DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).

In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA-protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3'-phospho-α,ß-unsaturated aldehyde (3'pUA) residue on SSB. The 3'pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3'pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA.

Dual chemical labeling enables nucleotide-resolution mapping of DNA abasic sites and common alkylation damage in human mitochondrial DNA.

Mitochondrial DNA (mtDNA) modifications play an emerging role in innate immunity and inflammatory diseases. Nonetheless, relatively little is known regarding the locations of mtDNA modifications. Such information is critically important for deciphering their roles in mtDNA instability, mtDNA-mediated immune and inflammatory responses, and mitochondrial disorders. The affinity probe-based enrichment of lesion-containing DNA represents a key strategy for sequencing DNA modifications. Existing methods are limited in the enrichment specificity of abasic (AP) sites, a prevalent DNA modification and repair intermediate. Herein, we devise a novel approach, termed dual chemical labeling-assisted sequencing (DCL-seq), for mapping AP sites. DCL-seq features two designer compounds for enriching and mapping AP sites specifically at single-nucleotide resolution. For proof of principle, we mapped AP sites in mtDNA from HeLa cells under different biological conditions. The resulting AP site maps coincide with mtDNA regions with low TFAM (mitochondrial transcription factor A) coverage and with potential G-quadruplex-forming sequences. In addition, we demonstrated the broader applicability of the method in sequencing other DNA modifications in mtDNA, such as N7-methyl-2'-deoxyguanosine and N3-methyl-2'-deoxyadenosine, when coupled with a lesion-specific repair enzyme. Together, DCL-seq holds the promise to sequence multiple DNA modifications in various biological samples.

Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation.

Unfolded protein response (UPR) is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. ER proteostasis is essential to adapt to cell proliferation and regeneration in development and tumorigenesis, but mechanisms linking UPR, growth control, and cancer progression remain unclear. Here, we report that the Ire1/Xbp1s pathway has surprisingly oncogenic and tumor-suppressive roles in a context-dependent manner. Activation of Ire1/Xbp1s up-regulates their downstream target Bip, which sequesters Yorkie (Yki), a Hippo pathway transducer, in the cytoplasm to restrict Yki transcriptional output. This regulation provides an endogenous defensive mechanism in organ size control, intestinal homeostasis, and regeneration. Unexpectedly, Xbp1 ablation promotes tumor overgrowth but suppresses invasiveness in a Drosophila cancer model. Mechanistically, hyperactivated Ire1/Xbp1s signaling in turn induces JNK-dependent developmental and oncogenic cell migration and epithelial-mesenchymal transition (EMT) via repression of Yki. In humans, a negative correlation between XBP1 and YAP (Yki ortholog) target gene expression specifically exists in triple-negative breast cancers (TNBCs), and those with high XBP1 or HSPA5 (Bip ortholog) expression have better clinical outcomes. In human TNBC cell lines and xenograft models, ectopic XBP1s or HSPA5 expression alleviates tumor growth but aggravates cell migration and invasion. These findings uncover a conserved crosstalk between the Ire1/Xbp1s and Hippo signaling pathways under physiological settings, as well as a crucial role of Bip-Yki interaction in tumorigenesis that is shared from Drosophila to humans.

The molecular chaperone mtHSC70-1 interacts with DjA30 to regulate female gametophyte development and fertility in Arabidopsis.

Arabidopsis mitochondria-targeted heat shock protein 70 (mtHSC70-1) plays important roles in the establishment of cytochrome c oxidase-dependent respiration and redox homeostasis during the vegetative growth of plants. Here, we report that knocking out the mtHSC70-1 gene led to a decrease in plant fertility; the fertility defect of the mutant was completely rescued by introducing the mtHSC70-1 gene. mtHSC70-1 mutants also showed defects in female gametophyte (FG) development, including delayed mitosis, abnormal nuclear position, and ectopic gene expression in the embryo sacs. In addition, we found that an Arabidopsis mitochondrial J-protein gene (DjA30) mutant, j30+/- , had defects in FG development and fertility similar to those of mtHSC70-1 mutant. mtHSC70-1 and DjA30 had similar expression patterns in FGs and interacted in vivo, suggesting that these two proteins might cooperate during female gametogenesis. Further, respiratory chain complex IV activity in mtHSC70-1 and DjA30 mutant embryo sacs was markedly downregulated; this led to the accumulation of mitochondrial reactive oxygen species (ROS). Scavenging excess ROS by introducing Mn-superoxide dismutase 1 or catalase 1 gene into the mtHSC70-1 mutant rescued FG development and fertility. Altogether, our results suggest that mtHSC70-1 and DjA30 are essential for the maintenance of ROS homeostasis in the embryo sacs and provide direct evidence for the roles of ROS homeostasis in embryo sac maturation and nuclear patterning, which might determine the fate of gametic and accessory cells.

Antibiotic resistance of Helicobacter pylori in Chinese children: A multicenter study from 2016 to 2023.

BACKGROUND: To investigate the antibiotic resistance of Helicobacter pylori (H. pylori) strains to clarithromycin, metronidazole, amoxicillin, levofloxacin, furazolidone, and tetracycline in Chinese children. MATERIALS AND METHODS: This multicenter, retrospective study was conducted from January 2016 through May 2023. Gastric mucosa biopsies were obtained from pediatric participants who underwent upper gastrointestinal endoscopy at 96 hospitals in northern, southwestern, and southeastern China. The susceptibility of H. pylori to six commonly used antibiotics was determined by agar dilution method. RESULTS: Among the 3074 H. pylori isolates, 36.7% were resistant to clarithromycin, 77.3% to metronidazole, 16.6% to levofloxacin, and 0.3% to amoxicillin. No strains were detected to be resistant to furazolidone or tetracycline. During the 8-year study period, resistance to clarithromycin and metronidazole showed a significant upward trend, while the resistance pattern of the other antibiotics demonstrated a slight but nonsignificant fluctuation. Significant regional differences were found in the distribution of clarithromycin resistance among the northern (66.0%), southwestern (48.2%), and southeastern (34.6%) regions. The metronidazole resistance rate was significantly lower in the southeastern coastal region (76.3%) than in the other two regions (88.2% in the north and 87.7% in the southwest). Multi-drug resistance for two or more antibiotics was detected in 36.3% of the H. pylori strains, and the predominant multi-resistance pattern was the dual resistance to clarithromycin and metronidazole. CONCLUSIONS: The prevalence of H. pylori resistance to clarithromycin and metronidazole is rather high in Chinese children and has been increasing over time. A relatively high resistance rate to levofloxacin was also noticed in children, while almost all strains were susceptible to amoxicillin, furazolidone, and tetracycline. It will be of great clinical significance to continuously monitor the antibiotic-resistance patterns of H. pylori in the pediatric population.

Evaluating the efficacy of laparoscopic radical antegrade modular pancreatosplenectomy in selected early-stage left-sided pancreatic cancer: a propensity score matching study.

BACKGROUND: Laparoscopic radical pancreatectomy is safe and beneficial for recectable pancreatic cancer, but the extent of resection for early-stage tumors remains controversial. METHODS: Consecutive patients with left-sided pancreatic cancer who underwent either laparoscopic radical antegrade modular pancreatosplenectomy (LRAMPS, n = 54) or laparoscopic distal pancreatosplecnectomy (LDP, n = 131) between October 2020 and December 2022 were reviewed. The preoperative radiological selection criteria were as follows: (1) tumor diameter ≤ 4 cm; (2) located ≥ 1 cm from the celiac trunk; (3) didn't invade the fascial layer behind the pancreas. RESULTS: After 1:1 propensity score matching (LRAMPS, n = 54; LDP, n = 54), baseline data were well-balanced with no differences. LRAMPS resulted in longer operation time (240.5 vs. 219.0 min, P = 0.020) and higher intraoperative bleeding volume (200 vs. 150 mL, P = 0.001) compared to LDP. Although LRAMPS harvested more lymph nodes (16 vs. 13, P = 0.008), there were no statistically significant differences in lymph node positivity rate (35.2% vs. 33.3%), R0 pancreatic transection margin (94.4% vs. 96.3%), and retroperitoneal margin (83.3% vs. 87.0%) rate. Postoperative complications did not significantly differ between the two groups. However, LRAMPS was associated with increased drainage volume (85.0 vs. 40.0 mL, P = 0.001), longer time to recover semi-liquid diet compared to LDP (5 vs. 4 days, P < 0.001) and increased daily bowel movement frequency. Tumor recurrence pattern and recurrence-free survival were comparable between the two groups, but the adjuvant chemotherapy regimens varied, and the completion rate of the 6-month intravenous chemotherapy was lower in the LRAMPS group compared to the LDP group (51.9% vs. 75.9%, P = 0.016). CONCLUSIONS: LRAMPS did not provide oncological benefits over LDP for left-sided pancreatic cancer within the selection criteria, but it increased operation time, intraoperative bleeding, and postoperative bowel movement frequency. These factors impacted the regimen selection and completion of adjuvant chemotherapy, consequently compromising the potential benefits of LRAMPS in achieving better local control.

Feasibility of laparoscopic versus open pancreatoduodenectomy following neoadjuvant chemotherapy for borderline resectable pancreatic cancer: a retrospective cohort study.

BACKGROUND: There is no evidence supporting the feasibility of laparoscopic pancreaticoduodenectomy (LPD) compared to open pancreatoduodenectomy (OPD) following neoadjuvant chemotherapy (NACT) for pancreatic ductal adenocarcinoma (PDAC). METHODS: The clinical data of consecutive patients with borderline resectable PDAC who received NACT and underwent either LPD or OPD between January 2020 and December 2022 at Fudan University Shanghai Cancer Center was prospectively collected and retrospectively analyzed. RESULTS: The analysis included 57 patients in the OPD group and 20 in the LPD group. Following NACT, the LPD group exhibited a higher median CA19-9 decrease rate compared to the OPD group (85.3% vs. 66.9%, P = 0.042). Furthermore, 3 anatomically borderline PDACs in the LPD group and 5 in the OPD group were downstaged into resectable status (30.0% vs. 12.3%, P = 0.069). According to RECIST criteria, 51 (66.2%) patients in the entire cohort were evaluated as having stable disease. The median operation time for the LPD group was longer than the OPD group (419 vs. 325 min, P < 0.001), while the venous resection rate was 35.0% vs. 43.9%, respectively (P = 0.489). There was no difference in the number of retrieved lymph nodes, with a median number of 18.5 in the LPD group and 22 in the OPD group, and the R1 margin rate (15.0% vs. 12.3%) was also comparable. The incidence of Clavien-Dindo complications (35.0% vs. 66.7%, P = 0.018) was lower in the LPD group compared to the OPD group. Multivariable regression analysis revealed that a tumor diameter > 3 cm before NACT (HR 2.185) and poor tumor differentiation (HR 1.805) were independent risk factors for recurrence-free survival, and a decrease rate of CA19-9 > 70% (OR 0.309) was a protective factor for early tumor recurrence and overall survival. CONCLUSIONS: LPD for PDAC following NACT is feasible and oncologically equivalent to OPD. Effective control of CA19-9 levels is beneficial in reducing early tumor recurrence and improving overall survival.

The 5'-phosphate enhances the DNA-binding and exonuclease activities of human mitochondrial genome maintenance exonuclease 1 (MGME1).

In higher eukaryotes, mitochondria play multiple roles in energy production, signaling, and biosynthesis. Mitochondria possess multiple copies of mitochondrial DNA (mtDNA), which encodes 37 genes that are essential for mitochondrial and cellular function. When mtDNA is challenged by endogenous and exogenous factors, mtDNA undergoes repair, degradation, and compensatory synthesis. mtDNA degradation is an emerging pathway in mtDNA damage response and maintenance. A key factor involved is the human mitochondrial genome maintenance exonuclease 1 (MGME1). Despite previous biochemical and functional studies, controversies exist regarding the polarity of MGME1-mediated DNA cleavage. Also, how DNA sequence may affect the activities of MGME1 remains elusive. Such information is not only fundamental to the understanding of MGME1 but critical for deciphering the mechanism of mtDNA degradation. Herein, we use quantitative assays to examine the effects of substrate structure and sequence on the DNA-binding and enzymatic activities of MGME1. We demonstrate that MGME1 binds to and cleaves from the 5'-end of single-stranded DNA substrates, especially in the presence of 5'-phosphate, which plays an important role in DNA binding and optimal cleavage by MGME1. In addition, MGME1 tolerates certain modifications at the terminal end, such as a 5'-deoxyribosephosphate intermediate formed in base excision repair. We show that MGME1 processes different sequences with varying efficiencies, with dT and dC sequences being the most and least efficiently digested, respectively. Our results provide insights into the enzymatic properties of MGME1 and a rationale for the coordination of MGME1 with the 3'-5' exonuclease activity of DNA polymerase γ in mtDNA degradation.

Sustainable natural chlorogenic acid as a functional molecular sensor toward viscosity detection in liquids.

Liquids are perishable at ease during the long-term transportation and storage processes, non-invasive and in situ inspection method is urgent to be developed. In consideration of the important role of viscosity, one kind of sustainable natural product chlorogenic acid (CA) extracted from honeysuckle has been used as a versatile optical sensor for viscosity determination during the liquid spoilage process. The natural molecule was conducted by the O-diphenyl and carboxylic acid ester groups in coincidence, a typical twisted intramolecular charge transfer phenomenon was formed. This sensor features wide adaptability, high selectivity, good sensitivity, and excellent photo stability in various liquids. And CA displays a larger Stokes shift, high viscosity sensitive coefficient (0.62), and narrower energy band. The rotatable conjugate structure can be acted as the recognition site, and the bright fluorescent signal of CA is specifically activated when in the high viscous micro-environment. Inspired by this objective phenomenon, CA has been applied to detect the thickening efficiency of various food thickeners. More importantly, the viscosity fluctuations during the deterioration stage of liquids can be screened through non-invasive and in situ monitoring. We expected that more natural products can be developed as molecular tools for liquids safety investigation, and fluorescent analytical methods can be expanded toward interdisciplinary research.

Tunable Synthesis of Monofluoroalkenes and Gem-Difluoroalkenes via Solvent-Controlled Rhodium-Catalyzed Arylation of 1-Bromo-2,2-difluoroethylene.

Divergent synthesis of fluorine-containing scaffolds starting from a suite of raw materials is an intriguing topic. Herein, we report the solvent-controlled rhodium-catalyzed tunable arylation of 1-bromo-2,2-difluoroethylene. The selection of the reaction solvents provides switchable defluorinated or debrominated arylation from readily available feedstock resources (both arylboronic acids/esters and 1-bromo-2,2-difluoroethylene are commercially available). This switch is feasible because of the difference in coordination ability between the solvent (CH2 Cl2 or CH3 CN) and the rhodium center, resulting in different olefin insertion. This protocol allows the convenient synthesis of monofluoroalkenes and gem-difluoroalkenes, both of which are important scaffolds in the fields of medicine and materials. Moreover, this newly developed solvent-regulated reaction system can be applied to the site-selective dechlorinated arylation of trichloroethylene. Overall, this study provides a useful strategy for the divergent synthesis of fluorine-containing scaffolds and provides insight into the importance of solvent selection in catalytic reactions.

The reversion of DNA methylation-induced miRNA silence via biomimetic nanoparticles-mediated gene delivery for efficient lung adenocarcinoma therapy.

BACKGROUND: Lung cancer is one of the fatal cancers worldwide, and over 60% of patients are lung adenocarcinoma (LUAD). Our clinical data demonstrated that DNA methylation of the promoter region of miR-126-3p was upregulated, which led to the decreased expression of miR-126-3p in 67 cases of lung cancer tissues, implying that miR-126-3p acted as a tumor suppressor. Transduction of miR-126-3p is a potential therapeutic strategy for treating LUAD, yet the physiological environment and properties of miRNA challenge current transduction approaches. METHODS: We evaluated the expression of miR-126-3p in 67 pairs of lung cancer tissues and the corresponding adjacent non-tumorous tissues by Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The relationship between the overall survival of lung cancer patients and miR-126-3p was analyzed by the Cancer Genome Atlas cohort database (Oncolnc, http://www.oncolnc.org ). We analyzed DNA methylation Methylation-specific PCR (MSP) analysis. To determine whether ADAM9 is the direct target of miR-126-3p, we performed the 3'-UTR luciferase reporter assay. The protein levels in the cells or tissues were evaluated with western blotting (WB) analysis. The biodistribution of nanoparticles were monitored by in vivo tracking system. RESULTS: We describe the development of novel stealth and matrix metalloproteinase 2 (MMP2)-activated biomimetic nanoparticles, which are constructed using MMP2-responsive peptides to bind the miR-126-3p (known as MAIN), and further camouflaged with red blood cell (RBC) membranes (hence named REMAIN). REMAIN was able to effectively transduce miRNA into lung cancer cells and release them via MMP2 responsiveness. Additionally, REMAIN possessed the advantages of the natural RBC membrane, including extended circulation time, lower toxicity, better biocompatibility, and immune escape. Moreover, in vitro and in vivo results demonstrated that REMAIN effectively induced apoptosis of lung cancer cells and inhibited LUAD development and progression by targeting ADAM9. CONCLUSION: The novel style of stealth and MMP2-activated biomimetic nanoparticles show great potential in miRNA delivery.

Promoter methylation-regulated miR-148a-3p inhibits lung adenocarcinoma (LUAD) progression by targeting MAP3K9.

Lung adenocarcinoma (LUAD) characterized by high metastasis and mortality is the leading subtype of non-small cell lung cancer. Evidence shows that some microRNAs (miRNAs) may act as oncogenes or tumor suppressor genes, leading to malignant tumor occurrence and progression. To better understand the molecular mechanism associated with miRNA methylation in LUAD progression and clinical outcomes, we investigated the correlation between miR-148a-3p methylation and the clinical features of LUAD. In the LUAD cell lines and tumor tissues from patients, miR-148a-3p was found to be significantly downregulated, while the methylation of miR-148a-3p promoter was notably increased. Importantly, miR-148a-3p hypermethylation was closely associated with lymph node metastasis. We demonstrated that mitogen-activated protein (MAP) kinase kinase kinase 9 (MAP3K9) was the target of miR-148a-3p and that MAP3K9 levels were significantly increased in both LUAD cell lines and clinical tumor tissues. In A549 and NCI-H1299 cells, overexpression of miR-148a-3p or silencing MAP3K9 significantly inhibited cell growth, migration, invasion and cytoskeleton reorganization accompanied by suppressing the epithelial-mesenchymal transition. In a nude mouse xenograft assay we found that tumor growth was effectively inhibited by miR-148a-3p overexpression. Taken together, the promoter methylation-associated decrease in miR-148a-3p could lead to lung cancer metastasis by targeting MAP3K9. This study suggests that miR-148a-3p and MAP3K9 may act as novel therapeutic targets for the treatment of LUAD and have potential clinical applications.

Quality improvement and patient safety in China, present and future.

With continued political support and increased health financing, China has achieved great progress in medical and health quality during the two decades. The strategy to improve health in China is built on reliable cross-sectoral information and data sharing along with quality improvement science and safety analytics balancing equitability, accessibility, quality outcomes, and safety in healthcare for everyone. As part of the healthcare system, pediatric anesthesiology has made great efforts to align with the China healthcare strategy to achieve quality outcomes, accessibility, and patient safety, but it still faces many problems such as unbalanced regional development, lack of awareness and relevant knowledge, and increased workload due to insufficient number of anesthesiologists. To address these problems, the Chinese Society of Anesthesiology and Chinese Society for Pediatric Anesthesiology supported by the Chinese hospital associations are strengthening interregional cooperation and international collaboration. In our experience, quality improvement can be successfully implemented at major centers through collaboration with experienced international institutions. In turn, the major centers educate and collaborate with the district hospitals to empower local improvements in safety and quality. Since the science in QI and patient safety is relatively new to anesthesiology in China, such collaborations must be greatly scaled up to reach the large geography and patient population in China. While the future is promising, there is still a long way to go.

Mitochondrial transcription factor A promotes DNA strand cleavage at abasic sites.

In higher eukaryotic cells, mitochondria are essential subcellular organelles for energy production, cell signaling, and the biosynthesis of biomolecules. The mitochondrial DNA (mtDNA) genome is indispensable for mitochondrial function because it encodes protein subunits of the electron transport chain and a full set of transfer and ribosomal RNAs. MtDNA degradation has emerged as an essential quality control measure to maintain mtDNA and to cope with mtDNA damage resulting from endogenous and environmental factors. Among all types of DNA damage known, abasic (AP) sites, sourced from base excision repair and spontaneous base loss, are the most abundant endogenous DNA lesions in cells. In mitochondria, AP sites trigger rapid DNA loss; however, the mechanism and molecular factors involved in the process remain elusive. Herein, we demonstrate that the stability of AP sites is reduced dramatically upon binding to a major mtDNA packaging protein, mitochondrial transcription factor A (TFAM). The half-life of AP lesions within TFAM-DNA complexes is 2 to 3 orders of magnitude shorter than that in free DNA, depending on their position. The TFAM-catalyzed AP-DNA destabilization occurs with nonspecific DNA or mitochondrial light-strand promoter sequence, yielding DNA single-strand breaks and DNA-TFAM cross-links. TFAM-DNA cross-link intermediates prior to the strand scission were also observed upon treating AP-DNA with mitochondrial extracts of human cells. In situ trapping of the reaction intermediates (DNA-TFAM cross-links) revealed that the reaction proceeds via Schiff base chemistry facilitated by lysine residues. Collectively, our data suggest a novel role of TFAM in facilitating the turnover of abasic DNA.

Value of lymphadenectomy in patients with surgically resected pancreatic neuroendocrine tumors.

BACKGROUND: Although some factors that predict the prognosis in pancreatic neuroendocrine tumor (pNET) have been confirmed, the predictive value of lymph node metastasis (LNM) in the prognosis of pNETs remains conflicting and it is not clear whether regional lymphadenectomy should be performed in all grades of tumors. METHODS: We included pNET patients undergoing surgery in Shanghai pancreatic cancer institute (SHPCI). The risk factors for survival were investigated by the Kaplan-Meier method and Cox regression model. We evaluated the predictors of LNM using Logistic regression. RESULTS: For 206 patients in the SHPCI series, LNM was an independent prognostic factor for entire cohort suggested by multivariate Cox regression analysis. LNM (P = 0.002) predicted poorer overall survival (OS) in grade 2/3 cohort, but there is no significant association between LNM and OS in grade 1 cohort. Grade (P < 0.001) and size (P = 0.049) predicted LNM in entire cohort. Grade (P = 0.002) predicted LNM while regardless of size in grade 2/3 cohort. CONCLUSIONS: Based on our own retrospective data obtained from a single center series, LNM seems to be associated with poorer outcome for patients with grade 2/3 and/or grade 1 > 4 cm tumors. On the other way, LNM was seems to be not associated with prognosis in patients with grade 1 tumors less than 4 cm. Moreover, tumor grade and tumor size seem to act as independent predictors of LNM. Thus, regional lymphadenectomy should be performed in grade 2/3 patients but was not mandatory in grade 1 tumors < 4 cm. It is reasonable to perform functional sparing surgery for grade 1 patients or propose a clinical-radiological monitoring.

Spectrum Sharing in the Sky and Space: A Survey.

In order to achieve the vision of seamless wireless communication coverage, a space-air-ground integrated network is proposed as a key component of the sixth-generation (6G) mobile communication system. However, the spectrum used by aerial networks has become gradually crowded with the increase in wireless devices. Space networks are also in dire need of developing new bands to address spectrum shortages. As an effective way to solve the spectrum shortage problem, spectrum sharing between aerial/space networks and ground networks has been extensively studied. This article summarizes state-of-the-art studies on spectrum sharing between aerial/space networks and ground networks. First, this article provides an overview of aerial networks and space networks and introduces the main application scenarios of aerial networks and space networks. Then, this article summarizes the spectrum sharing techniques between aerial/space networks and ground networks, including existing spectrum utilization rules, spectrum sharing modes and key technologies. Finally, we summarize the challenges of spectrum sharing between aerial/space networks and ground networks. This article provides guidance for spectrum allocation and spectrum sharing of space-air-ground integrated networks.

ALDOA inhibits cell cycle arrest induced by DNA damage via the ATM-PLK1 pathway in pancreatic cancer cells.

BACKGROUND: ALDOA is a glycolytic enzyme found mainly in developing embryos, adult muscle and various malignant tumours, including pancreatic tumours. Our previous study revealed that ALDOA, an oncogene, can promote the proliferation and metastasis of pancreatic tumours. Furthermore, ALDOA could predict poor prognosis in patients with pancreatic tumours. METHODS: IHC analysis of PDAC tissues was conducted. Western blotting, PCR, cellular IF experiments and cell cycle assessment were conducted utilizing cell lines. GSEA and KEGG pathway analysis were used to identify potential downstream pathways. RESULTS: To explore the effects of ALDOA on the occurrence and development of pancreatic tumours, we analysed the RNA sequencing results and found that ALDOA could inhibit the DDR. Under normal circumstances, when DNA is damaged, initiation of the DDR causes cell cycle arrest, DNA repair or cell apoptosis. Further experiments showed that ALDOA could inhibit DNA repair and reverse cell cycle arrest induced by DNA damage so that DNA damage persisted to promote the occurrence and progression of cancer. CONCLUSIONS: Regarding the molecular mechanism, we found that ALDOA inhibited the DDR and improved activation of the cell cycle checkpoint PLK1 by suppressing ATM, which promotes tumour cell progression. Consequently, ALDOA has a profound effect on pancreatic cancer development.

FGFBP1-mediated crosstalk between fibroblasts and pancreatic cancer cells via FGF22/FGFR2 promotes invasion and metastasis of pancreatic cancer.

Fibroblast growth factor-binding protein 1 (FGFBP1) promotes fibroblast growth factor (FGF) activity by releasing FGFs from extracellular matrix storage. We previously reported that the tumor suppressor F-box and WD repeat domain-containing 7 suppresses FGFBP1 by reducing expression of c-Myc, which inhibits the proliferation and migration of pancreatic cancer cells. However, the potential mechanism by which FGFBP1 facilitates pancreatic ductal adenocarcinoma (PDAC) remains unexplored. In this study, we focused on the function of FGFBP1 in the interplay between cancer-associated fibroblasts (CAFs) and pancreatic cancer cells (PCCs). Decreased FGF22 expression was detected in CAFs co-cultured with PCCs with FGFBP1 abrogation, which was verified in the cell culture medium by enzyme-linked immunosorbent assay. Active cytokine FGF22 significantly facilitated the migration and invasion of PANC-1 and Mia PaCa-2 cells. The number of penetrating PCCs cocultured with CAFs with FGF22 abrogation was significantly less than that of the control group. Interestingly, higher expressions of FGF22 and fibroblast growth factor receptor 2 (FGFR2) were associated with worse prognosis of patients with PDAC and FGFR2, an independent prognostic marker of PDAC. The PANC-1 and Mia PaCa-2 cells with silenced FGFR2 showed weaker invasion and metastasis, even if these cells were simultaneously treated with cytokine FGF22. These results revealed that FGFBP1-mediated interaction between CAFs and PCCs via FGF22/FGFR2 facilitates the migration and invasion of PCCs. FGFR2 could act as a prognostic marker for patients with PDAC.

SETD8 induces stemness and epithelial-mesenchymal transition of pancreatic cancer cells by regulating ROR1 expression.

Pancreatic cancer (PC) is one of the most deadly diseases, and its incidence is increasing year by year. The methyltransferase SETD8 has been demonstrated to play an important role in tumor cell proliferation and metastasis. However, little is known about whether SETD8 could affect the invasion and metastasis of PC and the mechanism underlying the regulation. Based on our previous report, here, we further found that SETD8 could promote the invasion and migration of PC cells by inducing the expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 was predominantly upregulated in PC tissues and was correlated with lymph node metastasis and worse prognosis. Mechanistically, SETD8 mediated ROR1 activity and regulated PC cells invasion and migration, although promoting the expression of stemness and epithelial-mesenchymal transition-related molecules. This promotion effect disappeared when the catalytically inactive mutant SETD8 was overexpressed, which could be counteracted by the SETD8-specific methyltransferase inhibitor UNC0379. Collectively, our results demonstrate that SETD8 may be a novel prognostic factor and a therapeutic target of PC.

Apical PtdIns(4,5)P2 is required for ciliogenesis and suppression of polycystic kidney disease.

Cilia are hair-like structures that function like antennae to detect chemical and mechanical signals in the environment. Recently, phosphoinositides were shown to play an important role in cilia assembly and disassembly. However, the precise molecular and cellular mechanisms underlying this process remain unknown. Here, we report that suppression of apical phosphatidylinositol 4,5- bisphosphate [PtdIns(4,5)P2], by overexpressing apically targeted PtdIns(4,5)P2 phosphatase or by knocking down type I phosphatidylinositol 4-phosphate 5-kinase (Pip5k1), leads to ciliogenesis defects and polycystic kidney disease (PKD) in zebrafish embryos that phenocopied inpp5e mutant, a Joubert syndrome model. We further demonstrate that decreased expression of apical PtdIns(4,5)P2 disrupted apical ezrin recruitment, F-actin organization, and basal body docking. Moreover, the ciliogenesis and polycystic kidney defects in PtdIns(4,5)P2-depleted embryos can be rescued by overexpression of ezrin. Finally, Pip5k1a overexpression rescued the ciliogenesis defects and PKD phenotypes in Inpp5e-depleted embryos. Taken together, our results reveal that apical PtdIns(4,5)P2 is essential for ciliogenesis and the prevention of PKD and suggest a novel possibility for treating PKD and other human ciliopathies.-Xu, W., Jin, M., Huang, W., Wang, H., Hu, R., Li, J., Cao, Y. Apical PtdIns(4,5)P2 is required for ciliogenesis and suppression of polycystic kidney disease.