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Abstract Background TBK1 positively regulates the growth factor-mediated mTOR signaling pathway by phosphorylating mTOR. However, it remains unclear how the TBK1-mTOR signaling pathway is regulated. Considering that STING not only interacts with TBK1 but also with MARCH1, we speculated that MARCH1 might regulate the mTOR signaling pathway by targeting TBK1. The aim of this study was to determine whether MARCH1 regulates the mTOR signaling pathway by targeting TBK1. Methods The co-immunoprecipitation (Co-IP) assay was used to verify the interaction between MARCH1 with STING or TBK1. The ubiquitination of STING or TBK1 was analyzed using denatured co-immunoprecipitation. The level of proteins detected in the co-immunoprecipitation or denatured co-immunoprecipitation samples were determined by Western blotting. Stable knocked-down cells were constructed by infecting lentivirus bearing the related shRNA sequences. Scratch wound healing and clonogenic cell survival assays were used to detect the migration and proliferation of breast cancer cells. Results We showed that MARCH1 played an important role in growth factor-induced the TBK1- mTOR signaling pathway. MARCH1 overexpression attenuated the growth factor-induced activation of mTOR signaling pathway, whereas its deficiency resulted in the opposite effect. Mechanistically, MARCH1 interacted with and promoted the K63-linked ubiquitination of TBK1. This ubiquitination of TBK1 then attenuated its interaction with mTOR, thereby inhibiting the growth factor-induced mTOR signaling pathway. Importantly, faster proliferation induced by MARCH1 deficiency was weakened by mTOR, STING, or TBK1 inhibition. Conclusion MARCH1 suppressed growth factors mediated the mTOR signaling pathway by targeting the STING-TBK1-mTOR axis.

Abstract Background Despite evidence supporting the high correlation of the novel platelet-to-albumin ratio (PAR) with survival in diverse malignancies, its prognostic relevance in nasopharyngeal carcinoma (NPC) remains underexplored. This study aimed to examine the link between PAR and overall survival (OS) in NPC and to establish a predictive model based on this biomarker. Methods We retrospectively assembled a cohort consisting of 858 NPC patients who underwent concurrent chemoradiotherapy (CCRT). Utilizing the maximally selected log-rank method, we ascertained the optimal cut-off point for the PAR. Subsequently, univariate and multivariate Cox proportional hazards models were employed to discern factors significantly associated with OS and to construct a predictive nomogram. Further, we subjected the nomogram’s predictive accuracy to rigorous independent validation. Results The discriminative optimal PAR threshold was determined to be 4.47, effectively stratifying NPC patients into two prognostically distinct subgroups (hazard ratio [HR] = 0.53; 95% confidence interval [CI]: 0.28–0.98, P = 0.042). A predictive nomogram was formulated using the results from multivariate analysis, which revealed age greater than 45 years, T stage, N stage, and PAR score as independent predictors of OS. The nomogram demonstrated a commendable predictive capability for OS, with a C-index of 0.69 (95% CI: 0.64–0.75), surpassing the performance of the conventional staging system, which had a C-index of 0.56 (95% CI: 0.65–0.74). Conclusions In the context of NPC patients undergoing CCRT, the novel nutritional-inflammatory biomarker PAR emerges as a promising, cost-efficient, easily accessible, non-invasive, and potentially valuable predictor of prognosis. The predictive efficacy of the nomogram incorporating the PAR score exceeded that of the conventional staging approach, thereby indicating its potential as an enhanced prognostic tool in this clinical setting.

To explore the effect of slightly acidic electrolyzed water (SAEW) on the storage quality of postharvest chives, the changes in the microbial load and storage quality of postharvest chives subjected to SAEW immersion treatment at different concentrations (0, 100, 200 and 300 mg/L) for 5 minutes were analyzed during low temperature ((4 ± 1) ℃) storage. The results showed that immersion treatment with 200 mg/L SAEW was more effective in maintaining the organoleptic quality of chives and inhibiting the increase of the total number of colonies when compared with the other groups. Furthermore, 200 mg/L SAEW treatment was able to inhibit the increase of mass loss and rot rate, slow down the decrease of chlorophyll, vitamin C, soluble sugar, and soluble protein contents, and reduce the accumulation of total free amino acids, malondialdehyde (MDA) and nitrite in chives. It is evident that immersion treatment with 200 mg/L SAEW can not only effectively inhibit microbial growth on chives during low-temperature storage, but also effectively delay the loss of nutrients in chives, thus improving the quality preservation of chives. Therefore, SAEW can be used as an effective sterilization and preservation method to maintain the storage quality and delay the aging process of postharvest chives.

PurposeThe goal of the study was to create a nomogram based on clinical risk factors to forecast the rate of locoregional recurrence-free survival (LRFS) in patients with esophageal squamous cell carcinoma (ESCC) who underwent radiotherapy (RT).MethodsIn this study, 574 ESCC patients were selected as participants. Following radiotherapy, subjects were divided into training and validation groups at a 7:3 ratio. The nomogram was established in the training group using Cox regression. Performance validation was conducted in the validation group, assessing predictability through the C-index and AUC curve, calibration via the Hosmer-Lemeshow (H-L) test, and evaluating clinical applicability using decision curve analysis (DCA).ResultsT stage, N stage, gross tumor volume (GTV) dose, location, maximal wall thickness (MWT) after RT, node size (NS) after RT, Δ computer tomography (CT) value, and chemotherapy were found to be independent risk factors that impacted LRFS by multivariate cox analysis, and the findings could be utilized to create a nomogram and forecast LRFS. the area under the receiver operating characteristic (AUC) curve and C-index show that for training and validation groups, the prediction result of LRFS using nomogram was more accurate than that of TNM. The LRFS in both groups was consistent with the nomogram according to the H-L test. The DCA curve demonstrated that the nomogram had a good prediction effect both in the groups for training and validation. The nomogram was used to assign ESCC patients to three risk levels: low, medium, or high. There were substantial variations in LRFS between risk categories in both the training and validation groups (p

Abstract Background CRISPR-Cas9 technology has advanced in vivo gene therapy for disorders like hemophilia A, notably through the successful targeted incorporation of the F8 gene into the Alb locus in hepatocytes, effectively curing this disorder in mice. However, thoroughly evaluating the safety and specificity of this therapy is essential. Our study introduces a novel methodology to analyze complex insertion sequences at the on-target edited locus, utilizing barcoded long-range PCR, CRISPR RNP-mediated deletion of unedited alleles, magnetic bead-based long amplicon enrichment, and nanopore sequencing. Results We identified the expected F8 insertions and various fragment combinations resulting from the in vivo linearization of the double-cut plasmid donor. Notably, our research is the first to document insertions exceeding ten kbp. We also found that a small proportion of these insertions were derived from sources other than donor plasmids, including Cas9-sgRNA plasmids, genomic DNA fragments, and LINE-1 elements. Conclusions Our study presents a robust method for analyzing the complexity of on-target editing, particularly for in vivo long insertions, where donor template integration can be challenging. This work offers a new tool for quality control in gene editing outcomes and underscores the importance of detailed characterization of edited genomic sequences. Our findings have significant implications for enhancing the safety and effectiveness of CRISPR-Cas9 gene therapy in treating various disorders, including hemophilia A.

ABSTRACTBackground: Music therapy is increasingly examined in randomized controlled trials (RCTs) and shows potential in treating post-traumatic stress disorder (PTSD).Objective: This systematic review and meta-analysis critically evaluates the current clinical evidence supporting the efficacy and acceptability of music therapy for PTSD.Method: RCTs comparing music therapy in addition to care as usual (CAU) versus either CAU alone or CAU combined with standard psychotherapy/pharmacotherapy for PTSD were retrieved from major English – and Chinese-language databases. Standardized mean differences (SMDs) for post-treatment PTSD symptom scores and risk differences (RDs) for retention rates upon treatment completion were calculated to assess the efficacy and acceptability of music therapy, respectively. The Cochrane risk of bias (RoB) tool 2.0 and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) were used to assess the RoB of included studies and certainty of the evidence, respectively.Results: Nine studies, incorporating 527 PTSD patients, were included, all with high RoB. The post-treatment PTSD symptom scores were significantly lower in the music therapy group than the inactive control group (SMD = −1.64, P

Abstract A set of high-quality pan-genomes would help identify important genes that are still hidden/incomplete in bird reference genomes. In an attempt to address these issues, we have assembled a de novo chromosome-level reference genome of the Silkie (Gallus gallus domesticus), which is an important avian model for unique traits, like fibromelanosis, with unclear genetic foundation. This Silkie genome includes the complete genomic sequences of well-known, but unresolved, evolutionarily, endocrinologically, and immunologically important genes, including leptin, ovocleidin-17, and tumor-necrosis factor-α. The gap-less and manually annotated MHC (major histocompatibility complex) region possesses 38 recently identified genes, with differentially regulated genes recovered in response to pathogen challenges. We also provide whole-genome methylation and genetic variation maps, and resolve a complex genetic region that may contribute to fibromelanosis in these animals. Finally, we experimentally show leptin binding to the identified leptin receptor in chicken, confirming an active leptin ligand-receptor system. The Silkie genome assembly not only provides a rich data resource for avian genome studies, but also lays a foundation for further functional validation of resolved genes.

Background The prevalence of prolonged grief disorder (PGD) and its symptoms among the bereaved population in China vary considerably.Aims This meta-analysis aims to estimate the prevalence of PGD and its symptoms among bereaved individuals in China.Methods We conducted a literature search in major Chinese and English databases from their inception to 4 October 2023, for cross-sectional studies on the prevalence of PGD or its symptoms in bereaved Chinese individuals. The risk of bias of the included studies and certainty of the evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data (‘JBI checklist’) and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE), respectively. The ‘metaprop’ package in R V.4.1.2 was used to synthesise the prevalence.Results A total of 28 studies involving 10 994 bereaved individuals were included in the analysis, with JBI checklist scores between 3 and 7. The combined prevalence (95% confidence interval) of PGD and its symptoms was 8.9% (4.2% to 17.6%) and 32.4% (18.2% to 50.8%), respectively. PGD and its symptoms were most prevalent among those who had lost their only child (22.7%) and those bereaved by earthquakes (80.4%), respectively. The GRADE system assigned a very low certainty level to the evidence for the pooled prevalence of PGD and its symptoms.Conclusions The pooled prevalence of PGD and its symptoms indicate a potential high need for grief counselling services among bereaved individuals in China. This need is particularly pronounced in those who have lost their only child and those bereaved due to earthquakes. Further methodologically rigorous studies are needed to provide more accurate prevalence estimates.PROSPERO registration number CRD42023432553.

Background: Dexmedetomidine is known to prolong the analgesic duration of spinal anesthesia, but it can be challenging to achieve further extension without opioids. Therefore, this study aimed to investigate a novel analgesic strategy using dexmedetomidine as an adjuvant to spinal-epidural anesthesia for elective cesarean surgery. Methods: The study was a randomized, double-blind, controlled trial conducted at a single center. Sixty parturients who underwent elective cesarean were randomly assigned to either group C or group D. Group D received an intrathecal injection of 12.5 mg ropivacaine and 5 μg dexmedetomidine followed by continuous epidural patient-controlled analgesia (PCA) infusion with a total volume of 100 ml, containing 0.2 % ropivacaine and 0.5 μg/kg dexmedetomidine. Group C received an intrathecal injection of 12.5 mg ropivacaine with an equivalent saline placebo followed by a similar PCA infusion, containing 0.2 % ropivacaine and an equivalent saline placebo. Results: The primary outcome was visual analog scale score on movement at 24 h after surgery. The results showed that the rest and motion pain scores in group D were significantly lower than those in group C at 6 h, 12 h, and 24 h after surgery (P