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Abstract The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that ATR is dispensable for the viability of G0-arrested naïve B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication and dNTP levels can be restored in Atr-deficient cells by suppressing origin firing, such as partial inhibition of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and importantly also other replication factors.

Homology-directed repair (HDR) of double-strand DNA breaks (DSBs) is dependent on enzymatic resection of DNA ends by the Mre11/Rad50/Nbs1 complex. DNA resection is triggered by the CtIP/Sae2 protein, which allosterically promotes Mre11-mediated endonuclease DNA cleavage at a position internal to the DSB. Although the mechanics of resection, including the initial endonucleolytic step, are largely conserved in eucaryotes, CtIP and its functional counterpart in Saccharomyces cerevisiae (Sae2) share only a modest stretch of amino acid homology. Nonetheless, this stretch contains two highly conserved phosphorylation sites for cyclin-dependent kinases (T843 in mouse) and the damage-induced ATM/ATR kinases (T855 in mouse), both of which are required for DNA resection. To explore the function of ATM/ATR phosphorylation at Ctip-T855, we generated and analyzed mice expressing the Ctip-T855A mutant. Surprisingly, unlike Ctip-null mice and Ctip-T843A-expressing mice, both of which undergo embryonic lethality, homozygous CtipT855A/T855A mice develop normally. Nonetheless, they are hypersensitive to ionizing radiation, and CtipT855A/T855A mouse embryo fibroblasts from these mice display marked defects in DNA resection, chromosomal stability, and HDR-mediated repair of DSBs. Thus, although ATM/ATR phosphorylation of CtIP-T855 is not required for normal animal development, it enhances CtIP-mediated DNA resection in response to acute stress, such as genotoxin exposure.

Abstract DNA damage, especially DNA double strand breaks (DSBs) and replication stress, activates a complex post-translational network termed DNA damage response (DDR). Our review focuses on three PI3-kinase related protein kinases—ATM, ATR and DNA-PKcs, which situate at the apex of the mammalian DDR. They are recruited to and activated at the DNA damage sites by their respective sensor protein complexes—MRE11/RAD50/NBS1 for ATM, RPA/ATRIP for ATR and KU70–KU80/86 (XRCC6/XRCC5) for DNA-PKcs. Upon activation, ATM, ATR and DNA-PKcs phosphorylate a large number of partially overlapping substrates to promote efficient and accurate DNA repair and to coordinate DNA repair with other DNA metabolic events (e.g., transcription, replication and mitosis). At the organism level, robust DDR is critical for normal development, aging, stem cell maintenance and regeneration, and physiological genomic rearrangements in lymphocytes and germ cells. In addition to endogenous damage, oncogene-induced replication stresses and genotoxic chemotherapies also activate DDR. On one hand, DDR factors suppress genomic instability to prevent malignant transformation. On the other hand, targeting DDR enhances the therapeutic effects of anti-cancer chemotherapy, which led to the development of specific kinase inhibitors for ATM, ATR and DNA-PKcs. Using mouse models expressing kinase dead ATM, ATR and DNA-PKcs, an unexpected structural function of these kinases was revealed, where the expression of catalytically inactive kinases causes more genomic instability than the loss of the proteins themselves. The spectrum of genomic instabilities and physiological consequences are unique for each kinase and depends on their activating complexes, suggesting a model in which the catalysis is coupled with DNA/chromatin release and catalytic inhibition leads to the persistence of the kinases at the DNA lesion, which in turn affects repair pathway choice and outcomes. Here we discuss the experimental evidences supporting this mode of action and their implications in the design and use of specific kinase inhibitors for ATM, ATR and DNA-PKcs for cancer therapy.

ATR kinase is a key regulator of chromosome integrity. Here the authors by analysing the phenotype of a mouse model expressing a kinase-dead ATR, reveal the effect of ATR inhibition compared to ATR loss and its consequences for meiosis, DNA replication, checkpoint activation and genome instability .

Non-homologous end-joining is the key pathway for repairing double-stranded DNA breaks in mammalian cells. Here the authors show that PAXX promotes the accumulation of KU at DNA breaks and is essential for end-joining in cells lacking XLF.

Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (AtmKD/-) is more oncogenic than loss of ATM (Atm-/-) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate AtmKD/-, but not Atm-proficientor Atm-/- leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy.

This study presented a novel Caputo fractional-order lung cancer model aimed at analyzing the population dynamics of cancer cells under untreated conditions and different treatment strategies. First, we explored the existence, uniqueness, and positivity of the model's solutions and analyzed the stability of the tumor-free equilibrium state and the internal equilibrium state. Second, we explored the existence, uniqueness, and positivity of the model's solutions and analyzed the stability of the tumor-free equilibrium state and the internal equilibrium state. We calculated the basic reproduction number and conducted a sensitivity analysis to evaluate the impact of various parameters on cancer cell growth. Next, by considering surgery and immunotherapy as control measures, we discussed the existence of an optimal solution and derived its expression using the Pontryagin maximum principle. We then performed numerical simulations of limit cycles, chaos, and bifurcation phenomena under uncontrolled conditions, as well as the dynamic behavior of cells under different control strategies. Finally, using real data from lung cancer patients, we conducted parameter estimation and curve fitting through the least squares method. The results indicated that combined therapy showed better effectiveness in inhibiting tumor cell growth, significantly outperforming single treatment strategies and more effectively controlling the progression of cancer.

Abstract Students in higher education often encounter significant academic pressure, which can have profound implications for their mental health and academic performance. The current study employs a two-wave longitudinal design to investigate the dynamic interrelationships among academic stress, academic motivation, emotional intelligence, and mindfulness. The study employed a cross-lagged panel model to investigate the temporal interactions among these four constructs and their influence on the academic experiences of doctoral students. The sample consisted of 643 individuals at Time 1 (September/October 2022), followed by a subsequent assessment involving 413 participants (July/August 2023). Notably, there was an overlap of 373 participants who were evaluated at both time points. The results indicated the presence of substantial reciprocal relationships among the constructs under investigation. The outcomes indicated that elevated emotional intelligence and mindfulness levels are associated with reduced academic stress and enhanced motivation. The implications of this analysis underscore the necessity of facilitating interventions aimed at enhancing emotional intelligence and mindfulness. These components are instrumental in promoting resilience and supporting academic success among students. These longitudinal insights hold significant importance within the academic literature as they elucidate the various stressors doctoral students encounter. Furthermore, this research provides practical implications for educators and policymakers in formulating targeted strategies to enhance student well-being and improve educational outcomes.

Abstract The current study was to explore the prevalence and risk factors elements of pre-frailty and frailty among patients undergoing hemodialysis (HD) in central China. A cross-sectional, multi-institutional investigation was conducted. From March to May 2024, using the convenience sampling method, a total of 408 HD patients from four hospitals in Xiangyang, China, were recruited for this study. The participants’ demographics, lifestyle factors, factors related to dialysis treatment, the FRAIL scale, psychological resilience, and medical coping modes were assessed using a questionnaire. Multi-categorical logistic regression was performed to examine factors associated with pre-frailty and frailty in this population. Furthermore, to evaluate the independent relationship between frailty and psychological resilience, multiple regression analysis was used to adjust potential confounders and obtain odds ratios (OR) and 95% confidence intervals (CI). Pearson correlation analysis was used for correlation analysis among various scales. Among the 408 participants, the prevalence of pre-frailty and frailty among participants for all ages was 26.2% and 38.5%. Multivariate logistic regression analysis showed that smoking status, falls, heart disease, and psychological resilience are all associated with pre-frailty and frailty. The Pearson correlation analysis showed that resignation was positively related to frailty and negatively related to psychological resilience in patients. Confrontation and avoidance were positively related to psychological resilience. Frailty was negatively related to psychological resilience. Psychological resilience was independently linearly associated with pre-frailty (OR 0.49, 95% CI 0.32–0.75, p

Abstract In response to image degradation caused by rain during image acquisition, this paper proposes a rain removal method for single image of dual-branch joint network based on a sparse Transformer (DBSTNet). The developed model comprises a rain removal subnet and a background recovery subnet. The former extracts rain trace information utilizing a rain removal strategy, while the latter employs this information to restore background details. Furthermore, a U-shaped encoder-decoder branch (UEDB) focuses on local features to mitigate the impact of rainwater on background detail textures. UEDB incorporates a feature refinement unit to maximize the contribution of the channel attention mechanism in recovering local detail features. Additionally, since tokens with low relevance in the Transformer may influence image recovery, this study introduces a residual sparse Transformer branch (RSTB) to overcome the limitations of the Convolutional Neural Network’s (CNN’s) receptive field. Indeed, RSTB preserves the most valuable self-attention values for the aggregation of features, facilitating high-quality image reconstruction from a global perspective. Finally, the parallel dual-branch joint module, composed of RSTB and UEDB branches, effectively captures the local context and global structure, culminating in a clear background image. Experimental validation on synthetic and real datasets demonstrates that rain removal images exhibit richer detail information, significantly improving the overall visual effect.

Abstract Sponges harbour complex microbiomes and as ancient metazoans and important ecosystem players are emerging as powerful models to understand the evolution and ecology of symbiotic interactions. Metagenomic studies have previously described the functional features of sponge symbionts, however, little is known about the metabolic interactions and processes that occur under different environmental conditions. To address this issue, we construct here constraint-based, genome-scale metabolic networks for the microbiome of the sponge Stylissa sp. Our models define the importance of sponge-derived nutrients for microbiome stability and discover how different organic inputs can result in net heterotrophy or autotrophy of the symbiont community. The analysis further reveals the key role that a newly discovered bacterial taxon has in cross-feeding activities and how it dynamically adjusts with nutrient inputs. Our study reveals insights into the functioning of a sponge microbiome and provides a framework to further explore and define metabolic interactions in holobionts.

Objective: To study the mechanism of quercetin (Que) in improving myocardial injury induced by doxorubicin (Dox) in mice. Methods: Fifty mice were randomly divided into normal group (Control), model group (Dox), quercetin low-dose, medium-dose and high-dose groups (Que-L, Que-M and Que-H), and myocardial injury model was established by intraperitoneal injection of Dox in addition to Control. The cardiac function of mice was evaluated by using echocardiography and hemodynamics, and creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH) levels were detected in serum of mice by ELISA. HE staining, Tunel staining and WGA staining respectively were used to observe the pathological changes of myocardial tissue, myocardial cell apoptosis and myocardial cell cross-sectional area changes. The expression of p-GSK-3β in myocardial tissue was detected by immunofluorescence, and the expression of PI3K/AKT/GSK-3β pathway and apoptotic protein in mouse myocardial tissue was detected by Western blot. Results: Compared with control group, left ventricular ejection fraction (LVEF) and left ventricular short axis shortening rate (LVFS) in Dox group were extremely significant decreased (P

Abstract Low-light image enhancement aims to enhance the visibility and contrast of low-light images while eliminating complex degradation issues such as noise, artifacts, and color distortions. Most existing low-light image enhancement methods either focus on quality while neglecting computational efficiency or have limited learning and generalization capabilities. To address these issues, we propose a Bilateral Enhancement Network with signal-to-noise ratio fusion, called BiEnNet, for lightweight and generalizable low-light image enhancement. Specifically, we design a lightweight Bilateral enhancement module with SNR (Signal-to-Noise Ratio) Fusion (BSF), which serves the SNR map of the input low-light image as the interpolation weights to dynamically fuse global brightness features and local detail features extracted from a bilateral network and achieve differentiated enhancement across different regions. To improve the network’s generalization ability, we propose a Luminance Normalization (LNM) module for preprocessing and a Dual-Exposure Processing (DEP) module for post-processing. LNM divides the channels of input features into luminance-related channels and luminance independent channels, and reduces the inconsistency of the degradation distribution of input low-light images by only normalizing the luminance-related channels. DEP learns overexposure and underexposure corrections simultaneously by employing the ReLU activation function, inverting operation, and residual network, which can improve the robustness of enhancement effects under different exposure conditions while reducing network parameters. Experiments on the LOL-V1 dataset shows BiEnNet significantly increased PSNR by 8.6 $$\%$$ and SSIM by 3.6 $$\%$$ compared to FLW-Net, reduced parameters by 98.78 $$\%$$ , and improved computational speed by 52.64 $$\%$$ compared to the classical KIND.

Abstract Background T cells have been implicated in various neurological conditions, yet their role in neonatal brain injuries remains unclear. This study aimed to investigate the impact of perinatal factors on frequencies of T cell subsets in preterm infants and to explore the differences in blood genome expression profiles between preterm infants with and without brain injury. Materials and methods Three cohorts of preterm infants were used. Blood samples were collected soon after birth for the first cohort and late timepoint for the second and third cohorts. In the first cohort (88 infants), flow cytometry measured the proportions of αβT and γδT cell subsets in peripheral blood, analyzing associations with gestational age, birth weight, sex, delivery type, and maternal conditions. The second cohort focused on the relationship between T cell subsets and brain injury. In the third cohort, transcriptome sequencing identified differentially expressed genes and pathways in infants with brain injury, highlighting immune-related changes. Results Infants born at 29–30 weeks or with a birth weight of 1000–1500 g had significantly higher proportions of Vδ2+ T cells compared to those born at 30–32 weeks or with a birth weight > 1500 g, while no significant difference was found between infants born at

PARP1 (poly-ADP ribose polymerase 1) is recruited and activated by DNA strand breaks, catalyzing the generation of poly-ADP-ribose (PAR) chains from NAD+. PAR relaxes chromatin and recruits other DNA repair factors, including XRCC1 and DNA Ligase 3, to maintain genomic stability. Here we show that, in contrast to the normal development of Parp1-null mice, heterozygous expression of catalytically inactive Parp1 (E988A, Parp1+/A) acts in a dominant-negative manner to disrupt murine embryogenesis. As such, all the surviving F1 Parp1+/A mice are chimeras with mixed Parp1+/AN (neoR retention) cells that act similarly to Parp1+/A. Pure F2 Parp1+/A embryos were found at Mendelian ratios at the E3.5 blastocyst stage but died before E9.5. Compared to Parp1-/- cells, genotype and expression-validated pure Parp1+/A cells retain significant ADP-ribosylation and PARylation activities but accumulate markedly higher levels of sister chromatid exchange and mitotic bridges. Despite proficiency for homologous recombination and nonhomologous end-joining measured by reporter assays and supported by normal lymphocyte and germ cell development, Parp1+/A cells are hypersensitive to base damages, radiation, and Topoisomerase I and II inhibition. The sensitivity of Parp1+/A cells to base damages and Topo inhibitors exceed Parp1-/- controls. The findings show that the enzymatically inactive PARP1 dominant negatively blocks DNA repair in selective pathways beyond wild-type PARP1 and establishes a crucial physiological difference between PARP1 inactivation vs. deletion. As a result, the expression of enzymatically inactive PARP1 from one allele is sufficient to abrogate murine embryonic development, providing a mechanism for the on-target side effect of PARP inhibitors used for cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract Wazwaz Kaur Boussinesq (WKB) equation can effectively simulate the behavior of water waves in shallow water, including the nonlinear effect and dispersion phenomenon of waves, which is of great significance for understanding the dynamic process of ocean, river and other water bodies. To enrich the wave equation theory, the (3+1)-dimensional integer order derivative of WKB equation is changed to the fractional one with beta derivative. The current work deals with the fractional (3+1)-dimensional WKB equation for discussing its chaotic behavior and establishing some new analytic solutions. The chaotic properties of the equation are verified by the trend of evolution along with time, Lyapunov exponents and initial sensitivity analysis. And then complete discrimination system for polynomial method is applied to derive some trigonometric, hyperbolic, Jacobi elliptic and other solutions. The graphical demonstrations are provided for part of these solutions. From these visualized graphs, the solitary, periodic and quasi-periodic wave are shown and the effect of fractional derivatives on the equation can be seen intuitively.

Abstract Objective This study aims to conduct an unbiased assessment of the synergistic effects of non-pharmacological Interventions of intermittent fasting and pulsed radiofrequency energy (PRFE) combination therapy on the facilitation of diabetic wound healing, while also exploring the underlying mechanisms. The findings of this research will provide a theoretical framework and innovative strategy for unconventional therapeutic interventions aimed at enhancing the healing process of diabetes-related wounds. Methods In vivo experiments involved the induction of diabetic models in C57 mice through streptozotocin injection. To simulate a combined therapeutic approach, diabetic mice underwent fasting on days 2 and 6, accompanied by twice daily PRFE applications for 8 days. In vitro experiments were conducted using a serum-free culture medium to replicate fasting conditions. The investigation encompassed wound healing rate, proliferation, migration, angiogenesis, oxidative stress, fibrogenesis, and sensory nerve growth through histological analysis and functional assessments in vivo. Additionally, this study utilized quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting (WB), and immunofluorescence staining techniques to elucidate the potential mechanisms underlying the effects of intermittent Fasting and PRFE combination therapy in diabetic wound healing, both in vitro and in vivo. Results The intermittent fasting and PRFE combination therapy demonstrated superior efficacy in enhancing diabetic wound healing compared to either treatment alone. It harnessed the respective strengths of individual therapies, fostering migration, mitigating oxidative stress, and enhancing fibrogenesis. Furthermore, the combination therapy manifested a synergistic effect in promoting proliferation, tube formation, angiogenesis, and sensory nerve growth. Conclusion This study demonstrates that intermittent fasting and PRFE combination therapy enhance diabetic wound healing, effectively leveraging the strengths of both therapies and even yielding synergistic benefits. Moreover, it indicates the potential engagement of the P75/HIF1A/VEGFA axis in mediating these effects.

Abstract Objective To investigate the value of 7E instructional model in the teaching of nursing students in nursing clinical probation. Methods One hundred and fifty-nine nursing undergraduates of the class of 2018 who were on probation in our hospital from November 2020 to June 2021 were selected as the control group by convenience sampling, and the traditional teaching model was adopted; an additional 171 nursing undergraduates of the class of 2019 who were on clinical probation in the same hospital from November 2021 to June 2022 were selected as the experimental group, and the 7E instructional model was adopted, including elicit, engagement, exploration, explain, elaborate, evaluate and extend. Results After the intervention, the experimental group was higher than the control group in theoretical knowledge scores (59.47 ± 4.51 VS 54.11 ± 8.46), practical skills scores (19.62 ± 1.36 VS 19.14 ± 1.24) and total course scores (90.13 ± 2.98 VS 84.67 ± 4.47); total scores of learning motivation (30.57 ± 5.24 VS 29.41 ± 4.77), learning cooperation ability (20.35 ± 4.41 VS 19.02 ± 4.25), information literacy (23.14 ± 4.36 VS 21.12 ± 3.95) and self-regulated learning ability (114.00 ± 19.72 VS 109.07 ± 18.61); total scores of viewpoint acquisition (43.58 ± 5.21 VS 42.16 ± 5.10), emotional care (33.41 ± 4.54 VS 32.09 ± 4.47), transposition thinking (13.04 ± 2.97 VS 11.56 ± 2.43) and empathy ability (89.03 ± 13.87 VS 85.81 ± 13.55); and total scores of positive attitudes toward communication skills (55.39 ± 7.03 VS 51.54 ± 6.54), with a statistically significant difference (P

Abstract Background Patients with psoriatic arthritis (PsA) often suffer from anxiety disorders. While upadacitinib has shown effectiveness in reducing various disease activity indicators in active PsA, its impact on anxiety disorders in PsA patients needs further investigation. Methods In this 12-week randomized, open-label, controlled trial, PsA patients with coexisting anxiety were randomly assigned to either the upadacitinib group or the adalimumab group in a 1:1 ratio. The upadacitinib group received a daily dose of 15 mg, while the adalimumab group received 40 mg every 2 weeks. The primary outcome measured the change in Hospital Anxiety Self-Assessment Scale (HADS-A) total scores after the 12-week intervention. Secondary outcomes included changes in the Health Assessment Questionnaire-Disability Index (HAQ-DI), the percentage of participants meeting the ACR20 criteria compared to baseline after 12 weeks, and the percentage of participants achieving a grade 0 or 1 in the psoriasis static Investigator’s overall assessment (sPGA) at week 12 with an improvement of at least 2 points from baseline (sPGA 0/1). One-way analysis of variance (ANOVA) was used to compare the means of normally distributed variables between the upadacitinib and adalimumab groups. Discussion The impact of upadacitinib on anxiety in PsA patients remains uncertain. This 12-week open randomized controlled trial aims to provide insights into disease progression and underscore the importance of addressing PsA-related anxiety during treatment. Trial registration ChiCTR2400079755. Registered on January 11, 2024, with ChiCTR. https://www.chictr.org.cn/showproj.html?proj=216538

Abstract This study aims to investigate the potential relationships between the systemic immune-inflammation index (SII) and body mass index (BMI), waist circumference, and the prevalence of obesity. A cross-sectional analysis was conducted on 7,645 individuals aged 20 and above from the NHANES 2017–2020. Multivariate linear regression analyses were conducted to evaluate the association of the logarithmically transformed SII (lgSII) with BMI and waist circumference. Additionally, multivariable logistic regression was utilized to explore the relationship between lgSII and the prevalence of obesity. Fitted smoothing curves and threshold-effect analysis were applied to elucidate nonlinear relationships. In the fully adjusted model, a positive relationship was observed between lgSII and BMI, waist circumference, and obesity prevalence (β = 3.13, 95% CI 2.10–4.16; β = 7.81, 95% CI 5.50–10.13; OR = 1.44, 95% CI 1.12–1.86). The variables of gender, age, race, education, marital status, poverty income ratio (PIR), energy intake, sleep disorder, smoking status, and alcohol use did not significantly modify the positive association between lgSII and obesity. However, physical activity appeared to influence the positive correlation between lgSII and obesity. Using a two-segment linear regression model, an inverted U-shaped relationship was observed between lgSII and both BMI and waist circumference. Furthermore, lgSII demonstrated a linear positive correlation with obesity prevalence. When stratified by physical activity, lgSII showed a non-significant negative correlation with obesity in the physically active group. Our findings underscore a robust association between the logarithmically transformed SII and BMI, waist circumference, and the prevalence of obesity.

Abstract Background This study investigates the molecular mechanisms of CC@AC&SF@PP NPs loaded with AC099850.3 siRNA and sorafenib (SF) for improving hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). Methods A dataset of 44 HBV-HCC patients and their survival information was selected from the TCGA database. Immune genes related to survival status were identified using the ImmPort database and WGCNA analysis. A prognostic risk model was constructed and analyzed using Lasso regression. Differential analysis was performed to screen key genes, and their significance and predictive accuracy for HBV-HCC were validated using Kaplan–Meier survival curves, ROC analysis, CIBERSORT analysis, and correlation analysis. The correlation between AC099850.3 and the gene expression matrix was calculated, followed by GO and KEGG enrichment analysis using AC099850.3 and its co-expressed genes. HepG2.2.15 cells were selected for in vitro validation, and lentivirus interference, cell cycle determination, CCK-8 experiments, colony formation assays, Transwell experiments, scratch experiments, and flow cytometry were performed to investigate the effects of key genes on HepG2.2.15 cells. A subcutaneous transplanted tumor model in mice was constructed to verify the inhibitory effect of key genes on HBV-HCC tumors. Subsequently, pH-triggered drug release NPs (CC@AC&SF@PP) were prepared, and their therapeutic effects on HBV-HCC in situ tumor mice were studied. Results A prognostic risk model (AC012313.9, MIR210HG, AC099850.3, AL645933.2, C6orf223, GDF10) was constructed through bioinformatics analysis, showing good sensitivity and specificity in diagnostic prediction. AC099850.3 was identified as a key gene, and enrichment analysis revealed its impact on cell cycle pathways. In vitro cell experiments demonstrated that AC099850.3 promotes HepG2.2.15 cell proliferation and invasion by regulating immune checkpoint CD276 expression and cell cycle progression. In vivo, subcutaneously transplanted tumor experiments showed that AC099850.3 promotes the growth of HBV-HCC tumors in nude mice. Furthermore, pH-triggered drug release NPs (CC@AC&SF@PP) loaded with AC099850.3 siRNA and SF were successfully prepared and delivered to the in situ HBV-HCC, enhancing the effectiveness of combined therapy for HBV-HCC. Conclusions AC099850.3 accelerates the cell cycle progression and promotes the occurrence and development of HBV-HCC by upregulating immune checkpoint CD276 expression. CC@AC&SF@PP NPs loaded with AC099850.3 siRNA and SF improve the effectiveness of combined therapy for HBV-HCC.

The nonhomologous end-joining (NHEJ) pathway is a major DNA double-strand break repair pathway in mammals and is essential for lymphocyte development. Ku70 and Ku80 heterodimer (KU) initiates NHEJ, thereby recruiting and activating the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). While DNA-PKcs deletion only moderately impairs end-ligation, the expression of kinase-dead DNA-PKcs completely abrogates NHEJ. Active DNA-PK phosphorylates DNA-PKcs at two clusters--PQR around S2056 (S2053 in mouse) and ABCDE around T2609. Alanine substitution at the S2056 cluster moderately compromises end-ligation on plasmid-based assays. But, mice carrying alanine substitution at all five serine residues within the S2056 cluster (DNA-PKcsPQR/PQR) display no defect in lymphocyte development, leaving the physiological significance of S2056 cluster phosphorylation elusive. Xlf is a nonessential NHEJ factor. Xlf-/- mice have substantial peripheral lymphocytes that are completely abolished by the loss of DNA-PKcs, the related ATM kinases, other chromatin-associated DNA damage response factors (e.g., 53BP1, MDC1, H2AX, and MRI), or RAG2-C-terminal regions, suggesting functional redundancy. While ATM inhibition does not further compromise end-ligation, here we show that in XLF-deficient background, DNA-PKcs S2056 cluster phosphorylation is critical for normal lymphocyte development. Chromosomal V(D)J recombination from DNA-PKcsPQR/PQR Xlf-/- B cells is efficient but often has large deletions that jeopardize lymphocyte development. Class-switch recombination junctions from DNA-PKcsPQR/PQR Xlf-/- mice are less efficient and the residual junctions display decreased fidelity and increased deletion. These findings establish a role for DNA-PKcs S2056 cluster phosphorylation in physiological chromosomal NHEJ, implying that S2056 cluster phosphorylation contributes to the synergy between XLF and DNA-PKcs in end-ligation. [ABSTRACT FROM AUTHOR]

Abstracts: An on-site, sensitive, and cost-effective method for determining aflatoxin B1 (AFB1) in rice samples is proposed, combining magnetic solid phase extraction (MSPE) and time-resolved fluorescence immunochromatography (TRFICA) techniques. Cost-effective rice husks were carbonized and combined with nanomaterials to make magnetic nanocomposites that acted as effective adsorbents in MSPE. Under optimal conditions, the entire process was completed in 15 min with a visual detection limit of 0.16 μg/kg. Recoveries ranged from 85.2 % to 109.4 %, with intra- and inter-day precisions below 11.5 %. The proposed MSPE-TRFICA method offers a viable alternative for the rapid and highly sensitive quantitative detection of AFB1 for quality assurance.

IntroductionAfter being discovered for the first time in China in 2017, porcine reproductive and respiratory syndrome virus (PRRSV) NADC34-like strains have become the prevalent strain of PRRSV in certain regions of China. Our previous study showed that reduced Ingelvac PRRS MLV vaccination dosages against NADC30-like CF PRRSV had a better protection effect than the normal dosage. However, the protective effect of reduced dosages vaccination of Ingelvac PRRS MLV against NADC34-like PRRSV is unclear. Therefore, this study compared the effectiveness of 0.1 and 1 dosages against a NADC34-like PRRSV infection using commercial PRRSV vaccines, Ingelvac PRRS MLV, which have been widely utilized in China.MethodsIn this study, we immunized piglets with two different dosages of the MLV vaccine and infected piglets within a nasal way with NADC34-like CF PRRSV at 42 days post-vaccination. We observed the changes in growth performance before and after the NADC34-like PRRSV DX strain challenge and the protective effect of different vaccine dosages through multiple assays.ResultsAfter the challenge, the piglets from the challenge control group displayed clinical signs typical of PRRSV infection, including transient fever, high viremia, mild clinical symptoms, and histopathological changes in the lungs and lymph nodes, which indicates DX is a virulent virus. Without the challenge, the average daily gain of the non-immunized group at 5 weeks after the vaccination is greater than that of the 0.01 dosage group than that of the 1 dosage group, which proved that the commercial MLV vaccine has a negative effect on the growth performance of pigs and this effect may be dose-dependent. After the NADC34-like PRRSV challenge, there was no difference in average daily gain between the immunized pigs and pigs from the challenge control group. From the perspective of clinical score, gross lung lesions, and microscopic lesions, immunization with MLV vaccine can indeed relieve symptoms and lesions caused by the virus, and 0.1 dosage vaccination has a better effect in these aspects. Also, both dosages of MLV immunization shortened viremia with similar effects.DiscussionOur research suggests that the MLV vaccine can provide piglets with some protection against NADC34-like PRRSV and the 0.1 dosage Ingelvac PRRS MLV vaccination showed greater benefits in our study. Therefore, considering the cost, side effects, and subsequent protective effects, we can adjust the immune dosage appropriately after further investigation to ensure safety, improve production efficiency, and reduce immunization costs.

IntroductionUV-B can be used as an additional technique for nutrient accumulation in blue-grained wheat, which has special nutritional properties due to its blue starch layer. The concentration of flavonoids in blue-grained wheat under UV-B irradiation is extremely important for further investigation and exploitation of the nutritional properties of blue-grained wheat.MethodsThis investigation focuses on the expression of flavonoids and associated genes in blue-grained wheat using transcriptomic and metabolomic analyzes.ResultsThe metabolome revealed 1846 compounds and 340 flavonoids after UV-B irradiation. Under UV-B irradiation, the amount of flavonoid metabolites decreased over time, but flavones and flavanols increased, and flavones and flavanols were more diverse and abundant. The content of some flavonoids of blue-grain wheat in period 2 was significantly higher under UV-B irradiation than its check and other periods of different treatments. There are 42344 differentially expressed genes identified from transcriptomic analysis, including 151 genes associated with the flavonoid pathway. The genes for the enzymes FLS, ANR, HCT, CYP75A and CYP73A are more abundant, with F3H and FLS showing higher expression levels.DiscussionThe expression of these genes decreased after early UV-B irradiation, but increased later. In the joint WGCNA study of the two groups, the FLS enzyme gene LOC123125079 plays an important role in the response of blue-grained wheat to UV-B irradiation. Our findings help to identify essential genes and processes that allow blue-grained wheat to respond appropriately to UV-B irradiation, which is critical for the accumulation of flavonoids and other bioactive compounds in colored wheat, maximising its nutritional properties.

ABSTRACTCoxiella burnetii (C. burnetii) is the causative agent of Q fever, a zoonotic disease. Intracellular replication of C. burnetii requires the maturation of a phagolysosome-like compartment known as the replication permissive Coxiella-containing vacuole (CCV). Effector proteins secreted by the Dot/Icm secretion system are indispensable for maturation of a single large CCV by facilitating the fusion of promiscuous vesicles. However, the mechanisms of CCV maintenance and evasion of host cell clearance remain to be defined. Here, we show that C. burnetii secreted Coxiella vacuolar protein E (CvpE) contributes to CCV biogenesis by inducing lysosome-like vacuole (LLV) enlargement. LLV fission by tubulation and autolysosome degradation is impaired in CvpE-expressing cells. Subsequently, we found that CvpE suppresses lysosomal Ca2+ channel transient receptor potential channel mucolipin 1 (TRPML1) activity in an indirect manner, in which CvpE binds phosphatidylinositol 3-phosphate [PI(3)P] and perturbs PIKfyve activity in lysosomes. Finally, the agonist of TRPML1, ML-SA5, inhibits CCV biogenesis and C. burnetii replication. These results provide insight into the mechanisms of CCV maintenance by CvpE and suggest that the agonist of TRPML1 can be a novel potential treatment that does not rely on antibiotics for Q fever by enhancing Coxiella-containing vacuoles (CCVs) fission.

Objectives T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) are highly malignant and aggressive hematologic tumors for which there is no standard first-line treatment. Chidamide, a novel histone deacetylase inhibitor, shows great promise. We assessed the efficacy and safety of an irradiation-containing conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and post-transplantation chidamide maintenance in patients with T-ALL/LBL.Methods We retrospectively analyzed the clinical data of six patients with T-ALL/LBL who underwent allo-HSCT with a radiotherapy-containing pretreatment regimen and post-transplant chidamide maintenance therapy. The endpoints were relapse, graft-versus-host disease (GVHD), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).Results All of the patients had uneventful post-transplant hematopoietic reconstitution, and all achieved complete molecular remission within 30 days. All six patients survived, and two relapsed with a median relapse time of 828.5 (170–1335) days. The 1-year OS rate was 100%, the 2-year PFS rate was 66.7%, and the TRM rate was 0%. After transplantation, two patients developed grade I-II acute GVHD (2/6); grade III-IV acute and chronic GVHD were not observed. The most common AEs following chidamide administration were hematological AEs, which occurred to varying degrees in all patients; liver function abnormalities occurred in two patients (grade 2), and symptoms of malaise occurred in one patient (grade 1).Conclusion Chidamide maintenance therapy after T-ALL/LBL transplantation is safe, but the efficacy needs to be further investigated.

Backgroud Li-Fraumeni syndrome is a hereditary tumor syndrome characterized by an elevated risk of malignancy, particularly acute lymphoblastic leukemia (ALL), which can be caused by the heterozygous germline mutation. TP53 gene germline mutation is considered a potential risk factor and crucial prognostic parameter for acute leukemia development and diagnosis, but rarely occurs in adults, and its specific pathogenic significance in acute leukemia is unclear.Case presentation We describes a case of a 45-year-old woman diagnosed with ALL. Whole-exome sequencing approach identified one of the TP53 germline mutations from her bone marrow sample with possible pathogenic significance, c.848G>A (p.Arg283His) heterozygous missense mutation located on exon 8, which was further verified in her hair, oral mucous and nail samples. Family pedigree screening revealed that the same TP53 genetic variant was present in the patient's father and non-donor son, whereas not in the donor. Digital PCR observed that this point mutation frequency dropped post-transplantation but remained low during maintenance therapy when the patient was leukemia-free.Conclusion This suspected Li-Fraumeni syndrome case report with a likely pathogenic heterozygous TP53 variant expands the cancer genetic spectrum. Screening her family members for mutations facilitates identifying the optimal relative donor and avoids unnecessary treatment by monitoring TP53 germline mutations for minimal residual disease following hematopoietic stem cell transplantation. Its potential roles in hematological malignant tumor development and clinical pathogenic implications necessitate further probing.

Chinese baijiu is highly regarded for its unique flavor, and a variety of crops can be utilized as raw materials in its production. Waxy crops are essential ingredients in the brewing of high-quality baijiu; however, there is currently no comprehensive identification of volatile organic compounds (VOCs) and non-volatile compounds (N-VOCs) in waxy wheat baijiu (WWB). This study aims to investigate the dynamic changes of VOCs and N-VOCs in WWB during several important time periods from new to aged. A total of 25 amino acids underwent changes in the samples, with numerous physiologically active beneficial amino acids showing significant accumulation after aging. Additionally, 517 VOCs changed after aging, predominantly comprising esters and terpenoids, with 72 major VOCs being identified. A total of 718 metabolites were identified in the metabolome, primarily comprising alterations in lipids, amino acids, phenolic acids, organic acids, and alkaloids. These metabolites significantly influenced the levels of amino acids and VOCs. Our study is the first to provide a comprehensive examination of these aspects of WWB, highlighting its unique advantages over other crops. We believe that this research will establish a theoretical foundation for the application of waxy wheat in the baijiu industry, improve baijiu quality, and promote the development of functional baijius.

The phenomenon of transforming natural marine space into proliferative capital holds global significance in modern modes of production. Under China’s socialist market economy, the property rights system and resource allocation methods have created a unique approach to the capitalization of marine space. Drawing on concepts related to the capitalization of space and land, this paper develops the idea of the capitalization of marine space. It is a process where the right to use the sea area is transferred by the rights holders through methods such as transfer, lease, or shares and is ultimately put into production as a means of production to realize the creation of capital value and surplus value. Using the mariculture industry on Guanglu Island in Changhai County as a case, this analysis delves into the process and mechanisms of the capitalization of marine space in China, the world’s leading mariculture nation, while considering the material agency of marine space. The research results show that: ① The specific realization process of marine space capitalization in the mariculture industry has gone through three stages: from natural marine space to marine space resources, from marine space resources to marine space assets, and the participation of marine space assets in creating value and surplus value. ② The material agency of marine space determines the feasibility of the capitalization of marine space and is also the decisive subject in shaping the specific practice of capitalization. The survival and profit needs of mariculture fishermen and enterprises drive the realization of the capitalization of marine space. China’s central and local governments participate in realizing the capitalization of marine space with the relevant institutional policies and norms aimed at economic development.

Ethnic minority settlements, as an important medium for the transmission of ethnic cultures, are also a key resource for accelerating the development of ethnic minorities and the regions where they are located. Currently, research on landscape patterns focuses on traditional villages and ancient villages, whereas there is a relative lack of discussion on ethnic minority settlements. This study focuses on the multi-ethnic Zahan Village in Hainan Province, adopting the analysis methods of landscape pattern index and land-use transfer matrix, based on the theoretical framework of landscape ecology, to systematically analyze the spatial and temporal characteristics of the landscape pattern of the village and its patterns between 2007 and 2022, and to qualitatively analyze the influencing factors of its landscape changes from two dimensions, namely, humanities and nature. Research findings: (1) As the dominant landscape type, the proportion of woodland (although decreasing year by year) still exceeds 80%, whereas other land types, such as watersheds and grasslands, are gradually transformed into construction land and arable land, whose increment is significant. (2) During the study period, Throughout the study period, the landscape homogeneity of Zahan Village became better and better, the landscape types tended to be richer, and the spatial heterogeneity of the landscape also increased. (3) The area of woodland landscapes shows a decreasing trend from year to year, whereas construction land and arable land show an overall increasing trend, and the area of watersheds and meadows also decreases slightly. (4) The village landscape is mainly spatially “clustered,” concentrated in the center and southern part of the village, with a few “dots” distributed in the east and northwest, and the overall trend is spreading from the center to the periphery. (5) The evolution of village landscapes is influenced by a combination of human factors, including demographic, economic, and policy factors, as well as natural geographic factors, such as topography, climate change, and precipitation. The study provides theoretical support and practical guidance for the sustainable development of Zahan Village, as well as valuable experience and inspiration for the optimal development of other minority villages.

The stochastic coupled Maccari's system (MS) is a kind of important nonlinear partial differential equations to describe fluid flow, plasma physics, nonlinear optics and so on. In this article, the dynamical behavior and some new exact traveling wave solutions of the system are investigated. By means of complex traveling wave transformation, the system is transformed into a nonlinear ordinary differential equation. The dynamical behavior of the system as well as its perturbation case are illustrated by bifurcation theory. And then, some new stochastic traveling wave solutions of the system are extracted based on the theory of polynomial complete discrimination system. To show the effect of stochastic factor on the solutions, their structures under different Brownian motion amplitudes are compared by several sets of graphs. The results obtained in this paper have supplemented the study of the system, and the technique used to exploit the traveling wave solutions are effective.

IntroductionAt present, the NADC30-like strain has become the prevalent strain of PRRSV in China. Many studies have found that existing commercial vaccines are ineffective or provide only limited protection. No study has investigated the cross-protection of different dosages of commercial MLV vaccines against NADC30-like PRRSV. Therefore, this study assessed the effectiveness of various dosages against a NADC30-like PRRSV infection using commercial PRRSV vaccines, Ingelvac PRRS MLV, which have been widely utilized in China.MethodsIn this study, we immunized piglets with four different dosages of the MLV vaccine and infected piglets within a nasal way with NADC30-like CF PRRSV at 28 days post-vaccination. We observed the status of pigs before and after the challenge of NADC30-like PRRSV CF strain and reflected the protective effect of different dosages of MLV vaccine through multiple assays.ResultsCompared to those piglets immunized with 1 dosage, the piglets immunized with 0.01 dosage had better performance, such as the highest average daily gain before the challenge, lesser lesions and viremia after the challenge, low clinical score, and stable temperature during the study. However, the piglets immunized with 0.01 dosage still showed viremia, viruses were detected in their lungs, tonsils, and inguinal lymph nodes, and pathological lesions occurred in their lung. Immunohistochemistry staining of the lung of vaccinated piglets revealed a similar viral load to that of unvaccinated piglets, suggesting that immunization could not completely remove the virus from the vaccinated piglets’ tissues.DiscussionOur research suggests that the MLV vaccine could provide limited protection against the NADC30-like PRRSV infection, and lowering the dosage to 0.01 may produce better protective efficacy. In the context of identifying the immunological target, comprehending the virulence of the virus in the field, and guaranteeing safety, we might be able to reevaluate vaccination dosages to achieve higher economic value.

BackgroundThe cognitive development of children and adolescents is crucial for their academic success and overall well-being. Physical activity has been linked to improved cognitive performance, but the specific effects of football training on cognitive function in this population remain unclear. This meta-analytic review aimed to comprehensively evaluate the impact of football training on cognitive performance in children and adolescents.MethodsLiterature was searched through PubMed, PsycINFO, SPORTDiscus, Embase, and Web of Science. Eligible studies were randomized controlled trials (RCTs) or crossover designs assessing cognitive performance following football training interventions. Outcome measures included attention, inhibitory control, and working memory. Data synthesis and meta-analysis were performed to determine the overall effect sizes.ResultsTwelve studies were included in the meta-analysis, comprising 1,574 children and 94 adolescents. Football training demonstrated moderate, statistically significant effects on attention (Hedges’ g = −0.77, p = 0.01), inhibitory control (Hedges’ g = −0.67, p = 0.02), and working memory (Hedges’ g = −0.44, p = 0.03). The findings suggest that football training positively influences cognitive performance in children and adolescents.ConclusionFootball training holds promise for enhancing cognitive function in children and adolescents, particularly in attention, inhibitory control, and working memory. Theoretical frameworks emphasizing environmental enrichment, cardiovascular fitness, and cognitive component skills help elucidate the underlying mechanisms. Future research should explore how football training compares to other sports and assess whether integrative drills that combine cognitive elements with skill practice offer greater cognitive benefits than skill training alone. These insights support the inclusion of football in educational programs to foster cognitive development.

Scutellarin (SCU), a flavonoid glucuronide derived from Scutellaria barbata and Erigeron breviscapus, exhibits broad pharmacological effects with promising therapeutic potential in treating various chronic diseases. It has demonstrated efficacy in modulating multiple biological pathways, including antioxidant, anti-inflammatory, anti-apoptotic, and vasodilatory mechanisms. These protective roles make SCU a valuable compound in treating chronic diseases such as cerebrovascular diseases, cardiovascular diseases, neurodegenerative disorders, and metabolic diseases. Despite its multi-targeted effects, SCU faces challenges such as low bioavailability and limited clinical data, which hinder its widespread therapeutic application. Current research supports its potential to prevent oxidative stress, reduce inflammatory responses, and enhance cell survival in cells and rats. However, more comprehensive studies are required to clarify its molecular mechanisms and to develop strategies that enhance its bioavailability for clinical use. SCU could emerge as a potent therapeutic agent for the treatment of chronic diseases with complex pathophysiological mechanisms. This review examines the current literature on Scutellarin to provide a comprehensive understanding of its pharmacological activity, mechanisms of action, and therapeutic potential in treating chronic diseases.