screen in DD/ID children, and help to facilitate early diagnose, clinical management and reproductive decisions, improve therapeutic response to medical treatment.

Genome-wide identification of GATA transcription factor family and the effect of different light quality on the accumulation of terpenoid indole alkaloids in Uncaria rhynchophylla.

Uncaria rhynchophylla is an evergreen vine plant, belonging to the Rubiaceae family, that is rich in terpenoid indole alkaloids (TIAs) that have therapeutic effects on hypertension and Alzheimer's disease. GATA transcription factors (TF) are a class of transcription regulators that participate in the light response regulation, chlorophyll synthesis, and metabolism, with the capability to bind to GATA cis-acting elements in the promoter region of target genes. Currently the charactertics of GATA TFs in U. rhynchophylla and how different light qualities affect the expression of GATA and key enzyme genes, thereby affecting the changes in U. rhynchophylla alkaloids have not been investigated. In this study, 25 UrGATA genes belonging to four subgroups were identified based on genome-wide analysis. Intraspecific collinearity analysis revealed that only segmental duplications were identified among the UrGATA gene family. Collinearity analysis of GATA genes between U. rhynchophylla and four representative plant species, Arabidopsis thaliana, Oryza sativa, Coffea Canephora, and Catharanthus roseus was also performed. U. rhynchophylla seedlings grown in either red lights or under reduced light intensity had altered TIAs content after 21 days. Gene expression analysis reveal a complex pattern of expression from the 25 UrGATA genes as well as a number of key TIA enzyme genes. UrGATA7 and UrGATA8 were found to have similar expression profiles to key enzyme TIA genes in response to altered light treatments, implying that they may be involved in the regulation TIA content. In this research, we comprehensively analyzed the UrGATA TFs, and offered insight into the involvement of UrGATA TFs from U. rhynchophylla in TIAs biosynthesis.

Multiparameter Assessment of Foam Cell Formation Progression Using a Dual-Color Switchable Fluorescence Probe.

The assessment of atherosclerosis (AS) progression has emerged as a prominent area of research. Monitoring various pathological features of foam cell (FC) formation is imperative to comprehensively assess AS progression. Herein, a simple benzospiropyran-julolidine-based probe, BSJD, with switchable dual-color imaging ability was developed. This probe can dynamically and reversibly adjust its molecular structure and fluorescent properties in different polar and pH environments. Such a polarity and pH dual-responsive characteristic makes it superior to single-responsive probes in dual-color imaging of lipid droplets (LDs) and lysosomes as well as monitoring their interaction. By simultaneously tracking various pathological features, including LD accumulation and size changes, lysosome dysfunction, and dynamically regulated lipophagy, more comprehensive information can be obtained for multiparameter assessment of FC formation progression. Using BSJD, not only the activation of lipophagy in the early stages and inhibition in the later phases during FC formation are clearly observed but also the important roles of lipophagy in regulating lipid metabolism and alleviating FC formation are demonstrated. Furthermore, BSJD is demonstrated to be capable of rapidly imaging FC plaque sites in AS mice with fast pharmacokinetics. Altogether, BSJD holds great promise as a dual-color organelle-imaging tool for investigating disease-related LD and lysosome changes and their interactions.

Intelligent Cell Profiling and Precision Release: Multimolecular Marker-Activated Transmembrane DNA Computing Nanosystem.

Accurate classification of tumor cells is of importance for cancer diagnosis and further therapy. In this study, we develop multimolecular marker-activated transmembrane DNA computing systems (MTD). Employing the cell membrane as a native gate, the MTD system enables direct signal output following simple spatial events of "transmembrane" and "in-cell target encounter", bypassing the need of multistep signal conversion. The MTD system comprises two intelligent nanorobots capable of independently sensing three molecular markers (MUC1, EpCAM, and miR-21), resulting in comprehensive analysis. Our AND-AND logic-gated system (MTDAND-AND) demonstrates exceptional specificity, allowing targeted release of drug-DNA specifically in MCF-7 cells. Furthermore, the transformed OR-AND logic-gated system (MTDOR-AND) exhibits broader adaptability, facilitating the release of drug-DNA in three positive cancer cell lines (MCF-7, HeLa, and HepG2). Importantly, MTDAND-AND and MTDOR-AND, while possessing distinct personalized therapeutic potential, share the ability of outputting three imaging signals without any intermediate conversion steps. This feature ensures precise classification cross diverse cells (MCF-7, HeLa, HepG2, and MCF-10A), even in mixed populations. This study provides a straightforward yet effective solution to augment the versatility and precision of DNA computing systems, advancing their potential applications in biomedical diagnostic and therapeutic research.

Establishment of a placental lncRNA-mRNA expression network for early-onset preeclampsia.

BACKGROUND: This study aimed to establish a placental long non-coding RNA (lncRNA)-mRNA expression network for early-onset preeclampsia (early-onset PE). METHODS: The RNA sequencing data of the GSE14821 dataset were acquired. Several crucial lncRNAs and mRNAs were exerted based on the differential expression analysis of lncRNA and mRNA. By analyzing the differentially expressed lncRNA and mRNA, we constructed a regulatory network to explore the mechanism of the lncRNA in early onset preeclampsia. RESULTS: A total of 4436 differentially expressed lncRNAs (DElncRNAs) were identified in early-onset PE placenta samples compared with control placenta samples. Pearson correlation analysis revealed significant correlations between 3659 DElncRNAs and 372 DEmRNAs. KEGG analysis showed that the DEmRNAs were enriched in cytokine-cytokine receptor and hypoxia-inducible factor (HIF)-1 pathways. Several well-known early-onset PE-related mRNAs, such as vascular endothelial growth factor A (VEGFA) and VEGF receptor 1 (FLT1), were involved in the two pathways. Weighted gene co-expression network analysis and cis-regulatory analysis further suggested the involvement of the two pathways and potential DElncRNA-DEmRNA interactions in early-onset PE. Moreover, the upregulation of representative DElncRNAs, such as RP11-211G3.3 and RP11-65J21.3, and DEmRNAs, such as VEGFA and FLT1, were validated in clinical placenta samples from patients with early-onset PE by quantitative reverse transcription PCR. Importantly, overexpression of RP11-65J21.3 significantly promoted the proliferation of HTR-8 trophoblast cells at 72 h after transfection. CONCLUSIONS: In conclusion, we identified placental DElncRNAs of early-onset PE and established a DElncRNA-DEmRNA network that was closely related to the cytokine-cytokine receptor and HIF-1 pathways. Our results provide potential diagnostic markers and therapeutic targets for early-onset PE management.

ASReml-based estimation of early genetic parameters in hybrid mutton sheep populations.

The aim of this study was to analyze the effects of non-genetic factors on the estimation of genetic parameters of early growth traits in hybrid mutton sheep using ASReml software, in order to provide theoretical basis for screening the optimal hybriding combinations and accelerating the breeding process of new breeds of specialized housed-feeding mutton sheep. We selected the wellgrown hybrid Southhu (Southdown × Hu sheep) and Dorhu (Dorset × Hu sheep) sheep as the research objects, constructed weight correction formulae for SH and DH sheep at 60 and 180 days; and used ASReml software to investigate the effects of non-genetic factors on the estimation of genetic parameters of early growth traits in hybrid sheep. The results showed that the birth month and birth type were found significant for all traits (p < 0.001); the heritability of maternal effects ranged from 0.0709 to 0.1859. It was found that both SH and DH sheep emerged the potential for rapid early growth and development, early growth traits are significantly affected by maternal genetic effects, thereby the maternal effect should be taken into consideration for the purpose of improving accuracy in parameter estimations and therefore increasing the success of breeding programs.

Online-to-offline combined with problem-based learning is an effective teaching modality in the standardized residency training of nephrology.

BACKGROUND: The online-to-offline (O2O) teaching method is recognized as a new educational model that integrates network learning into offline classroom education, while problem-based learning (PBL) is a teaching modality that guides students to apply acquired theoretical knowledge to solve practical problems. However, implementing O2O combined with PBL has not been extensively explored in nephrology residency training. This study aims to explore the efficacy of O2O combined with PBL in the standardized residency training of nephrology by comparing it with the traditional lecture-based teaching (LBT). METHODS: Sixty residency trainees who participated in the standardized training of internal medicine in the nephrology department of the Second Affiliated Hospital of Zhejiang University School of Medicine were equally allocated into O2O combined with PBL (O2O/PBL) or the LBT group demographically matched. Examinations of theory, practice skills, clinical thinking and teaching satisfaction surveys were utilized to assess the teaching effects of the two groups. RESULTS: Participants from the O2O/PBL group outperformed those from the LBT group in the examination of theory (81.233 ± 9.156 vs. 75.800 ± 7.009, mean ± SEM), practice skills (104.433 ± 3.569 vs.100.316 ± 4.628, mean ± SEM) and clinical thinking (88.933 ± 4.473 vs. 86.667 ± 3.844, mean ± SEM). There was no significant difference in the teaching satisfaction between the two groups. CONCLUSION: The current study shows the positive impact of O2O combined with PBL approach on standardized residency training in nephrology without reducing teaching satisfaction.

Genome-Wide Identification of Seven in Absentia E3 Ubiquitin Ligase Gene Family and Expression Profiles in Response to Different Hormones in Uncaria rhynchophylla.

SINA (Seven in absentia) E3 ubiquitin ligases are a family of RING (really interesting new gene) E3 ubiquitin ligases, and they play a crucial role in regulating plant growth and development, hormone response, and abiotic and biotic stress. However, there is little research on the SINA gene family in U. rhynchophylla. In this study, a total of 10 UrSINA genes were identified from the U. rhynchophylla genome. The results of multiple sequence alignments and chromosomal locations show that 10 UrSINA genes were unevenly located on 22 chromosomes, and each UrSINA protein contained a SINA domain at the N-terminal and RING domains at the C-terminal. Synteny analysis showed that there are no tandem duplication gene pairs and there are four segmental gene pairs in U. rhynchophylla, contributing to the expansion of the gene family. Furthermore, almost all UrSINA genes contained the same gene structure, with three exons and two introns, and there were many cis-acting elements relating to plant hormones, light responses, and biotic and abiotic stress. The results of qRT-PCR show that most UrSINA genes were expressed in stems, with the least expression in roots; meanwhile, most UrSINA genes and key enzyme genes were responsive to ABA and MeJA hormones with overlapping but different expression patterns. Co-expression analysis showed that UrSINA1 might participate in the TIA pathway under ABA treatment, and UrSINA5 and UrSINA6 might participate in the TIA pathway under MeJA treatment. The mining of UrSINA genes in the U. rhynchophylla provided novel information for understanding the SINA gene and its function in plant secondary metabolites, growth, and development.

The Upregulation of Leucine-Rich Repeat Containing 1 Expression Activates Hepatic Stellate Cells and Promotes Liver Fibrosis by Stabilizing Phosphorylated Smad2/3.

Liver fibrosis poses a significant global health risk due to its association with hepatocellular carcinoma (HCC) and the lack of effective treatments. Thus, the need to discover additional novel therapeutic targets to attenuate liver diseases is urgent. Leucine-rich repeat containing 1 (LRRC1) reportedly promotes HCC development. Previously, we found that LRRC1 was significantly upregulated in rat fibrotic liver according to the transcriptome sequencing data. Herein, in the current work, we aimed to explore the role of LRRC1 in liver fibrosis and the underlying mechanisms involved. LRRC1 expression was positively correlated with liver fibrosis severity and significantly elevated in both human and murine fibrotic liver tissues. LRRC1 knockdown or overexpression inhibited or enhanced the proliferation, migration, and expression of fibrogenic genes in the human hepatic stellate cell line LX-2. More importantly, LRRC1 inhibition in vivo significantly alleviated CCl4-induced liver fibrosis by reducing collagen accumulation and hepatic stellate cells' (HSCs) activation in mice. Mechanistically, LRRC1 promoted HSC activation and liver fibrogenesis by preventing the ubiquitin-mediated degradation of phosphorylated mothers against decapentaplegic homolog (Smad) 2/3 (p-Smad2/3), thereby activating the TGF-ß1/Smad pathway. Collectively, these results clarify a novel role for LRRC1 as a regulator of liver fibrosis and indicate that LRRC1 is a promising target for antifibrotic therapies.

The use of bimetallic metal-organic frameworks as restoration materials for pollutants removal from water environment.

Bimetallic metal-organic frameworks (BMOFs) are a class of functional porous materials constructed by coordination between nodes containing two different metal ions and organic ligands. Studies have shown that the catalytic activity of BMOFs is greatly improved owing to the adjustment of charge distribution and the increase of active sites as well as the synergistic effect between the bimetals, and the advantages of their large specific surface area, high porosity, unique structure and dispersed active centres make them available as important organic materials applied in the field of wastewater treatment. In this review, the preparation and construction methods for BMOFs in recent years are summarized, and we focus on their removal of different types of pollutants in the aqueous environment, including ions, dyes, pharmaceuticals or personal care products, phenolic compounds and microorganisms, as well as their corresponding removal mechanisms. In addition, we provide an outlook on their future opportunities and challenges in wastewater treatment.

Metabolomics comparison of metabolites and functional pathways in the SH-SY5Y cell model of Parkinson's disease under PEMF exposure.

Objective: PEMF is an emerging technique in the treatment of Parkinson's disease (PD) due to its potential improvement of movement speed. The aim of this study was to investigate the metabolic profiles of pulsed electromagnetic fields (PEMFs) in an SH-SY5Y cell model of PD. Methods: The SH-SY5Y cell model of PD was induced by 1-methyl-4-phenylpyridinium (MPP+). Liquid chromatography mass spectrometry (LC‒MS)-based untargeted metabolomics was performed to examine changes in the PD cell model with or without PEMF exposure. We conducted KEGG pathway enrichment analysis to explore the potentially related pathways of the differentially expressed metabolites. Results: A total of 275 metabolites were annotated, and 27 significantly different metabolites were found between the PEMF treatment and control groups (VIP >1, P < 0.05), mainly including 4 amino acids and peptides, 4 fatty acid esters, 2 glycerophosphoethanolamines, 2 ceramides and 2 monoradylglycerols; among them, 12 metabolites were upregulated, and 15 were downregulated. The increased expression levels of glutamine, adenosine monophosphate and taurine were highly associated with PEMF stimulation in the PD model. The enrichment results of differentially abundant metabolite functional pathways showed that biological processes such as the mTOR signaling pathway, PI3K-Akt signaling pathway, and cAMP signaling pathway were significantly affected. Conclusion: PEMFs affected glutamine, adenosine monophosphate and taurine as well as their functional pathways in an in vitro model of PD. Further functional studies regarding the biological effect of these changes are required to evaluate the clinical efficacy and safety of PEMF treatment in PD.

Structural Elucidation and Anti-Tumor Activity of a Polysaccharide (CP2-S) from Cordyceps militaris Fruit Bodies.

A polysaccharide (CP2-S), consisting of glucose with a weight average molecular weight of 5.9 × 106, was purified from the fruit bodies of Cordyceps militaris. In this work, the corresponding structure and anti-tumor activity in vivo were investigated. Methylation and NMR analysis revealed that CP2-S was composed of a →4)-α-D-Glcp-(1→ backbone with partial substitution occurring at O-6 by T-linked α-D-Glcp in every ten residues, which has not been reported in previous reports. In vivo anti-tumor experiments showed that CP2-S could inhibit the growth of Lewis lung carcinoma in mice. Tumor inhibition rates were 17.8%, 24.5%, and 29.5% at dosages of 12.5, 50, and 100 mg/kg/d, respectively. Compared with the cisplatin group, mice treated with CP2-S exhibited a significant increase in spleen index (increased 22.7-42.4%) and thymus index (increased 47.7-36.8%). Additionally, serum levels of IgM and IgG in tumor-bearing mice increased by approximately 6.11~10.75-folds and 1.31~1.38-folds, respectively. These findings prove that CP2-S significantly inhibited the growth of Lewis lung carcinoma through immune-enhancing activity in mice.

The effects of football juggling learning on executive function and brain functional connectivity.

This study aimed to explore the relationship between motor skill learning and executive function (EF), with an emphasis on the potential effects of football juggling learning. A randomized controlled trial involving 111 participants aged 17-19 years was conducted. Participants were randomly assigned to either the football juggling learning (FJL) group or a control group. The FJL group underwent 70 sessions of football juggling learning, while the control group engaged in their normal daily activities without any exercise intervention during the same time frame. Both groups were assessed for EF performance and underwent functional magnetic resonance imaging (fMRI) scans before and after the experiment. The executive function test included three tasks, namely, inhibition, working memory, and shifting. The results showed significant improvement in inhibition and shifting in both groups, and the FJL group showed greater improvement in these aspects of EF compared to the control group. Additionally, in comparison to the control group, the FJL group exhibited increased functional connectivity within the frontal, temporal, and cerebellar regions from the pre-test to the post-test. Notably, enhanced functional connectivity between the right superior temporal gyrus (posterior division) and left cerebellum 6 was identified in the FJL group and was associated with improved EF performance induced by football juggling learning. These findings shed light on the potential causal relationship between motor skill learning, EF, and brain plasticity. Importantly, our study provides preliminary evidence supporting the use of motor skill learning, such as football juggling, as a potential avenue for cognitive enhancement.

Synergistic catalysis: cobalt-catalyzed cascade reaction for the oxidative cleavage of olefins to access esters.

An efficient strategy for the oxidative cleavage of CC bonds in olefins to form esters with one or multiple carbon atoms less over heterogeneous cobalt/nitrogen-doped carbon catalyst with dioxygen as the oxidant was described. The protocol features a wide substrate range including the challenging inactive aliphatic and long-chain alkyl aryl olefins. The reactivity of the catalyst did not decrease after reused for seven times. Characterization and control experiments reveal that synergistic effects between the metallic Co nanoparticles and Co-Nx sites provide access to the excellent catalytic activity.

Effects of mini-basketball training program on social communication impairments and regional homogeneity of brain functions in preschool children with autism spectrum disorder.

BACKGROUND: Social communication impairments (SCI) is a core symptom of autism spectrum disorder (ASD) and is marked by challenges in social interaction. Although physical exercise has been shown to improve SCI, this finding has not been supported by comprehensive scientific evidence. Existing research has established a strong link between the SCI in children with ASD and abnormalities in regional homogeneity (ReHo). Therefore, investigating the effects of physical exercise on SCI and Reho in patients with ASD may help to elucidate the neurological mechanisms involved. METHODS: The present study included 30 preschool children diagnosed with ASD, with 15 participants in each group (experimental and control). The experimental group underwent a 12-week mini-basketball training program (MBTP) based on routine behavioral rehabilitation, while the control group only received routine behavioral rehabilitation. The Social Responsiveness Scale-Second Edition (SRS-2) was employed to assess SCI in both groups. Resting-state functional magnetic resonance imaging technology was used to evaluate ReHo in both groups. RESULTS: After 12-week of MBTP, significant group × time interactions were observed between the experimental and control groups in total SRS-2 scores (F = 14.514, p < 0.001, ηp2 = 0.341), as well as in the domains of social cognition (F = 15.620, p < 0.001, ηp2 = 0.358), social communication (F = 12.460, p < 0.01, ηp2 = 0.308), and autistic mannerisms (F = 9.970, p < 0.01, ηp2 = 0.263). No statistical difference was found in the scores for the social awareness subscale and social motivation subscale in the group × time interaction (all p > 0.05). The experimental group exhibited increased ReHo in the right Cerebellum_Crus1 and right parahippocampal gyrus, coupled with decreased ReHo in the left middle frontal gyrus (orbital part), left superior frontal gyrus (dorsolateral), left postcentral gyrus, and right superior parietal gyrus. Furthermore, a decrease in ReHo in the left postcentral gyrus positively correlated with changes in social communication scores in SCI behaviors (p < 0.05). CONCLUSIONS: Our study underscores the effectiveness of a 12-week MBTP in ameliorating SCI and abnormalities in ReHo among preschool children with ASD. TRIAL REGISTRATION: The trial is retrospectively registered on the Chinese Clinical Trial Registry (ChiCTR1900024973; August 5, 2019).

Genome-Wide Mining of CULLIN E3 Ubiquitin Ligase Genes from Uncaria rhynchophylla.

CULLIN (CUL) protein is a subtype of E3 ubiquitin ligase that is involved in a variety of biological processes and responses to stress in plants. In Uncaria rhynchophylla, the CUL gene family has not been identified and its role in plant development, stress response and secondary metabolite synthesis has not been studied. In this study, 12 UrCUL gene members all contained the typical N-terminal domain and C-terminal domain identified from the U. rhynchophylla genome and were classified into four subfamilies based on the phylogenetic relationship with CULs in Arabidopsis thaliana. They were unevenly distributed on eight chromosomes but had a similar structural composition in the same subfamily, indicating that they were relatively conserved and potentially had similar gene functions. An interspecific and intraspecific collinearity analysis showed that fragment duplication played an important role in the evolution of the CUL gene family. The analysis of the cis-acting elements suggests that the UrCULs may play an important role in various biological processes, including the abscisic acid (ABA) response. To investigate this hypothesis, we treated the roots of U. rhynchophylla tissue-cultured seedlings with ABA. The expression pattern analysis showed that all the UrCUL genes were widely expressed in roots with various expression patterns. The co-expression association analysis of the UrCULs and key enzyme genes in the terpenoid indole alkaloid (TIA) synthesis pathway revealed the complex expression patterns of 12 UrCUL genes and some key TIA enzyme genes, especially UrCUL1, UrCUL1-likeA, UrCUL2-likeA and UrCUL2-likeB, which might be involved in the biosynthesis of TIAs. The results showed that the UrCULs were involved in the response to ABA hormones, providing important information for elucidating the function of UrCULs in U. rhynchophylla. The mining of UrCULs in the whole genome of U. rhynchophylla provided new information for understanding the CUL gene and its function in plant secondary metabolites, growth and development.

[Analysis of the current quality of life status and influencing factors of sepsis survivors in intensive care unit].

OBJECTIVE: To explore the current situation and influencing factors of quality of life of septic patients in intensive care unit (ICU) after discharge, and to provide theoretical basis for clinical early psychological intervention and continuity of care. METHODS: A prospective observational study was conducted. The septic patients who were hospitalized in the department of critical care medicine of the Affiliated Hospital of Jining Medical University and discharged with improvement from January 1 to December 31, 2022 were selected as the research objects. The demographic information, basic diseases, infection site, vital signs at ICU admission, severity scores of the condition within 24 hours after ICU admission, various biochemical indexes, treatment process, and prognostic indexes of all the patients were recorded. All patients were assessed by questionnaire at 3 months of discharge using the 36-item short-form health survey scale (SF-36 scale), the activities of daily living scale (ADL scale), and the Montreal cognitive assessment scale (MoCA scale). Multiple linear regression was used to analyze the factors influencing the quality of life of septic patients after discharge from the hospital. RESULTS: A total of 200 septic patients were discharged with improvement and followed up at 3 months of discharge, of which 150 completed the questionnaire. Of the 150 patients, 57 had sepsis and 93 had septic shock. The total SF-36 scale score of septic patients at 3 months of discharge was 81.4±23.0, and the scores of dimensions were, in descending order, role-emotional (83.4±23.0), mental health (82.9±23.6), bodily pain (82.8±23.3), vitality (81.6±23.2), physical function (81.4±23.5), general health (81.1±23.3), role-physical (79.5±27.0), and social function (78.8±25.2). There was no statistically significant difference in the total SF-36 scale score between the patients with sepsis and septic shock (82.6±22.0 vs. 80.7±23.6, P > 0.05). Incorporating the statistically significant indicators from linear univariate analysis into multiple linear regression analysis, and the results showed that the factors influencing the quality of life of septic patients at 3 months after discharge included ADL scale score at 3 months after discharge [ß= 0.741, 95% confidence interval (95%CI) was 0.606 to 0.791, P < 0.001], length of ICU stay (ß= -0.209, 95%CI was -0.733 to -0.208, P = 0.001), duration of mechanical ventilation (ß= 0.147, 95%CI was 0.122 to 0.978, P = 0.012), total dosage of norepinephrine (ß= -0.111, 95%CI was -0.044 to -0.002, P = 0.028), mean arterial pressure (MAP) at ICU admission (ß= -0.102, 95%CI was -0.203 to -0.007, P = 0.036) and body weight (ß= 0.097, 95%CI was 0.005 to 0.345, P = 0.044). CONCLUSIONS: The quality of life of patients with sepsis at 3 months after discharge is at a moderately high level. The influencing factors of the quality of life of patients with sepsis at 3 months after discharge include the ADL scale score at 3 months after discharge, the length of ICU stay, the duration of mechanical ventilation, the total dosage of norepinephrine, MAP at ICU admission and body weight, and healthcare professionals should enhance the treatment and care of the patients during their hospitalization based on the above influencing factors, and pay attention to early psychological intervention and continued care for such patients.

CRISPR-Cas9-mediated chicken prmt5 gene knockout and its critical role in interferon regulation.

Protein arginine methyltransferase 5 (PRMT5), a type II arginine methyltransferase, controls arginine dimethylation of a variety of substrates. While many papers have reported the function of mammalian PRMT5, it remains unclear how PRMT5 functions in chicken cells. In this study, we found that chicken (ch) PRMT5 is widely expressed in a variety of chicken tissues and is distributed in both the cytoplasm and the nucleus. Ectopic expression of chPRMT5 significantly suppresses chIFN-ß activation induced by chMDA5. In addition, a prmt5 gene-deficient DF-1 cell line was constructed using CRISPR/Cas9. In comparison with the wild-type cells, the prmt5-/- DF-1 cells displays normal morphology and maintain proliferative capacity. Luciferase reporter assay and overexpression showed that prmt5-/- DF-1 cells had increased IFN-ß production. With identified chicken PRMT5 and CRISPR/Cas9 knockout performed in DF-1 cells, we uncovered a functional link of chPRMT5 in suppression of IFN-ß production and interferon-stimulated gene expression.

Characterization and functional analysis of chicken CDK protein.

The family of cell cycle-dependent kinases (CDKs) serves as catalytic subunits within protein kinase complexes, playing a crucial role in cell cycle progression. While the function of CDK proteins in regulating mammalian innate immune responses and virus replication is well-documented, their role in chickens remains unclear. To address this, we cloned several chicken CDKs, specifically CDK6 through CDK10. We observed that CDK6 is widely expressed across various chicken tissues, with localization in the cytoplasm, nucleus, or both in DF-1 cells. In addition, we also found that multiple chicken CDKs negatively regulate IFN-ß signaling induced by chicken MAVS or chicken STING by targeting different steps. Moreover, during infection with infectious bursal disease virus (IBDV), various chicken CDKs, except CDK10, were recruited and co-localized with viral protein VP1. Interestingly, overexpression of CDK6 in chickens significantly enhanced IBDV replication. Conversely, knocking down CDK6 led to a marked increase in IFN-ß production, triggered by chMDA5. Furthermore, targeting endogenous CDK6 with RNA interference substantially reduced IBDV replication. These findings collectively suggest that chicken CDKs, particularly CDK6, act as suppressors of IFN-ß production and play a facilitative role in IBDV replication.

AN698/40746067 suppresses bone marrow adiposity to ameliorate hyperlipidemia-induced osteoporosis through targeted inhibition of ENTR1.

Hyperlipidemia-induced osteoporosis is marked by increased bone marrow adiposity, and treatment with statins for hyperlipidemia often leads to new-onset osteoporosis. Endosome-associated trafficking regulator 1 (ENTR1) has been found to interact with different proteins in pathophysiology, but its exact role in adipogenesis is not yet understood. This research aimed to explore the role of ENTR1 in adipogenesis and to discover a new small molecule that targets ENTR1 for evaluating its effectiveness in treating hyperlipidemia-induced osteoporosis. We found that ENTR1 expression increased during the adipogenesis of bone marrow mesenchymal cells (BMSCs). ENTR1 gain- and loss-of-function assays significantly enhanced lipid droplets formation. Mechanistically, ENTR1 binds peroxisome proliferator-activated receptor γ (PPARγ) and enhances its expression, thereby elevating adipogenic markers including C/EBPα and LDLR. Therapeutically, AN698/40746067 attenuated adipogenesis by targeting ENTR1 to suppress PPARγ. In vivo, AN698/40746067 reduced bone marrow adiposity and bone loss, as well as prevented lipogenesis-related obesity, inflammation, steatohepatitis, and abnormal serum lipid levels during hyperlipidemia. Together, these findings suggest that ENTR1 facilitates adipogenesis by PPARγ involved in BMSCs' differentiation, and targeted inhibition of ENTR1 by AN698/40746067 may offer a promising therapy for addressing lipogenesis-related challenges and alleviating osteoporosis following hyperlipidemia.