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Abstract Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types, including osteoblast (OB) differentiation and function. Exactly how Wnt/β-catenin signaling is regulated in OBs remain elusive. ATP6AP2, an accessory subunit of V-ATPase, plays important roles in multiple cell types/organs and multiple signaling pathways. However, little is known whether and how ATP6AP2 in OBs regulates Wnt/β-catenin signaling and bone formation. Here we provide evidence for ATP6AP2 in the OB-lineage cells to promote OB-mediated bone formation and bone homeostasis selectively in the trabecular bone regions. Conditionally knocking out (CKO) ATP6AP2 in the OB-lineage cells (Atp6ap2 Ocn-Cre ) reduced trabecular, but not cortical, bone formation and bone mass. Proteomic and cellular biochemical studies revealed that LRP6 and N-cadherin were reduced in ATP6AP2-KO BMSCs and OBs, but not osteocytes. Additional in vitro and in vivo studies revealed impaired β-catenin signaling in ATP6AP2-KO BMSCs and OBs, but not osteocytes, under both basal and Wnt stimulated conditions, although LRP5 was decreased in ATP6AP2-KO osteocytes, but not BMSCs. Further cell biological studies uncovered that osteoblastic ATP6AP2 is not required for Wnt3a suppression of β-catenin phosphorylation, but necessary for LRP6/β-catenin and N-cadherin/β-catenin protein complex distribution at the cell membrane, thus preventing their degradation. Expression of active β-catenin diminished the OB differentiation deficit in ATP6AP2-KO BMSCs. Taken together, these results support the view for ATP6AP2 as a critical regulator of both LRP6 and N-cadherin protein trafficking and stability, and thus regulating β-catenin levels, demonstrating an un-recognized function of osteoblastic ATP6AP2 in promoting Wnt/LRP6/β-catenin signaling and trabecular bone formation.

Phosphine is a major fumigant for insects control in stored products. However, the current fumigation with aluminum phosphide to generate phosphine is facing many challenges, such as require manual operation, fumigation produce can’t be automatically performed, and management of residue contaminants. To address these issues, the study utilizes a combination of pure phosphine gas from cylinders and nitrogen from a membrane separation nitrogen generator. Phosphine and nitrogen are mixed at predetermined ratios, and the resulting gas mixture is delivered directly into sealed grain storage facilities via a controlled release device and circulated within the grain piles to ensure fumigant evenly distribution. This maintains effective phosphine concentrations within the storage facility. The exposure duration lasted for 13 days, during which phosphine concentrations were monitored, and the total mortality rate of adult insects within the grain piles was recorded. Within 9 hours of treatment initiation, gas concentrations reached 736 mL/m3, peaking at 1 160 mL/m3, with an effective average concentration above 200 mL/m3 sustained for 10 days. The gas circulated and distributed uniformly within the treated space, enabling effective control of major stored commodity pests within a relatively short exposure period.

Hepatocellular carcinoma (HCC) is a highly aggressive cancer with a poor prognosis. The molecular mechanisms underlying its development remain unclear. Recent studies have highlighted the crucial role of RNA modifications in HCC progression, which indicates their potential as therapeutic targets and biomarkers for managing HCC. In this review, we discuss the functional role and molecular mechanisms of RNA modifications in HCC through a review and summary of relevant literature, to explore the potential therapeutic agents and biomarkers for diagnostic and prognostic of HCC. This review indicates that specific RNA modification pathways, such as N6-methyladenosine, 5-methylcytosine, N7-methylguanosine, and N1-methyladenosine, are erroneously regulated and are involved in the proliferation, autophagy, innate immunity, invasion, metastasis, immune cell infiltration, and drug resistance of HCC. These findings provide a new perspective for understanding the molecular mechanisms of HCC, as well as potential targets for the diagnosis and treatment of HCC by targeting specific RNA-modifying enzymes or recognition proteins. More than ten RNA-modifying regulators showed the potential for use for the diagnosis, prognosis and treatment decision utility biomarkers of HCC. Their application value for HCC biomarkers necessitates extensive multi-center sample validation in the future. A growing number of RNA modifier inhibitors are being developed, but the lack of preclinical experiments and clinical studies targeting RNA modification in HCC poses a significant obstacle, and further research is needed to evaluate their application value in HCC treatment. In conclusion, this review provides an in-depth understanding of the complex interplay between RNA modifications and HCC while emphasizing the promising potential of RNA modifications as therapeutic targets and biomarkers for managing HCC.

Abstract This study aimed to evaluate the safety and efficacy of camrelizumab combined with chemotherapy during preoperative neoadjuvant therapy in patients with locally advanced resectable esophageal squamous cell carcinoma (ESCC) of clinical Stages II and III. The patients received camrelizumab plus chemotherapy regimen on Day 1 for up to three to four cycles (3 weeks per cycle). The probabilities of overall survival (OS) were 55.6% at 12 months and 35.6% at 18 months (45 patients). The disease‐free survival (DFS) rates were 70.0% at 12 months and 63.3% at 18 months (30 patients). The median OS and DFS were not reached. The proportion of patients at postneoadjuvant pathological tumor stages ypT0, ypT2, and ypT3 were 10 (33.3%), 14 (46.7%), and 6 (20.0%), respectively, and those at stages ypN0 and ypN1 were 19 (63.3%) and 11 (36.7%), respectively. Additionally, the pathological complete response rate was 33.3% (95% confidence interval [CI]: 0.154–0.512), and the major pathologic response rate was 46.7% (95% CI: 0.277–0.656). Grade ≥3 adverse events (AEs) were reported in five patients (11.1%), with vomiting being the most common AE (three patients; 3.3%). Other common AEs of any grade included decreased lymphocyte count (48.9%), reactive capillary endothelial proliferation (46.7%), decreased white blood cell count (40.0%), anemia (31.1%), and vomiting (31.1%). The combination of camrelizumab and neoadjuvant chemotherapy in patients with locally advanced resectable ESCC demonstrated promising efficacy and acceptable safety.

Abstract Background To evaluate retinal structural and functional changes after silicone oil (SO) removal in eyes with macula-off rhegmatogenous retinal detachment (RRD). Methods Best-corrected visual acuity (BCVA) testing, microperimetry, and optical coherence tomography angiography were performed in 48 eyes with macula-off RRD before and 3 months after SO removal. The values of healthy contralateral eyes were used as control data. Correlations between retinal vessel density (VD), retinal nerve fiber layer thickness (RNFLT), the interval between retinal detachment and surgery, the duration of SO tamponade, the follow-up time after SO removal, and visual function were analyzed. Results Significant increases in 2˚ fixation rate (FR), 4˚ FR, 2˚ mean retinal sensitivity (MRS), 6˚ MRS, parafoveal superficial capillary plexus VD and RNFLT were observed after SO removal (all P 0.05). Conclusion Retinal structure and function improved to different degrees after SO removal. Fixation stability and retinal sensitivity increased more than BCVA postoperatively. Retinal sensitivity, which was affected by the interval between retinal detachment and surgery and the duration of SO tamponade, gradually recovered after SO removal.

Lanthanum chloride and sodium p-aminosalicylate were used as raw materials to synthesize a new environmental-friendly accelerator lanthanum p-aminosalicylate (PAS-La) by precipitation method. The product was characterized and its mole-cular formula was determined to be La(C7H6NO3)3·H2O by elemental, thermal and infrared spectral analysis. The effects of PAS-La on the vulcanization characteristics, crosslinking density and mechanical pro-perties of natural rubber were investigated using rotorless vulcanzation apparatus, equilibrium swelling method and universal testing machine, and the vulcanization kinetics were analyzed. The results showed that with the increase of PAS-La amount, there was a maximum value of positive vulcanization time of natural rubber, and the scorch time firstly decreased and then increased. The crosslinking density of vulcanized rubber increased, and the mecha-nical properties were significantly enhanced. When PAS-La was added at amount of 1.2 phr (by mass), its vulcanization promotion effect on natural rubber was optimal. Kinetic calculations revealed that the reactivity of the crosslinked precursors was enhanced with the increase of PAS-La amount, and the activation energy decreased first and then increased.

Chronic obstructive pulmonary disease (COPD) and other respiratory diseases frequently present with airway mucus hypersecretion, which not only affects the patient's quality of life but also poses a constant threat to their life expectancy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, affects cell differentiation, tissue growth, and disease development. However, its role in airway mucus hypersecretion induced by COPD remains elusive. In this study, USP7 expression was significantly upregulated in airway epithelial samples from patients with COPD, and USP7 was also overexpressed in mouse lung and human airway epithelial cells in models of airway mucus hypersecretion. Inhibition of USP7 reduced the expression of nuclear factor kappa B (NF-κB), phosphorylated-NF-κB (p-NF-κB), and phosphonated inhibitor of nuclear factor kappa B (p-IκBα), and alleviated the airway mucus hypersecretion in vivo and in vitro. Further research revealed that USP7 stimulated airway mucus hypersecretion through the activation of NF-κB nuclear translocation. In addition, the expression of mucin 5AC (MUC5AC) was suppressed by the NF-κB inhibitor erdosteine. These findings suggest that USP7 stimulates the NF-κB signaling pathway, which promotes airway mucus hypersecretion. This study identifies one of the mechanisms regulating airway mucus secretion and provides a new potential target for its prevention and treatment.

Abstract Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population.

Abstract Introduction Parietal pleurectomy with bullectomy has been established as an effective method for preventing the recurrence of primary spontaneous pneumothorax (PSP). Our center introduced enhanced technical measures in uniportal thoracoscopic parietal pleurectomy with bullectomy for patients with PSP, aiming to document our initial experience and assess the procedure's effectiveness in preventing the recurrence of PSP. Methods We analyzed the clinical data of 86 patients with PSP who underwent the improved uniportal thoracoscopic parietal pleurectomy with bullectomy between July 2019 and August 2022. During the procedure, the parietal pleura above the second intercostal space was stripped but not removed. Instead, it was retained in the thoracic cavity using a piece of pedunculated pleura. Subsequently, the stumps of the lung were covered by the preserved parietal pleura. Results The results of the study showed that the mean operative time was 59.87 ± 16.93 min, and the postoperative drainage duration averaged 3.94 ± 2.17 days. The mean intraoperative blood loss was 24.33 ± 48.91 ml, and the mean postoperative drainage volume was 289.00 ± 170.03 ml. Prolonged air leakage for more than 5 days was observed in five patients (5.81%), but no other postoperative complications were recorded. During the follow‐up, one patient (1.16%) experienced a recurrence of pneumothorax. Conclusions The perioperative results of bullectomy with the improved pleurectomy technique are deemed satisfactory. The various technical steps attempted at our center are found to be feasible and safe, and they may contribute to reducing the rates of recurrence in PSP.

Abstract Background Domestication and introduction of dairy animals facilitated the permanent human occupation of the Tibetan Plateau. Yet the history of dairy pastoralism in the Tibetan Plateau remains poorly understood. Little is known how Tibetans adapted to milk and dairy products. Results We integrated archeological evidence and genetic analysis to show the picture that the dairy ruminants, together with dogs, were introduced from West Eurasia into the Tibetan Plateau since ~ 3600 years ago. The genetic admixture between the exotic and indigenous dogs enriched the candidate lactase persistence (LP) allele 10974A > G of West Eurasian origin in Tibetan dogs. In vitro experiments demonstrate that − 13838G > A functions as a LP allele in Tibetans. Unlike multiple LP alleles presenting selective signatures in West Eurasians and South Asians, the de novo origin of Tibetan-specific LP allele − 13838G > A with low frequency (~ 6–7%) and absence of selection corresponds − 13910C > T in pastoralists across eastern Eurasia steppe. Conclusions Results depict a novel scenario of genetic and cultural adaptations to diet and expand current understanding of the establishment of dairy pastoralism in the Tibetan Plateau.

Objectives: The prevalence of G6PD deficiency has not been reported in Yangjiang, a western city in Guangdong province. This study aims to investigate the molecular characteristics of G6PD deficiency in this region.Methods: Blood samples were collected from adults at a local hospital to screen for G6PD deficiency. The deficient samples were subjected to further analysis using PCR and reverse dot blot to determine the specific G6PD variants.Results: Among the 3314 male subjects, 250 cases of G6PD deficiency were found using the G6PD enzyme quantitative assay, resulting in a prevalence of 7.54% (250/3314) in the Yangjiang region. The prevalence of G6PD deficiency in females was 3.42% (176/5145). Out of the 268 cases of G6PD deficiency tested for G6PD mutations, reverse dot blot identified 20 different G6PD variants. The most common G6PD variant was c.1388G>A (81/268), followed by c.1376G>T (48/268), c.95A>G (32/268), c.1024C>T (9/268), c.392G>T (7/268), and c.871G>A/c.1311C>T (6/268). It was observed that c.871G>A was always linked to the polymorphism of c.1311C>T in this population.Conclusion: This investigation into G6PD deficiency in this area is expected to significantly improve our understanding of the prevalence and molecular characterization of this condition.

AIM: To explore the effects of anti-vascular endothelial growth factor(VEGF)agents(Conbercept)before pars plana vitrectomy(PPV)on inflammatory cytokine levels of patients with proliferative diabetic retinopathy(PDR).METHODS: A total of 49 patients(49 eyes)who diagnosed with PDR at the First Affiliated Hospital with Nanjing Medical University from June 2017 to January 2018 were recruited and randomly divided into two groups. A total of 25 cases(25 eyes)who did not receive intravitreal injection before PPV were included in no-intravitreal injection of Conbercept(IVC)group, and 24 cases(24 eyes)who received IVC 5～7d before PPV were included in IVC group. The vitreous samples were collected from all the patients at the start of PPV. Levels of VEGF-A, monocyte chemotactic protein-1(MCP-1)and inflammatory cytokines in the vitreous humor were measured using Luminex technology.RESULTS: Compared with the no-IVC group, the level of VEGF-A decreased significantly(P