Search

Abstract The LLaMA family, a collection of foundation language models ranging from 7B to 65B parameters, has become one of the most powerful open-source large language models (LLMs) and the popular LLM backbone of multi-modal large language models (MLLMs), widely used in computer vision and natural language understanding tasks. In particular, LLaMA3 models have recently been released and have achieved impressive performance in various domains with super-large scale pre-training on over 15T tokens of data. Given the wide application of low-bit quantization for LLMs in resource-constrained scenarios, we explore LLaMA3’s capabilities when quantized to low bit-width. This exploration can potentially provide new insights and challenges for the low-bit quantization of LLaMA3 and other future LLMs, especially in addressing performance degradation issues that suffer in LLM compression. Specifically, we comprehensively evaluate the 10 existing post-training quantization and LoRA fine-tuning (LoRA-FT) methods of LLaMA3 on 1-8 bits and various datasets to reveal the low-bit quantization performance of LLaMA3. To uncover the capabilities of low-bit quantized MLLM, we assessed the performance of the LLaMA3-based LLaVA-Next-8B model under 2-4 ultra-low bits with post-training quantization methods. Our experimental results indicate that LLaMA3 still suffers from non-negligible degradation in linguistic and visual contexts, particularly under ultra-low bit widths. This highlights the significant performance gap at low bit-width that needs to be addressed in future developments. We expect that this empirical study will prove valuable in advancing future models, driving LLMs and MLLMs to achieve higher accuracy at lower bit to enhance practicality.

Abstract Emerging evidence suggests that cancer cells may disseminate early, prior to the formation of traditional macro-metastases. However, the mechanisms underlying the seeding and transition of early disseminated cancer cells (DCCs) into metastatic tumors remain poorly understood. Through single-cell RNA sequencing, we show that early lung DCCs from esophageal squamous cell carcinoma (ESCC) exhibit a trophoblast-like ‘tumor implantation’ phenotype, which enhances their dissemination and supports metastatic growth. Notably, ESCC cells overexpressing GPRC5A demonstrate improved implantation and persistence, resulting in macro-metastases in the lungs. Clinically, elevated GPRC5A level is associated with poorer outcomes in a cohort of 148 ESCC patients. Mechanistically, GPRC5A is found to potentially interact with WWP1, facilitating the polyubiquitination and degradation of LATS1, thereby activating YAP1 signaling pathways essential for metastasis. Importantly, targeting YAP1 axis with CA3 or TED-347 significantly diminishes early implantation and macro-metastases. Thus, the GPRC5A/WWP1/LATS1/YAP1 pathway represents a crucial target for therapeutic intervention in ESCC lung metastases.

Abstract The effect of serum glucose-to-potassium ratio (GPR) on cerebrovascular diseases has been previously validated. However, the value of the GPR in patients with severe intracerebral hemorrhage (ICH) requiring ICU admission remains unclear. This study aimed to investigate the association between the GPR and the clinical prognosis of critically ill patients with ICH. This study identified patients with severe ICH requiring ICU admission from the Medical Information Mart for Intensive Care (MIMIC-IV) database and divided them into quartiles based on GPR levels. Outcomes included 30-day, 90-day, and 1-year mortality rates. The association between the GPR and clinical outcomes in critically ill patients with ICH was elucidated using Cox proportional hazards regression analysis and restricted cubic splines. In total, 2018 patients (53.8% male), with a median age of 70 years, were enrolled in the study. The 30-day, 90-day, and 1-year mortality rates were 23.9%, 30.1%, and 38.4%, respectively. Per multivariate Cox proportional hazards analysis, an elevated GPR was significantly associated with all-cause mortality. After adjusting for age, sex, Charlson Comorbidity Index, white blood cell count, red blood cell count, platelet count, and Glasgow Coma Scale, patients with an elevated GPR had a higher 30-day mortality (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.22–1.42; P

ABSTRACT: Products of lipolysis released during digestion positively affect the metabolism of newborns. In contrast to the 3-layer biological membranes covering human milk (HM) fat, the lipid droplets in infant milk formula (IMF) are covered by a single membrane composed of casein and whey proteins. To reduce the differences in lipid structure between IMF and HM, studies have used milk fat globule membrane (MFGM) components such as milk polar lipids (MPL) to prepare emulsions mimicking HM fat globules However, few studies have elucidated the effect of membrane proteins (MemP) on lipid digestion in infants. In this study, 3 kinds of emulsions were prepared: one with MPL as the interface of lipid droplets (RE-1), one with membrane protein concentrate (MPC; RE-2) as the interface of lipid droplets, and one with both MPL and MPC (1:2) as the co-interface of lipid droplets (RE-3). The interfacial coverage of the emulsions was confirmed by measuring the contents of MPL and MPC at the lipid droplet interface, and by confocal laser scanning microscopy analysis. By controlling the homogenization intensity, the specific surface area of lipid droplets was controlled at the same level among the 3 emulsions. The stability constants of the emulsions varied, and RE-1 was the most stable. During simulated in vitro infant gastrointestinal digestion, the amount of free fatty acids (FFA) released from the lipid droplets was significantly higher from those with MPC at the interface (RE-2, RE-3) than from that with MPL at the interface (RE-1). The amount of FFA released at the end of intestinal digestion of RE-1, RE-2, and RE-3 was (mean ± SD; n = 3) 255.00 ± 3.54 µmol, 328.75 ± 5.30 µmol, 298.50 ± 9.19 µmol, respectively. Compared with the lipid droplets in RE-2, those with MPL at the interface (RE-1, RE-3) released more UFA during digestion. The emulsifying activity index was highest in RE-3 (MPL and MPC co-interface). The presence of MPL at the emulsion interface increased the release of UFA, and the presence of MPC increased the release of FFA. These results show that both MPL and MemP are indispensable in the construction of MFGM. Understanding their effects on digestion can provide new strategies for the development of infant foods.

To evaluate the effects of long-term frozen storage on the flavor quality of Rosa roxburghii juice, sensory evaluation, electronic nose, and headspace solid phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) were utilized to analyze the dynamic changes of sensory and aroma characteristics of Rosa roxburghii juice at −20 ℃ for various storage times(0, 2, 4, 6, 8 M). The results revealed the identification of a total of 127 volatile compounds, the majority of which were alcohols (31), hydrocarbons (34), and esters (24). The contents of 1-hexanol, (Z)-3-hexen-1-ol, 1-octene-3-ol, linalool, 1-octanol, α-copaene, ethyl hexanoate, ethyl octanoate, and methyl eugenol decreased over time, indicating that the fragrance of green grass, fruit, and flowers may diminish over time. The concentration of nonanal increased substantially (P

Abstract Conventional dielectric solid materials, both natural and artificial, lack electromagnetic self-duality and thus require additional coatings to achieve impedance matching with free space. Here, we present a class of dielectric metamaterials that are effectively self-dual and vacuum-like, thereby exhibiting full-polarization omnidirectional impedance matching as an unusual Brewster effect extended across all incident angles and polarizations. With both birefringence and reflection eliminated regardless of wavefront and polarization, such anisotropic metamaterials could establish the electromagnetic equivalence with “stretched free space” in transformation optics, as substantiated through full-wave simulations and microwave experiments. Our findings open a practical pathway for realizing unprecedented polarization-independence and omnidirectional impedance-matching characteristics in pure dielectric solids.

Chronic kidney disease (CKD) is expected to become the fifth leading cause of death globally by 2040. Cardiovascular disease (CVD), particularly heart failure (HF), is a severe complication in CKD patients on hemodialysis. This study aimed to develop a nomogram to predict the risk of heart failure hospitalization in hemodialysis patients, providing a valuable tool for clinical decision-making. We retrospectively analyzed data from 196 patients at Kunming Yanan Hospital's hemodialysis center, including demographic, dialysis-related, and laboratory information. Significant HF predictors identified through univariate and multivariate logistic regression were age, diabetes, dialysis duration, left ventricular mass index (LVMI), albumin (ALB), and ejection fraction (EF). These predictors formed the basis of the nomogram, which demonstrated good discrimination (AUC = 0.728) and calibration (Hosmer-Lemeshow test, P = 0.463). Decision curve analysis confirmed the nomogram's clinical utility across various threshold probabilities. This study's findings can help clinicians identify high-risk patients, improving management strategies and potentially reducing HF-related hospitalizations in the hemodialysis population.

IntroductionSynbiotics have revealed the possibility of improving constipation through gut microbiota. The synergistic efficacy of Bifidobacterium animalis subsp. lactis BL-99 (BL-99) and fructooligosaccharide (FOS) on constipation have not been investigated.MethodsLoperamide-induced constipated mice model was established to explore the effect of BL-99, FOS, and BL-99+FOS on changes of defecation-related parameters, gut microbiota and metabolites.Results and discussionThe results showed that BL-99, FOS, and BL-99+FOS each alleviated constipation, with the synbiotic showing significant efficacy in the first black stool defecation time, fecal number, fecal weight, and the gastrointestinal transit rate (P < 0.05). Additionally, significant increased in serum 5-HT and IL-10 were observed in the BL-99+FOS group, alongside an increased relative abundance of Lachnospiraceae_NK4A136_group, Blautia, and Clostridium sensu stricto 1, while significantly reducing the relative abundance of Alistipes and Bacteroides. These changes facilitated alterations in short-chain fatty acids (SCFAs) metabolism, and were closely associated with the expression of genes related to the 5-HT pathway and the modulation of serum inflammatory factors. This study provides a theoretical basis for BL-99 and FOS synbiotics to improve constipation by regulating the gut microbiota and metabolites.

In this study, the magnetic CoFe2O4 was fabricated and utilized as catalysts to activate peroxymonosulfate (PMS) for removal of dibenzothiophene (DBT) in model oil with the extraction-coupled catalytic combined with oxidation desulfurization system (ECODS). The prepared magnetic CoFe2O4 was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), X-ray Photoelectron Spectroscopy (XPS), Vibrating Sample Magnetometer VSM etc. The results showed that the prepared magnetic CoFe2O4 with a large specific surface area and exhibited excellent magnetism, phase composition, crystallinity and uniform distribution of the elements. The sulfur removal of DBT in n-octane was 95 % in 60 min at 40 °C under the conditions: 6 mL of model oil (600 ppm), O/S = 3:1 and 125 mg of CoFe2O4 powder. The possible mechanism of desulfurization was proposed by GC–MS. In conclusion, CoFe2O4 magnetic nanoparticles function well in both desulfurization and catalysis for PMS.

Lewis base additives typically undergo interactions with SnI2 to achieve effective defect passivation in lead-free perovskite films. In this work, the thiophene ring in 2-thiophenethylammonium chloride (TEACl) has coordination interactions with Sn2+ and the -NH3+ therein forms hydrogen bonds with I-. This facilitates the deposition of homogeneous and dense films with fewer defects during crystallization process. Otherwise, 2-pyridinethylammonium chloride (AEPCl) gives poorly perovskite films with high defect density because of the overly strong interaction with SnI2. As a result, the average photoluminescence life time of TEACl-passivated perovskite film was substantially increased to 22.04 ns, compared with the control film (5.15 ns) and the AEPCl-passivated film (3.55 ns). Ultimately, the target solar cell with TEACl passivation presented a power conversion efficiency of 13.24% and excellent shelf-stand stability with a 90% retaining of initial efficiency after 2000 h of aging in N2 atmosphere. This work sheds new light on the structural tailoring of Lewis base passivators for efficient defect passivation in lead-free tin halide perovskites.

Objectives We aim to delineate the digestive congenital abnormalities burden in children under 14 years old between 1990 and 2021.Design We implemented data from the Global Burden of Disease (GBD) 2021 database to evaluate digestive congenital abnormalities burden with different measures in 204 countries and territories from 1990 to 2021. We present precise estimations with 95% uncertainty intervals. In addition, we computed the estimated annual percentage change (EAPC) to examine the temporal patterns of these indicators.Setting It uses prevalence, deaths and disability-adjusted life years (DALYs) data from the GBD study to analyse this issue.Participants Patients with digestive congenital abnormalities diagnosis.Outcomes Total numbers, age-standardised rates (ASRs) of prevalence, mortality and DALYs and their EAPCs were the main outcomes among children aged 0–14 years.Results In 2021, 2206.79 thousand prevalent cases were reported worldwide, with digestive congenital anomalies accounting for 47.16 thousand deaths and 4324.56 thousand DALYs among children aged 0–14 years. Digestive congenital anomalies prevalence was mitigated by 8.15% between 1990 and 2021, with the global ASR of prevalence declining to 40.09 per 100 000. Digestive congenital anomalies mortality was mitigated by 35.35% between 1990 and 2021, with an ASR of deaths declining to 0.77 per 100 000. The worldwide burden of digestive congenital anomalies decreased by 34.96% in terms of DALYs from 1990 to 2021, with an ASR of 70.44 DALYs per 100 000 population. There was a significant hindrance in the prevalence, particularly among older children. The likelihood of digestive congenital abnormalities peaked during infancy (2–4 years) in all regions.Conclusion We highlight promising global declines in the digestive congenital anomalies burden among children over the past 32 years. Prevalence, deaths and DALYs associated with these anomalies have shown consistent decreases, although regional variations persist. These findings offer crucial insights for shaping effective prevention and management strategies for paediatric digestive congenital anomalies.

IntroductionBASIC PENTACYSTEINE (BPC) is a small transcription factor family known for its role in various developmental processes in plants, particularly in binding GA motifs and regulating flower and seed development. However, research on the functional characteristics and target genes of BPCs in coconut (Cocos nucifera) is limited.MethodsIn this study, we systematically characterized the gene structure, conserved protein domains, gene expansion, and target genes of CnBPCs in the coconut genome. We conducted yeast one-hybrid (Y1H) and dual-luciferase assay to explore gene interactions. We identified genes with the GA motif in their promoter regions and combined this information with a weighted gene co-expression network to identify the target genes of CnBPCs.ResultsEight CnBPCs were identified, including three Class I CnBPCs from triplication, four Class II CnBPCs (with CnBPC6A and CnBPC6B resulting from segmental duplication), and one Class III CnBPC (CnBPC7). Three conserved DNA-binding motifs were detected, exhibiting variation in certain sites. Widespread BPC gene expansion was detected in coconut and other plant species, while only three BPCs were found in the most basal extant flowering plant. Notably, 92% of protein-coding genes contained at least one GA motif, with the (GA)3 motif being most prevalent. Genes containing the GA motif that exhibit a high expression correlation with CnBPCs, tend to interact strongly with the corresponding CnBPCs. Additionally, promoters rich in the GA motif tend to interact with all members of CnBPC. The dual-luciferase assay showed that CnBPCs could activate or repress the transcriptional activities of promoters containing either (GA)3 or (GA)11 motif but with a bias toward certain genes. Furthermore, we constructed co-expressed networks identifying 426 genes with GA motifs as potential CnBPC targets.DiscussionOur findings suggest that CnBPCs may play significant roles in seed germination, flower development, and mesocarp development by interacting with genes such as CnAG1, CnAG2, CnSTK, CnMFT, and CnCS. This study characterized CnBPCs’ binding motif and possible target genes, laying a theoretical foundation to reveal CnBPCs’ function in flower and seed development.

Summary: The relationship between heterogeneity and plant diversity remains unclear in low-resource karst. We made in situ observations at different spatial scales within a fixed plot on abandoned farmland that had been enclosed for 4 years. Species richness was spatially scale dependent, while species evenness remained consistently low across all scales. Species diversity was positively related to resource heterogeneity only at a fine scale (1 m × 1 m), mainly driven by an increase in the species richness of non-dominant groups. Resource heterogeneity reduced overall plant growth at a large scale. However, it reduced the growth of the dominant families (Asteraceae and Poaceae) at a fine scale, but promoted it at a large scale. Our results suggest that soil resource heterogeneity exerts a scale-dependent positive impact on species richness during the early restoration of abandoned farmland by low resource availability and highlight the importance of fine-scale ecological information in karst areas.

Objective The current guidelines and canonical norms of diagnosis or treatment for Post-traumatic stress disorder (PTSD) with sleep disorder are still conflicting and have not yet reached a consensus. This study aimed to unravel the most effective countermeasures between two categories (psychotherapy and pharmacotherapy) put forward by the National Institute for Health and Clinical Excellence (NICE) and World Federation of Societies of Biological Psychiatry (WFSBP) respectively to treat PTSD individuals co-exist with sleep disorders.Methods Four databases, including PubMed, EMBASE, Cochrane Library, and APA PsyNet, were searched from inception to February 02, 2023.Results Twenty articles with 24 Randomized controlled trials (RCTs) and a total number of 1,647 participants were included. As demonstrated in the network meta-analysis comparison results, CBT-I (standardized mean differences (SMD) = –1.51,95% confidence interval (CI):–2.55 to −0.47), CBT-I plus IRT (SMD = –1.71, 95%CI:–3.39, −0.03), prazosin (SMD = –0.87,95%CI:–1.59 to −0.16) and hydroxyzine (SMD = –1.06, 95%CI: −1.94 to −0.19) significantly reduced PTSD symptoms compared with placebo. In contrast to placebo, CBT-I (SMD = –5.61,95%CI:-8.82 to –2.40) significantly improved sleep quality. For nightmare severity, IRT (SMD =–0.65, 95%CI:-1.00 to −0.31), prazosin (SMD = –1.20,95%CI:–1.72 to −0.67) and hydroxyzine (SMD = –0.98,95%CI:-1.58 to −0.37) significantly reduced nightmare severity in comparison with placebo.Conclusions This study suggested that under most circumstances, psychotherapy namely CBT-I had a favorable profile, but pharmacotherapy with prazosin was effective in managing nightmare severity. The sole avail of CBT-I was recommended to improving sleep quality while CBT-I and CBT-I plus IRT showed excellent management of PTSD symptom severity. Exposure to CBT-I isrecommended for depression. The relevant clinical guidelines for the management of individuals with PTSD and sleep disorders may regard this as a reference.PROSPERO CRD42023415240.

Abstract A wide variety of metabolic gene clusters exist in eukaryotic genomes, but fatty acid metabolic gene clusters have not been discovered. Here, combining with metabolic and phenotypic genome-wide association studies, we identify a major locus containing a six-gene fatty acid metabolic gene cluster on chromosome 3 (FGC3) that controls the cutin monomer hydroxymonoacylglycerols (HMGs) contents and rice yield, possibly through variation in the transcription of FGC3 members. We show that HMGs are sequentially synthesized in the endoplasmic reticulum by OsFAR2, OsKCS11, OsGPAT6, OsCYP704B2 and subsequently transported to the apoplast by OsABCG22 and OsLTPL82. Mutation of FGC3 members reduces HMGs, leading to defective male reproductive development and a significant decrease in yield. OsMADS6 and OsMADS17 directly regulate FGC3 and thus influence male reproduction and yield. FGC3 is conserved in Poaceae and likely formed prior to the divergence of Pharus latifolius. The eukaryotic fatty acid and plant primary metabolic gene cluster we identified show a significant impact on the origin and evolution of Poaceae and has potential for application in hybrid crop breeding.

Abstract Temozolomide (TMZ) resistance is a major challenge in the treatment of glioblastoma (GBM). Tumour reproductive cells (TRCs) have been implicated in the development of chemotherapy resistance. By culturing DBTRG cells in three-dimensional soft fibrin gels to enrich GBM TRCs and performing RNA-seq analysis, the expression of stanniocalcin-1 (STC), a gene encoding a secreted glycoprotein, was found to be upregulated in TRCs. Meanwhile, the viability of TMZ-treated TRC cells was significantly higher than that of TMZ-treated 2D cells. Analysis of clinical data from CGGA (Chinese Glioma Genome Atlas) database showed that high expression of STC1 was closely associated with poor prognosis, glioma grade and resistance to TMZ treatment, suggesting that STC1 may be involved in TMZ drug resistance. The expression of STC1 in tissues and cells was examined, as well as the effect of STC1 on GBM cell proliferation and TMZ-induced DNA damage. The results showed that overexpression of STC1 promoted and knockdown of STC1 inhibited TMZ-induced DNA damage. These results were validated in an intracranial tumour model. These data revealed that STC1 exerts regulatory functions on MGMT expression in GBM, and provides a rationale for targeting STC1 to overcome TMZ resistance.

Abstract Background UV-B, an important environmental factor, has been shown to affect the yield and quality of rice (Oryza sativa) worldwide. However, the molecular mechanisms underlying the response to UV-B stress remain elusive in rice. Results We perform comprehensive metabolic profiling of leaves from 160 diverse rice accessions under UV-B and normal light conditions using a widely targeted metabolomics approach. Our results reveal substantial differences in metabolite accumulation between the two major rice subspecies indica and japonica, especially after UV-B treatment, implying the possible role and mechanism of metabolome changes in subspecies differentiation and the stress response. We next conduct a transcriptome analysis from four representative rice varieties under UV-B stress, revealing genes from amino acid and flavonoid pathways involved in the UV-B response. We further perform a metabolite-based genome-wide association study (mGWAS), which reveals 3307 distinct loci under UV-B stress. Identification and functional validation of candidate genes show that OsMYB44 regulates tryptamine accumulation to mediate UV-B tolerance, while OsUVR8 interacts with OsMYB110 to promote flavonoid accumulation and UV-B tolerance in a coordinated manner. Additionally, haplotype analysis suggests that natural variation of OsUVR8 groupA contributes to UV-B resistance in rice. Conclusions Our study reveals the complex biochemical and genetic foundations that govern the metabolite dynamics underlying the response, tolerance, and adaptive strategies of rice to UV-B stress. These findings provide new insights into the biochemical and genetic basis of the metabolome underlying the crop response, tolerance, and adaptation to UV-B stress.

Abstract Molecular targeted therapy resistance remains a major challenge in treating lung adenocarcinoma (LUAD). The resistance of Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitor) plays a dominant role in molecular targeted therapy. Our previous research demonstrated the role of MALAT-1 (Metastasis-associated lung adenocarcinoma transcript 1) in the formation of Erlotinib-resistant LUAD cells. This study aims to uncover the mechanism of MALAT-1 overexpression in Erlotinib-resistant LUAD cells. The RT2 LncRNA PCR array system was used to explore MALAT-1 regulation in Erlotinib-resistant LUAD cells through patient serum analysis. Dual luciferase reporter experiments confirmed the binding between MALAT-1 and miR-125, leading to regulation of miR-125 expression. Functional assays were performed to elucidate the impact of MALAT1 on modulating drug resistance, growth, and Epithelial-mesenchymal transition (EMT, Epithelial-mesenchymal transition) in both parental and Erlotinib-resistant LUAD cells. The investigation unveiled the mechanism underlying the competing endogenous RNA (ceRNA, competing endogenouse RNA) pathway. MALAT1 exerted its regulatory effect on miR-125 as a competing endogenous RNA (ceRNA). Moreover, MALAT1 played a role in modulating the sensitivity of LUAD cells to Erlotinib. Rab25 was identified as the direct target of miR-125 and mediated the functional effects of MALAT1 in Erlotinib-resistant LUAD cells. In conclusion, our study reveals overexpress MALAT-1 cause the drug resistance of EGFR-TKIs in non-small cell lung cancer (NSCLC) through the MALAT-1/miR-125/Rab25 axis. These findings present a potential novel therapeutic target and perspective for the treatment of LUAD.

Background: Osteomyelitis (OM) is an inflammatory condition of bone characterized by cortical bone devascularization and necrosis. Dysregulation of bone remodelling is triggered by OM. Bone remodelling is precisely coordinated by bone resorption and formation via a reversal phase. However, the cellular and molecular mechanisms underlying bone remodelling failure after osteomyelitis remain elusive. Methods: To elucidate the cellular and molecular mechanism underlying bone healing after osteomyelitis, we employed single-cell RNA sequencing (scRNA-seq) to depict the atlas of human cortical bone in normal, infected and reconstructed states. Dimensionality reduction by t-stochastic neighbourhood embedding (t-SNE) and graph-based clustering were applied to analyse the detailed clusters of osteoclast lineages. After trajectory analysis of osteoclast lineages over pseudotime, real-time PCR and immunofluorescence (IF) staining were applied to identify marker gene expression of various osteoclast lineages in the osteoclast induction model and human bone sections, respectively. The potential function and communication of osteoclasts were analysed via gene set enrichment analysis (GSEA) and CellChat. The chemotactic ability of mesenchymal stem cells (MSCs) and osteoclast lineage cells in various differentiation states was determined by transwell assays and coculture assays. The effects of various osteoclast lineages on the osteogenic differentiation potential of MSCs were also determined by using this coculture system. A normal mouse tibia fracture model and an osteomyelitis-related tibia fracture model were generated via injection of luciferase-labelled Staphylococcus aureus to verify the relationships between a novel osteoclast lineage and MSCs. Then, the infection was detected by a bioluminescence imaging system. Finally, immunofluorescence staining was used to detect the expression of markers of MSCs and novel osteoclast lineages in different remodelling phases in normal and infected bone remodelling models. Results: In this study, we constructed a cell atlas encompassing normal, infected, and reconstructed cortical bone. Then, we identified a novel subset at the earlier stage of the osteoclast lineage that exhibited increased expression of IDO1, CCL3, and CCL4. These IDO1highCCL3highCCL4high cells, termed osteostaticytes (OSCs), were further regarded as the reservoir of osteoclasts in the reversal phase. Notably, OSCs exhibited the highest chemotactic activity, surpassing other lineage subsets. We also discovered that cells at the earlier stage of the osteoclast lineage play a significant role in recruiting mesenchymal stem cells (MSCs). Finally, the data revealed that OSCs might be positively related to the occurrence of bone MSCs and the contribution of bone remodelling. Conclusion: Collectively, our findings revealed a novel stage (OSC) within the osteoclast lineage, potentially representing elusive bone reversal cells due to its increased chemotactic ability towards MSCs and potential contribution to bone remodelling. This study provides valuable insights into the intricate mechanisms of the reversal phase during bone remodelling and unveils potential therapeutic strategies for diseases associated with bone uncoupling. Translational potential of this article: This study identified a new subset, referred to as IDO1(plus symbol) CCL3(plus symbol) CCL4(plus symbol) osteostaticytes which displayed the highest chemotactic activity among all osteoclast lineages and may serve as reversal cells in bone remodelling. These findings offer new insights and insights for understanding bone reversal-related diseases and may serve as novel therapeutic targets for conditions such as osteomyelitis and delayed bone healing.

Abstract The global spread of COVID-19 has profoundly affected health and economies, highlighting the need for precise epidemic trend predictions for effective interventions. In this study, we used infectious disease models to simulate and predict the trajectory of COVID-19. An SEIR (susceptible, exposed, infected, removed) model was established using Wuhan data to reflect the pandemic. We then trained a genetic algorithm-based SEIR (GA-SEIR) model using data from a specific U.S. region and focused on individual susceptibility and infection dynamics. By integrating socio-psychological factors, we achieved a significant enhancement to the GA-SEIR model, leading to the development of an optimized version. This refined GA-SEIR model significantly improved our ability to simulate the spread and control of the epidemic and to effectively track trends. Remarkably, it successfully predicted the resurgence of COVID-19 in mainland China in April 2023, demonstrating its robustness and reliability. The refined GA-SEIR model provides crucial insights for public health authorities, enabling them to design and implement proactive strategies for outbreak containment and mitigation. Its substantial contributions to epidemic modelling and public health planning are invaluable, particularly in managing and controlling respiratory infectious diseases such as COVID-19.

Abstract Background Aripiprazole is the most frequently recommended antipsychotic for the treatment of tics in children and adolescents with Tourette’s disorder (TD). However, to date, a randomized controlled trial for aripiprazole oral solution has not been conducted despite being widely preferred by children. Therefore, we examined whether aripiprazole oral solution is effective for treating tics. Methods All patients received a flexible dose of aripiprazole oral solution (1 mg/mL, range: 2–20 mg) with a starting dose of 2 mg. The target dose for patients weighing

Abstract This paper investigates the soliton solutions and dynamical analysis of (2+1)-dimensional Heisenberg ferro-magnetic spin chains model with beta fractional derivative, which is transformed into the ordinary differential equation. By using the second-order complete discriminant system, the soliton solutions are presented. By utilizing the theory of planar dynamical system, the phase portraits of the dynamical system and its disturbance system are drawn. Moreover, three-dimensional, two-dimensional, and contour plots of soliton solutions for (2+1)-dimensional Heisenberg ferro-magnetic spin chains model with beta fractional derivative have also been plotted.

In this experiment, goat milk casein was used as raw material. Goat milk casein was treated with different ultrasonic intensities to explore the effects of ultrasonic treatment on the pH, conductivity, Zeta potential, turbidity and other physical and chemical indexes, as well as the functional characteristics of emulsification and foaming. The results showed that compared with untreated group, after ultrasonic treatment, the pH decreased and the conductivity had no significant change (P>0.05). The absolute value of Zeta potential reached the maximum value of 27.85±1.55 mV when treated at 400 W for 2 min. Turbidity was significantly decreased compared with untreated group (P

Abstract Background Tree seedling regeneration in forests is often hindered by the competitive influence of dense understory bamboo competition. While localized studies have investigated the ecological effects of understory bamboo removal on tree seedlings, a comprehensive analysis at a global scale is lacking. In this meta-analysis, we synthesized 497 observations from 32 experimental studies to assess the overall effects of understory bamboo removal on tree seedling regeneration. Results The results showed that understory bamboo removal enhanced tree seedling survival, emergence, and height growth. However, the response of tree seedlings to bamboo removal varied depending on regeneration characteristics, forest types, and bamboo removal methods. Specifically, understory bamboo removal increased the survival rate of deciduous seedlings but had no significant effect on evergreen seedlings. For regeneration stages, bamboo removal had a significant positive effect on the survival rate of saplings but not on seedlings. Regarding differences across forest types, bamboo removal significantly increased the emergence density of seedlings in deciduous broadleaf forests but had a significant negative influence in evergreen and mixed evergreen-deciduous forests. Additionally, natural removal of bamboo showed a greater positive effect on seedlings than bamboo removal by artificial or animal gnawing methods. Furthermore, we found that the duration of bamboo removal, mean annual temperature, precipitation of seasonality, and soil pH strongly influenced the response ratios of tree seedling regeneration. Conclusions Our meta-analysis demonstrates the significant effects of understory bamboo removal on multiple facets of tree seedling dynamics across different regeneration characteristics, forest types, and bamboo removal methods. In addition, our study emphasizes that the duration of bamboo removal, climate, and soil pH have a critical effect on tree seedling regeneration. Our findings elucidate the effects of understory bamboo removal on seedling regeneration, offering robust scientific insights for sustainable forest management.

Abstract The main purpose of this article is to investigate the qualitative behavior and traveling wave solutions of the fractional stochastic Kraenkel–Manna–Merle equations, which is commonly used to simulate the zero conductivity nonlinear propagation behavior of short waves in saturated ferromagnetic materials. Firstly, fractional stochastic Kraenkel–Manna–Merle equations are transformed into ordinary differential equations by using the traveling wave transformation. Secondly, the phase portraits, sensitivity analysis, and Poincaré sections of the two-dimensional dynamic system and its perturbation system of ordinary differential equations are drawn. Finally, the traveling wave solutions of fractional stochastic Kraenkel–Manna–Merle equations are obtained based on the analysis theory of planar dynamical system. Moreover, the obtained three-dimensional graphs of random solutions, two-dimensional graphs of random solutions, and three-dimensional graphs of deterministic solutions are drawn.

Abstract Background Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disease. The aim of this research is to identify new biomarkers and therapeutic targets for the treatment of such deadly diseases. Methods Single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT algorithms were used to identify distinct immune cell infiltration types between AAA and normal abdominal aortas. Single-cell RNA sequencing data were used to analyse the hallmark genes of AAA-associated macrophage cell subsets. Six macrophage-related hub genes were identified through weighted gene co-expression network analysis (WGCNA) and validated for expression in clinical samples and AAA mouse models. We screened potential therapeutic drugs for AAA through online Connectivity Map databases (CMap). A network-based approach was used to explore the relationships between the candidate genes and transcription factors (TFs), lncRNAs, and miRNAs. Additionally, we also identified hub genes that can effectively identify AAA and atherosclerosis (AS) through a variety of machine learning algorithms. Results We obtained six macrophage hub genes (IL-1B, CXCL1, SOCS3, SLC2A3, G0S2, and CCL3) that can effectively diagnose abdominal aortic aneurysm. The ROC curves and decision curve analysis (DCA) were combined to further confirm the good diagnostic efficacy of the hub genes. Further analysis revealed that the expression of the six hub genes mentioned above was significantly increased in AAA patients and mice. We also constructed TF regulatory networks and competing endogenous RNA networks (ceRNA) to reveal potential mechanisms of disease occurrence. We also obtained two key genes (ZNF652 and UBR5) through a variety of machine learning algorithms, which can effectively distinguish abdominal aortic aneurysm and atherosclerosis. Conclusion Our findings depict the molecular pharmaceutical network in AAA, providing new ideas for effective diagnosis and treatment of diseases.

Abstract This research aimed to devise and assess a mobile game therapy software for children with Attention-Deficit/Hyperactivity Disorder (ADHD), as well as evaluating its suitability and effectiveness in improving the cognitive ability of typically developing children. The study encompassed 55 children diagnosed with ADHD and 55 neurotypical children. Initial assessments involved ADHD-related scales, computerized tests for information processing, and physiological-psychological evaluations. After a 4-week home-based game intervention, participants underwent re-evaluation using baseline measures and provided feedback on treatment satisfaction. Considering the small proportion of study participants who dropped out, data was analyzed using both the Intention-to-Treat (ITT) analysis and the Per-protocol (PP) analysis. The trial was registered at ClinicalTrials.gov (NCT06181747). In ITT analysis, post-intervention analysis using linear mixed models indicated that the ADHD group improved significantly more than the neurotypical group particularly in Continuous Performance Test (CPT) accuracy (B = −23.92, p

The World Health Organization (WHO) 2017 classifications for neuroendocrine neoplasms (NENs) subdivided grade 3 pancreatic neuroendocrine neoplasms (pNENs) into G3 well-differentiated pancreatic neuroendocrine tumors (G3 pNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), according to the mitotic count, Ki-67 index, and cell differentiation. As a new category, G3 pNETs remain a challenging group of tumors to manage by lacking large randomized trials and consensus to support its clinical practice. Therefore, the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association gathered experts in this field to formulate this consensus for the diagnosis and treatment of G3 pNETs.

Highlights Stable interfaces were successfully achieved through designing channel structures in electrodes to sufficiently incorporate polymer gel electrolyte fabricated through in situ polymerization. The resultant fibre lithium battery (FLB) demonstrated superior energy density output of 128 Wh kg−1 and enabled scalable production capability. Such high-performance FLBs presented prospect applications in diverse scenarios, for example, firefighting, space exploration, and human–computer interaction, even under harsh environments.

Bisphenol A (BPA) is a widespread endocrine disruptor that mimics estrogen. The accumulation of BPA within the human body has been shown to be detrimental to ovarian function. However, few studies have focused on the specific mechanisms by which it causes harm to granulosa cells (GCs), pivotal ovarian cells that are responsible for the growth and function of oocytes. In vitro research was conducted using human GC lines (KGN cells). The cells were exposed to various concentrations of BPA (0.1, 1, 10, or 100 µM) for either 24 or 48 hours. Here, our findings indicate that 100 μM BPA inhibits KGN cell proliferation and promotes cell autophagy through inhibiting the PI3K/Akt/mTOR pathway. Interestingly, these effects could be partly reversed by an NTRK2 activator (LM22b-10). NTRK2 is the receptor for BDNF. Moreover, via the use of bioinformatics tools, miR-204 was predicted to target BDNF. Additionally, our findings confirmed that miR-204 has the ability to directly target BDNF through a luciferase assay. Downregulation of miR-204 abrogated the BPA exposure-mediated effects on proliferation and autophagy. Furthermore, the inhibition of miR-204 significantly reversed the downregulation of PI3K/Akt/mTOR pathway-related molecules. Similarly, we validated miR-204 as a novel miRNA involved in BPA-mediated damage to GC proliferation and autophagy, and our data provide the first in vitro evidence that increasing miR-204 expression and inhibiting the BDNF/NTRK2-mediated PI3K/Akt/mTOR signaling pathway are involved in the BPA-induced toxic effects in KGN cells.

Dynamic conformational and structural changes in proteins and protein complexes play a central and ubiquitous role in the regulation of protein function, yet it is very challenging to study these changes, especially for large protein complexes, under physiological conditions. Here, we introduce a novel isobaric crosslinker, Qlinker, for studying conformational and structural changes in proteins and protein complexes using quantitative crosslinking mass spectrometry. Qlinkers are small and simple, amine-reactive molecules with an optimal extended distance of ~10 Å, which use MS2 reporter ions for relative quantification of Qlinker-modified peptides derived from different samples. We synthesized the 2-plex Q2linker and showed that the Q2linker can provide quantitative crosslinking data that pinpoints key conformational and structural changes in biosensors, binary and ternary complexes composed of the general transcription factors TBP, TFIIA, and TFIIB, and RNA polymerase II complexes.

Objective The types and number of day surgeries have significantly increased, but the construction of the whole process nursing service system (WPNSS) for preoperative education, intraoperative cooperation, postoperative knowledge, and follow-up for day surgery patients is still in the exploratory stage. The aim of this study is to establish the WPNSS for day surgery patients using the Kano model and to preliminarily assess its efficacy. Methods WPNSS for day surgery was devised leveraging Internet hospital information systems and patient mobile terminals (WeChat), guided by the World Health Organization's conceptual framework for scaling-up strategies. The system was methodically developed, progressing from defining the overall framework to delineating modular functions and developing specific educational materials and tools. A pilot test was conducted in a hospital in China. Results WPNSS, a patient-centric remote education and monitoring system, seamlessly amalgamates health education, online consultations, and follow-up functionalities; offering semi-automated surgical consultations, inquiry services, and postoperative follow-ups, as well as autonomously disseminating perioperative health education content. Comprising both client and server components, patients utilizing the system are inclined to recommend day surgery at the hospital to others Conclusions WPNSS delivers personalized and precise health education, consultation, and postoperative follow-up services for day surgery patients. Current results suggest that the WPNSS may improve patients’ experience. Trial Registration Chinese Clinical Trial Register (ChiCTR2200066782).

Abstract In this letter, the working mechanism of suggested bandpass filters with connected symmetric short‐circuit stub multimode resonators is described. Because of the design flexibility, the suggested bandpass filters' centre frequencies may be modified based on the design approach. Meanwhile, the suggested bandpass filters have reduced insertion losses and compact sizes. A prototype is built and tested with six passbands centred at 1.57/2.38/3.55/5.14/5.83/6.78 GHz to confirm the design and analysis. Good agreement between the simulated, and measured results is observed, indicating that the proposed structure can be applied in the field of communication, information, and automation.

Protein aggregation, a defining characteristic of numerous human diseases, poses a significant challenge to cellular health. Autophagy, an essential cellular recycling process, specifically targets and degrades these harmful protein aggregates through a specialized mechanism known as aggrephagy. However, the precise mechanisms underlying the exquisite selectivity of aggrephagy in identifying and eliminating only aggregated proteins while sparing healthy cellular components have remained enigmatic. Here, in this mini review, we highlights the essential role of CCT2, a subunit of the chaperonin TRiC complex, in regulating aggrephagy. CCT2, traditionally viewed as a molecular chaperone, has emerged as a novel autophagy receptor that specifically targets solid protein aggregates for degradation. This ubiquitination-independent mode of recognition by CCT2 expands our understanding of protein degradation pathways. The functional switch of CCT2 from a chaperone to an autophagy receptor underscores its dynamic nature and ability to adapt to cellular stress. The selectivity of CCT2-mediated aggrephagy for solid aggregates has implications for neurodegenerative diseases. Further research is warranted to explore the therapeutic potential of enhancing CCT2-mediated aggrephagy in such diseases.

IntroductionAs a malignant hematological disease, the incidence of acute myeloid leukemia (AML) has exhibited an upward trend in recent years. Nevertheless, certain limitations persist in the treatment of AML. Sperm-associated antigen 6 (SPAG6) has been implicated in the onset and progression of various human cancers, with its expression levels significantly elevated in AML. Consequently, we undertook a series of experiments to investigate the role and underlying mechanisms of SPAG6 in AML cell lines.MethodsIn the in vitro experiments of this study, DEPs and GO and KEGG enrichment analysis subsequent to SPAG6 down-regulation were detected by TMT. CCK8 was employed to determine cell viability. The levels of apoptosis and ROS were measured by flow cytometry. In the in vivo experiments, a xenografted tumor model was constructed, and the expression of SPAG6 and GSTP1 in tumor tissues was detected by IHC.ResultsUltimately, our findings indicated that over-expression of SPAG6 promoted cell growth and decreased reactive oxygen species (ROS) and malondialdehyde levels. Furthermore, SPAG6 knockdown was found to diminish mitochondrial membrane potential and facilitate cell apoptosis. In vivo, SPAG6 could also promote tumor growth, suggesting that SPAG6 may serve as a pro-tumor factor. In addition, daunorubicin (DNR) may cause oxidative stress and initiate apoptosis, resulting in oxidative damage to AML cells. However, the overexpression of SPAG6 may attenuate the efficacy of DNR. This was due to SPAG6 promoted GSTP1 expression, thereby reducing ROS levels. Simultaneously, the elevation of GSTP1 and JNK complex may reduce the expression of p-JNK and inhibit the activation of JNK pathway, which might inhibit cell apoptosis.DiscussionIn conclusion, our experiments suggested that upregulated SPAG6 might mitigate the pro-apoptotic effects of DNR through ROS/JNK MAPK axis in a GSTP1-dependent manner.

Cities constitute a critical component of the “dual carbon” strategy, highlighting the importance of examining the carbon emission trends within various city categories to formulate a low-carbon development path. In this paper, 21 cities (prefectures) in Sichuan province were divided into 4 categories (service-based cities, resource-based cities, industry-based cities, and other cities) through K-means clustering, and the differences in driving factors of carbon emissions in different types of cities were explored. At the same time, baseline scenarios, technological innovation scenarios, controlled development scenarios, and mandatory emission reduction scenarios were set up to dynamically simulate the evolution path of urban carbon emissions in the next 30 years from the bottom-up. The results show that: (1) Input scale is the main driving factor for carbon emission growth in Sichuan province, while input carbon intensity is the leading factor for carbon emission reduction. Environmental input and population scale have opposite effects on carbon emission of different urban types. (2) Resource-based cities face challenges in completing the phased goal of “carbon peaking” under both baseline scenarios and controlled development scenarios. These cities have gradually become the predominant city type of emission source in Sichuan province, surpassing service-based cities. (3) Except for the normal scenario, Sichuan province can achieve the target of “carbon peaking” in other scenarios, and is expected to achieve the target of 90 % greenhouse gas reduction by 2050. (4) Among the 81 development paths derived from the urban scenario combinations, the path labeled M−B−C−M exhibits the lowest economic-ecological comprehensive impact coefficient. The bottom-up carbon emission scenario analysis framework established in this paper offers a novel perspective for the study of “carbon peaking” and can provide theoretical support for policymakers in devising regional low-carbon development strategies.

Bananas (Musa spp.) are a popular tropical fruit grown worldwide and are typically harvested when 70% to 80% plump. Postharvest storage is crucial for maintaining fruit quality, with temperature playing a key role due to banana sensitivity to low temperatures. Red peeled bananas, such as the cultivar Hongmeiren, stand out for their unique red peel and pink pulp when ripe. These bananas offer nutritional benefits and are rich in anthocyanins compared with yellow bananas. This study focused on the hardness change, anthocyanin content, and the expression of related genes in red peeled bananas at different temperatures. Results showed that pulp hardness reached an edible state after 4 days at 19 and 25 °C, with stability thereafter. Storage time at 10 °C was longer and anthocyanin content remained stable across temperatures. Gene expression analysis indicated that genes including MaPAL, MaCHS, MaCHI, MaDFR, and MaANS related to anthocyanin synthesis were highly expressed at 10 °C, potentially preserving anthocyanin content and fruit appearance. Although higher anthocyanin content was observed at 19 and 25 °C, black spots appeared on the fruit peel after 8 days, affecting its quality. After 30 days of storage at 10 °C, a significant number of black spots appeared on the peel of the fruit, leading to a gradual loss of its nutritional value. This study indicates that red peeled bananas can be stored for longer periods while maintaining their appearance quality at 10 °C, as opposed to 19 and 25 °C. Hence, it is recommended to store red peeled bananas at low temperatures, especially following ethylene treatment or during periods of high temperatures.

ObjectiveWe aimed to investigate human epididymis protein 4 (HE4) as a potential biomarker in patients with pediatric-onset systemic lupus erythematosus (pSLE), particularly on the association of serum HE4 levels with disease activity and other laboratory tests.MethodsWe included 137 patients with pSLE and 75 age- and sex-matched healthy controls (HCs). Serum HE4 level was measured by a chemiluminescent microparticle on an Abbott ARCHITECT i2000SR Immunoassay Analyzer. Comparisons between groups were performed using the independent Student t-test, Mann–Whitney U test, Chi-square test, or Fisher’s exact test, as appropriate. We also determined the relationships between HE4 and clinical parameters and evaluated disease activity using SLE Disease Activity Index (SLEDAI) and renal SLEDAI (rSLEDAI).ResultsSerum HE4 levels in patients with pSLE (44.6 pmol/L; IQR, 32.5–73.5) were significantly higher than those in HCs (38.9 pmol/L; IQR, 34–46.1). HE4 levels were significantly higher in moderate to severe disease activities (57.4 pmol/L, IQR 37.7–164.5) than in mild disease activities (38.8 pmol/L, IQR 30.1–48.5) or HCs (38.9 pmol/L, IQR 34.0–46.1), as well as in active renal disease activities (77.2 pmol/L, IQR 47.4–224.1) than in inactive renal disease activities (36.1 pmol/L, IQR 27.8–46.7). The ROC curve analysis showed that HE4 could discriminate pSLE with renal (AUC, 0.717; 95% CI, 0.632–0.801), hematological (AUC, 0.740; 95% CI, 0.648–0.831), and cardiovascular involvement (AUC:0.775, 95% CI 0.669–0.880). Serum HE4 levels significantly correlated with several indicators related to renal morbidity, such as creatinine, blood urea nitrogen, uric acid, cystatin C, urine protein/24 h, etc.ConclusionSerum HE4 levels in pSLE were elevated and highly associated with disease activity and systemic involvement, indicating HE4 as a potential biomarker for pSLE.

Abstract Flexible electro‐optical dual‐mode sensor fibers with capability of the perceiving and converting mechanical stimuli into digital‐visual signals show good prospects in smart human‐machine interaction interfaces. However, heavy mass, low stretchability, and lack of non‐contact sensing function seriously impede their practical application in wearable electronics. To address these challenges, a stretchable and self‐powered mechanoluminescent triboelectric nanogenerator fiber (MLTENGF) based on lightweight carbon nanotube fiber is successfully constructed. Taking advantage of their mechanoluminescent‐triboelectric synergistic effect, the well‐designed MLTENGF delivers an excellent enhancement electrical signal of 200% and an evident optical signal whether on land or underwater. More encouragingly, the MLTENGF device possesses outstanding stability with almost unchanged sensitivity after stretching for 200%. Furthermore, an extraordinary non‐contact sensing capability with a detection distance of up to 35 cm is achieved for the MLTENGF. As application demonstrations, MLTENGFs can be used for home security monitoring, intelligent zither, traffic vehicle collision avoidance, and underwater communication. Thus, this work accelerates the development of wearable electro‐optical textile electronics for smart human‐machine interaction interfaces.

Atherosclerotic cardiovascular disease is closely correlated with elevated low density lipoprotein-cholesterol. In feeding state, glucose and insulin activate mammalian target of rapamycin 1 that phosphorylates the deubiquitylase ubiquitin-specific peptidase 20 (USP20). USP20 then stabilizes HMG-CoA reductase, thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity, and increased energy expenditure through elevating UCP1. In Ldlr−/− mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat metabolic disease.

Abstract. Background:. Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important role in the maintenance of vascular tone and blood flow. However, the role of GRK2 in the pathogenesis of PAH is unknown. Methods:. GRK2 levels were detected in lung tissues from healthy people and PAH patients. C57BL/6 mice, vascular smooth muscle cell-specific Grk2-knockout mice (Grk2ΔSM22), and littermate controls (Grk2flox/flox) were grouped into control and hypoxia mice (n = 8). Pulmonary hypertension (PH) was induced by exposure to chronic hypoxia (10%) combined with injection of the SU5416 (cHx/SU). The expression levels of GRK2 and Yes-associated protein (YAP) in pulmonary arteries and PASMCs were detected by Western blotting and immunofluorescence staining. The mRNA expression levels of Grk2 and Yes-associated protein (YAP) in PASMCs were quantified with real-time polymerase chain reaction (RT-PCR). Wound-healing assay, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, and 5-Ethynyl-2′-deoxyuridine (EdU) staining were performed to evaluate the proliferation and migration of PASMCs. Meanwhile, the interaction among proteins was detected by immunoprecipitation assays. Results:. The expression levels of GRK2 were upregulated in the pulmonary arteries of patients with PAH and the lungs of PH mice. Moreover, cHx/SU-induced PH was attenuated in Grk2ΔSM22 mice compared with littermate controls. The amelioration of PH in Grk2ΔSM22 mice was accompanied by reduced pulmonary vascular remodeling. In vitro study further confirmed that GRK2 knock-down significantly altered hypoxia-induced PASMCs proliferation and migration, whereas this effect was severely intensified by overexpression of GRK2. We also identified that GRK2 promoted YAP expression and nuclear translocation in PASMCs, resulting in excessive PASMCs proliferation and migration. Furthermore, GRK2 is stabilized by inhibiting phosphorylating GRK2 on Tyr86 and subsequently activating ubiquitylation under hypoxic conditions. Conclusion:. Our findings suggest that GRK2 plays a critical role in the pathogenesis of PAH, via regulating YAP expression and nuclear translocation. Therefore, GRK2 serves as a novel therapeutic target for PAH treatment.

Abstract Immune thrombocytopenia (ITP), an acquired autoimmune disease, is characterized by immune-mediated platelet destruction. A biomarker is a biological entity that contributes to disease pathogenesis and reflects disease activity. Metabolic alterations are reported to be associated with the occurrence of various diseases. As metabolic biomarkers for ITP have not been identified. This study aimed to identify metabolism-related differentially expressed genes as potential biomarkers for pathogenesis of ITP using bioinformatic analyses.The microarray expression data of the peripheral blood mononuclear cells were downloaded from the Gene Expression Omnibus database (GSE112278 download link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112278 ). Key module genes were intersected with metabolism-related genes to obtain the metabolism-related key candidate genes. The hub genes were screened based on the degree function in the coytoscape sofware. The key ITP-related genes were subjected to functional enrichment analysis. Immune infiltration analysis was performed using a single-sample gene set enrichment analysis algorithm to evaluate the differential infiltration levels of immune cell types between ITP patient and control. Molecular subtypes were identified based on the expression of hub genes. The expression of hub genes in the ITP patients was validated using quantitative real-time polymerase chain reaction analysis. This study identified five hub genes (ADH4, CYP7A1, CYP1A2, CYP8B1, and NR1H4), which were be associated with the pathogenesis of ITP, and two molecular subtypes of ITP. Among these hub genes, CYP7A1 and CYP8B1 involved in cholesterol metabolism,were further verified in clinical samples.

Abstract Background This study aimed to investigate the interplay between anxiety and depressive symptoms in Chinese college freshmen using the causal system perspective (CSP), which differs from the traditional common cause perspective (CCP) by providing an alternative explanation by attributing comorbidity to direct interactions among symptoms. Methods A convenience sample of 2,082 Chinese college freshmen (39.51% male, M age = 18.61) from a normal university completed the Generalized Anxiety Disorder 7-Item Scale (GAD-7) and the Patient Health Questionnaire (PHQ-9). Network analysis was conducted and evaluated as to centrality, stability, node predictability, and bridging features. Moreover, the moderated network model (MNM) was utilized to detect the moderation effects of gender in the comorbidity network. Results The network of anxiety and depressive symptoms exhibited stability, characterized by the core symptoms of “restlessness”, “lack of energy”, and “excessive worry about control”, as well as the bridging symptoms of “fearfulness”, “sad mood”, and “irritability”. Notably, the nodes representing “uncontrollable worry” and “difficulty in relaxation” demonstrated the highest predictive power. Gender did not exert any moderating effects on the anxiety and depressive symptom network. Conclusion These results reinforce that certain anxiety or depressive symptoms are more central than others, and thus play a more vital role in the comorbid network. These findings highlight underlying potential targeting symptoms to consider in future interventions.

Background: Colostrum, abundant in immunoglobulins and growth factors, plays a vital role in supporting immunity. Both yak and buffalo milk are characterized by their high protein and fat content. However, the metabolomic profiles of yak colostrum (YC), buffalo colostrum (BC), and bovine colostrum (CC) remain largely unexplored. The objective of this study is to identify unique metabolites that may impact the nutritional value of colostrum. Methods: This study employed ultra-high performance liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) for untargeted metabolomics analysis of YC, BC, and CC. Results: The analysis revealed 97, 70, and 75 differentially expressed metabolites in the YC-CC, BC-CC, and YC-BC comparisons, respectively. In comparison to CC, both YC and BC shared common features, including reduced choline levels and elevated O-acetylcarnitine. Moreover, metabolites such as 2-hydroxy-6-pentadecylbenzoic acid, DL-glycerol-1-phosphate, thiamine, L-carnitine, methyl β-D-galactoside, and uridine diphosphate (UDP) were identified as potential biomarkers for YC, while 21-deoxycortisol, D-synephrine, uridine, mannitol-1-phosphate, nonadecanoic acid, and perillic acid were specific to BC. Conclusions: YC has greater advantages in energy supply, antioxidant activity, immune regulation, and cell homeostasis, and BC holds unique significance in physical development and energy balance regulation. These findings provide valuable insights, enabling the selection of unique bioactive metabolites to develop targeted functional foods from colostrum, catering to diverse nutritional needs.

ABSTRACT: This study aimed to improve the eating quality of yellow-feathered broiler chicks by feeding them corn–soybean meal diets supplemented with 250, 500, and 1,000 mg/kg quercetin. we examined the impact of varying doses of dietary quercetin on the sensory quality of chicken breast meat as well as on the antioxidant enzymes, antioxidant-related signaling molecules, structure and thermal stability of myofibrillar protein (MPs), and microstructure of myogenic fibers in the meat during 24 h of postslaughter aging. Additionally, we investigated the potential correlations among antioxidant capacity, MP structure, and meat quality parameters. The results indicated that dietary supplementations with 500 and 1,000 mg/kg quercetin improved the physicochemical properties and eating quality of yellow-feathered broiler chicken breast meat during 12 to 24 h postslaughter. Additionally, quercetin improved the postslaughter oxidative stress status and reduced protein and lipid oxidation levels. It also increased hydrogen bonding interactions and α-helix content during 6 to 12 h postslaughter and decreased β-sheet content during 12 to 24 h postslaughter in chicken breast MP. This resulted in improved postslaughter MP structure and thermal stability. The correlation results indicated that the enhancement of antioxidant capacity and MP structure enhanced the physicochemical and edible qualities of yellow-feathered broiler chicken breast meat. In conclusion, the current findings suggest that dietary supplementation with quercetin is an ideal approach for improving the eating quality of chicken meat, thereby broadening our understanding of theoretical and technological applications for improving the quality of chicken.

IntroductionSnakebites are acute systemic toxic diseases caused by snake venom entering the body through wounds. Failure to use antivenom immediately and difficulty in obtaining antivenoms are frequently responsible for worsening disease. Traditional Chinese medicine is commonly used to supplement and replace antivenom in treating snakebites. The Jidesheng snake pill (JDS) is a widely used traditional Chinese medicine that has achieved good clinical therapeutic effects; however, its mechanism remains unclear. Therefore, metabolomics techniques were employed to explore the pathophysiological mechanisms of JDS treatment of Agkistrodon halys (Ah) snake venom-poisoned mice.MethodsThe Ah group mouse model was established by intramuscular injection of Ah venom into the hind legs of the mice. The Ah venom + JDS group model was established using JDS after the affected area was treated with Ah venom. Hematoxylin and eosin (HE) staining was used to evaluate the severity of gastrocnemius injury. Quantitative polymerase chain reaction (qPCR) was utilized to detect the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1), muscle-specific creatine kinase (CKM), thrombin antithrombin complex (TAT), and tumor necrosis factor-alpha (TNF-α). Gas chromatography-mass spectrometry (GC-MS) was performed with multivariate statistical analysis to provide new insights into the global metabolic profile of Ah venom-poisoned mice.ResultsHE staining revealed increased red cell necrosis, local hemorrhage, and neutrophil infiltration in the Ah venom group than in the control group. Several compounds were identified, including lipids, amino acids, peptides, and organooxygen. Eighty differential metabolites were screened between the control group and the Ah venom group, and 24 were screened between the Ah venom and JDS groups. The mechanism of Ah venom poisoning in mice may involve aminoacyl-tRNA biosynthesis, various amino acid metabolism disorders, tricarboxylic acid circulation disorders, and abnormal fatty acid metabolism. JDS may reduce symptoms by affecting long-chain fatty acid and amino acid metabolism and promoting nicotinamide-nicotinamide metabolism.ConclusionOur results suggest that metabolomics has huge prospects for elucidating the pathophysiology of Agkistrodon haly venom poisoning and therapeutic mechanisms of JDS.