DMT1 ubiquitination by Nedd4 protects against ferroptosis after intracerebral hemorrhage.

OBJECTIVE: Neuronal precursor cells expressed developmentally down-regulated 4 (Nedd4) are believed to play a critical role in promoting the degradation of substrate proteins and are involved in numerous biological processes. However, the role of Nedd4 in intracerebral hemorrhage (ICH) remains unknown. This study aims to investigate the regulatory role of Nedd4 in the ICH model. METHODS: Male C57BL/6J mice were induced with ICH. Subsequently, the levels of glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, as well as the expression of divalent metal transporter 1 (DMT1) and Nedd4 were assessed after ICH. Furthermore, the impact of Nedd4 overexpression was evaluated through analyses of hematoma area, ferroptosis, and neurobehavioral function. The mechanism underlying Nedd4-mediated degradation of DMT1 was elecidated using immunoprecipitation (IP) after ICH. RESULTS: Upon ICH, the level of DMT1 in the brain increased, but decreased when Nedd4 was overexpressed using Lentivirus, suggesting a negative correlation between Nedd4 and DMT1. Additionally, the degradation of DMT1 was inhibited after ICH. Furthermore, it was found that Nedd4 can interact with and ubiquitinate DMT1 at lysine residues 6, 69, and 277, facilitating the degradation of DMT1. Functional analysis indicated that overexpression of Nedd4 can alleviate ferroptosis and promote recovery following ICH. CONCLUSION: The results demonstrated that ferroptosis occurs via the Nedd4/DMT1 pathway during ICH, suggesting it potential as a valuable target to inhibit ferroptosis for the treatment of ICH.

Desmoplastic fibroma of the pediatric cranium with CTNNB1 mutation: case report and literature review.

PURPOSE: Desmoplastic fibroma (DF) is an uncommon intermediate bone tumor rarely involving the skull with unidentified pathogenesis. We report the first case of pediatric temporoparietal cranial desmoplastic fibroma (DF) with a CTNNB1 gene mutation and review the previous literature. CASE PRESENTATION: A 3-year-old boy had a firm, painless mass on the right temporoparietal region for 22 months. The cranial CT scan showed isolated osteolytic destruction in the outer plate and diploe of the right temporoparietal bone. Gross total resection of the lesion and cranioplasty were performed. After that, a growing epidural hematoma was observed so another operation was performed to remove the artificial titanium plate. Postoperative pathology indicated a DF diagnosis and molecular pathology suggested a missense mutation in exon 3 of the CTNNB1 gene (c.100G > A,p.Gly34Arg). CONCLUSION: Pediatric cranial DF is rare and easy to be misdiagnosed before operation. For cranial DF, lesion resection can be performed and perioperative management should be strengthened. Mutations in the CTNNB1 gene might be one of the molecular pathologic features of DF.

Review of Phenotypic Heterogeneity of Neuronal Intranuclear Inclusion Disease and NOTCH2NLC-Related GGC Repeat Expansion Disorders.

Neuronal intranuclear inclusion disease (NIID) is an underdiagnosed neurodegenerative disorder caused by pathogenic GGC expansions in NOTCH2NLC. However, an increasing number of reports of NOTCH2NLC GGC expansions in patients with Alzheimer disease, essential tremor, Parkinson disease, amyotrophic lateral sclerosis, and oculopharyngodistal myopathy have led to the proposal of a new concept known as NOTCH2NLC-related GGC repeat expansion disorders (NREDs). The majority of studies have mainly focused on screening for NOTCH2NLC GGC repeat variation in populations previously diagnosed with the associated disease, subsequently presenting it as a novel causative gene for the condition. These studies appear to be clinically relevant but do have their limitations because they may incorrectly regard the lack of MRI abnormalities as an exclusion criterion for NIID or overlook concomitant clinical presentations not typically observed in the associated diseases. Besides, in many instances within these reports, patients lack pathologic evidence or undergo long-term follow-up to conclusively rule out NIID. In this review, we will systematically review the research on NOTCH2NLC 5' untranslated region GGC repeat expansions and their association with related neurologic disorders, explaining the limitations of the relevant reports. Furthermore, we will integrate subsequent studies to further demonstrate that these patients actually experienced distinct clinical phenotypes of NIID.

Impact of stent retriever size on clinical outcomes in the RECO registry.

Objective: In the RECO study, we investigated the impact of the operator's choice of stent retriever size on patients with internal carotid artery (ICA) occlusion. Methods: Data from the RECO Registry, a prospective multicentre study, were utilized. Patients who underwent mechanical thrombectomy (MT) were divided according to the size of the stent into the RECO 4 × 20 group, the RECO 5 × 30 group and the RECO 6 × 30 group. The outcome measures assessed in the study were the 3-month modified Rankin Scale (mRS) score, occurrence of any intracranial haemorrhage (aICH), workflow timing, recanalization success rate, number of attempts, and all-cause mortality within a 3-month period. Results: Analysis was conducted on a total of 89 patients with ICA occlusion. RECO 4 × 20, 5 × 30, and 6 × 30 stent retrievers were used in 19 (21.3%), 52 (58.4%), and 18 (20.2%) patients, respectively. The demographic and baseline characteristics showed considerable similarity across the three groups. The puncture-to-recanalization time of the RECO 6 × 30 group [56.5 min (IQR, 41.5-80.8)] was significantly shorter than that of the RECO 4 × 20 group [110 min (IQR, 47-135)]. In 10 out of 18 patients (55.6%), the RECO 6 × 30 stent retriever achieved reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score 2b-3) after the initial attempt, surpassing the rates of 31.6% in the RECO 4 × 20 group and 32.7% in the RECO 5 × 30 group. In the RECO 4 × 20 group, the median number of passes was 2 (IQR, 1-3); in the RECO 5 × 30 group, it was 2 (IQR, 1-3); and in the RECO 6 × 30 groups, it was 1 (IQR, 1-2.5). There were no statistically significant differences observed among the three groups concerning aICH or good outcomes (mRS score 0-2). Conclusion: Our study demonstrated the practical implications of stent-retriever size selection in the context of the MT for ICA occlusion. The routine use of a RECO 6 × 30 stent retriever holds the potential for early revascularization in clinical practice. The significant reduction in the puncture-to-reperfusion time and the greater first-pass effect associated with this stent size underscore its efficiency in treating ICA occlusion.

Value of neutrophil-to-lymphocyte ratio in neuronal intranuclear inclusion disease.

Background and objectives: The neutrophil-to-lymphocyte ratio (NLR) is a widely recognized marker of inflammation in peripheral blood. However, its specific role in neuronal intranuclear inclusion disease (NIID) has not been reported. This study aims to investigate the relationship between NIID and NLR. Methods: A multicenter database was collected, including 157 NIID patients from seven hospitals (The Affiliated Hospital of Xuzhou Medical University, Yantai Yuhuangding Hospital, Tengzhou Central People's Hospital,The Affiliated Brain Hospital of Nanjing Medical University, Liaocheng People's Hospital,The Second Hospital of Shandong University, Inner Mongolia People's Hospital, Xuanwu Hospital Capital Medical University,The First Affiliated Hospital of USTC), along with 157 age- and gender-matched healthy control subjects. White blood cell counts (including neutrophils, lymphocytes, monocytes, eosinophils, and basophils) were obtained, and the NLR was calculated. Additionally, cognitive impairment was assessed using clinical evaluation scores. Results: NIID patients exhibited significantly higher NLR values compared to the healthy control group (p < 0.001). The plasma NLR levels in NIID patients showed a weak positive correlation with disease duration (r = 0.219, p = 0.016). However, no significant correlations were found between NLR and age of onset or cognitive impairment (p > 0.05). Conclusion: There is a significant association between NLR and NIID, suggesting a potential role of peripheral blood inflammation in the pathogenesis of NIID.

Impact of sex and age on the lateralisation of the tibial tubercle in normal paediatric and adolescent populations.

PURPOSE: Numerous methods have been proposed to characterise tubercle lateralisation. However, their normal values and related changes remain unclear. Accordingly, it was aimed to determine the potential sex and age effects and determined the optimal individualised method of diagnosing lateralisation of the tibial tubercle in patients with recurrent patellar dislocation (RPD). METHODS: Measurements included the tibial tubercle-trochlear groove (TT-TG) distance, tibial tubercle-posterior cruciate ligament (TT-PCL) distance and tibial tubercle lateralisation (TTL); and the proximal tibial width (PTW), trochlear width (TW) and trochlear dysplasia index (TDI), for adjustment. A two-way analysis of variance was used to determine the effect of age, sex and their interaction within the normal group. When the age effect was statistically significant, a nonlinear regression was created. Areas under the receiver-operating characteristic curve (AUCs) were calculated to assess diagnostic accuracy. RESULTS: A total of 277 normal participants (mean [SD] age, 13.5 [2.6] years; 125 [45.1%] female) and 227 patients with RPD (mean [SD] age, 13.5 [2.6] years; 161 [58.1%] female) were analysed. It was found that in the normal group, in patients aged 7-10, TT-PCL distance (p = 0.006), TTL (p = 0.007) and TT-PCL/PTW (p < 0.001) were significantly larger in females than in males. A significant sex effect was also detected on TT-TG/TW (p = 0.014). TT-TG distance, TT-PCL distance, TTL and TT-PCL/PTW (in male patients) approached an established normal adult value of 12.3 mm, 20.9 mm, 0.64 and 0.28, respectively, with increasing age (p < 0.001). The AUC was greater for TT-TG/TDI and TT-TG/TW (p ≤ 0.01) and TT-TG/TDI outperformed TT-TG/TW in patients aged 15-18 (p = 0.004). CONCLUSIONS: Tubercle lateralisation increased with age and was affected by sex, with the exception of TT-TG distance and TT-TG/TDI. TT-TG/TDI is the optimal method of diagnosing a lateralized tibial tubercle in patients with RPD. These findings assist with the evaluation of tubercle lateralisation in that they provide a proper protocol for paediatric and adolescent populations with RPD; and thus, will help determine whether medial tubercle transfer should be included among the tailored surgical procedures considered for the treatment of patients with RPD. LEVEL OF EVIDENCE: Level III.

The interactions of subcellular organelles in pulmonary fibrosis induced by carbon black nanoparticles: a comprehensive review.

Owing to the widespread use and improper emissions of carbon black nanoparticles (CBNPs), the adverse effects of CBNPs on human health have attracted much attention. In toxicological research, carbon black is frequently utilized as a negative control because of its low toxicity and poor solubility. However, recent studies have indicated that inhalation exposure to CBNPs could be a risk factor for severe and prolonged pulmonary inflammation and fibrosis. At present, the pathogenesis of pulmonary fibrosis induced by CBNPs is still not fully elucidated, but it is known that with small particle size and large surface area, CBNPs are more easily ingested by cells, leading to organelle damage and abnormal interactions between organelles. Damaged organelle and abnormal organelles interactions lead to cell structure and function disorders, which is one of the important factors in the development and occurrence of various diseases, including pulmonary fibrosis. This review offers a comprehensive analysis of organelle structure, function, and interaction mechanisms, while also summarizing the research advancements in organelles and organelle interactions in CBNPs-induced pulmonary fibrosis.

ZMYND8 protects breast cancer stem cells against oxidative stress and ferroptosis through activation of NRF2.

Breast cancer stem cells (BCSCs) mitigate oxidative stress to maintain their viability and plasticity. However, the regulatory mechanism of oxidative stress in BCSCs remains unclear. We recently found that the histone reader ZMYND8 was upregulated in BCSCs. Here, we showed that ZMYND8 reduced ROS and iron to inhibit ferroptosis in aldehyde dehydrogenase-high (ALDHhi) BCSCs, leading to BCSC expansion and tumor initiation in mice. The underlying mechanism involved a two-fold posttranslational regulation of nuclear factor erythroid 2-related factor 2 (NRF2). ZMYND8 increased stability of NRF2 protein through KEAP1 silencing. On the other hand, ZMYND8 interacted with and recruited NRF2 to the promoters of antioxidant genes to enhance gene transcription in mammospheres. NRF2 phenocopied ZMYND8 to enhance BCSC stemness and tumor initiation by inhibiting ROS and ferroptosis. Loss of NRF2 counteracted ZMYND8's effects on antioxidant genes and ROS in mammospheres. Interestingly, ZMYND8 expression was directly controlled by NRF2 in mammospheres. Collectively, these findings uncover a positive feedback loop that amplifies the antioxidant defense mechanism sustaining BCSC survival and stemness.

Exposure to micron-grade silica particles triggers pulmonary fibrosis through cell-to-cell delivery of exosomal miR-107.

Long-term exposure to inhalable silica particles may lead to severe systemic pulmonary disease, such as silicosis. Exosomes have been demonstrated to dominate the pathogenesis of silicosis, but the underlying mechanisms remain unclear. Therefore, this study aimed to explore the roles of exosomes by transmitting miR-107, which has been linked to the toxic pulmonary effects of silica particles. We found that miR-107, miR-122-5p, miR-125a-5p, miR-126-5p, and miR-335-5p were elevated in exosomes extracted from the serum of patients with silicosis. Notably, an increase in miR-107 in serum exosomes and lung tissue was observed in the experimental silicosis mouse model, while the inhibition of miR-107 reduced pulmonary fibrosis. Moreover, exosomes helped the migration of miR-107 from macrophages to lung fibroblasts, triggering the transdifferentiation of cell phenotypes. Further experiments demonstrated that miR-107 targets CDK6 and suppresses the expression of retinoblastoma protein phosphorylation and E2F1, resulting in cell-cycle arrest. Overall, micron-grade silica particles induced lung fibrosis through exosomal miR-107 negatively regulating the cell cycle signaling pathway. These findings may open a new avenue for understanding how silicosis is regulated by exosome-mediated cell-to-cell communication and suggest the prospect of exosomes as therapeutic targets.

Transcriptomic analysis and oxidative stress induced by sodium dichloroisocyanurate in the intestine of Phascolosoma esculenta.

Sodium dichloroisocyanurate (NaDCC, C3Cl2N3NaO3) is a solid chlorine-containing product that is widely used as a disinfectant in living environments, which has potential toxic effects on human and rats. Phascolosoma esculenta is a species native to the southeast coast of China and can be used as an indicator organism. In the present study, 150 P. esculenta were used to determine the LC50 of NaDCC for P. esculenta, then 100 P. esculenta were used to analysis the change of histopathology, oxidative stress and transcriptome after NaDCC exposure. The results showed that the LC50 of NaDCC for 48 h was 50 mg/L. NaDCC stress induced pathological events in P. esculenta, including blisters, intestinal structural damage and epithelial cell ruptured or even loss. The highest and lowest intestinal activity of superoxide dismutase in individual survivors was detected at 12 h and 72 h, respectively. Malondialdehyde levels in the intestine declined gradually from 3 h and increased at 9 h, and peaked at 12 h. Total antioxidant capacity declined at 3 h and dropped below the levels of control group after 9 h. Transcriptome sequencing analysis yielded a total of 48.65 Gb of clean data. A total of 34,759 new genes were found including 957 differentially expressed genes (DEGs). The DEGs were significantly enriched in ferroptosis, response to chemicals, response to stress, immune system, ion transport, cell death, oxidation-reduction, cellular homeostasis, protein ubiquitination, and protein neddylation. Additionally, the levels of detoxification enzymes, such as glutathione-S-transferase, cytochrome P450, ABC, UDP-glycosyltransferase and SLC transporters of endogenous and exogenous solutes were significantly changed. Overall, the results provide reference for reasonable use of disinfectants during farming, and also provide insight into the mechanisms related to NaDCC toxicity in P. esculenta.

A review of "plant gold" Eucommia ulmoides Oliv.: A medicinal and food homologous plant with economic value and prospect.

Eucommia ulmoides Oliv. is an ancient and precious plant that has been used as medicine in China for more than 2000 years. Because its bark, leaves, seeds, and male flowers can be used in medicine, it plays an important role in medicine, food, chemical industry, and other fields, so it is also called "plant gold". 246 compounds have been isolated from E. ulmoides, which endow E. ulmoides with many unique pharmacological effects and make it wide to study in the fields of osteoporosis, hypertension, liver protection, and so on. Besides, E. ulmoides also has significant medicinal effects on anti-inflammatory, antioxidant, immunomodulation, and neuroprotection, and is often used in clinical compound medicines of traditional Chinese medicine. In addition to updating its ethnobotany, phytochemistry, pharmacology, and toxicology information, the economic botany of leaves, seeds, and male flowers was also introduced. It hopes hoping to fully understand this economically important Chinese medicine and provide a scientific basis for further development and utilization of E. ulmoides.

The role of large mammalian herbivores in shaping and maintaining soil microbial communities of natural mineral licks: A case study on sika deer at the firebreak adjacent to the Sino-Russian border.

Mineral licks are indispensable habitats to the life history of large mammal herbivores (LMH). Geophagy at licks may provide the necessary minerals for LMH, while LMH may be ecosystem engineers of licks by altering vegetation cover and soil physicochemical properties (SPCP). However, the precise relationship between the LMH and licks remains unclear. To clarify the geophagy function of licks for LMH and their influence on soil at licks, we recorded visitation patterns of sika deer around licks and compared SPCP and microbial communities with the surrounding matrix in a firebreak adjacent to the Sino-Russian border. Our study indirectly supports the "sodium supplementation" hypothesis. Proofs included (1) a significantly higher sodium, iron, and aluminum contents than the matrix, while lower carbon, nitrogen, and moisture contents; (2) significantly higher deer visitation during sodium-demand season (growing season), along with an avoidance of licks with high iron contents, which is toxic when overdose. The microbes at the licks differed from those at the matrix, mainly driven by low soil carbon and nitrogen and altered biogeochemical cycles. The microbial communities of licks are vulnerable because of their unstable state and susceptibility to SPCP changes. Structural equation modeling (SEM) clearly showed a much stronger indirect effect of deer on microbes at licks than at the matrix, especially for bacteria. Multiple deer behaviors at licks, such as grazing, trampling, and excretion, can indirectly shape and stabilize microbes by altering carbon and nitrogen input. Our study is the first to characterize soil microbial communities at mineral licks and demonstrate the processes by which LMH shapes those communities. More studies are required to establish a general relationship between the LMH and licks to promote the conservation of natural licks for wildlife.

Investigation of Anticancer Therapy Using pH-Sensitive Carbon Dots-Functionalized Doxorubicin in Cubosomes.

Cancer remains a highly lethal disease due to its elusive early detection, rapid spread, and significant side effects. Nanomedicine has emerged as a promising platform for drug delivery, diagnosis, and treatment monitoring. In particular, carbon dots (CDs), a type of fluorescent nanomaterial, offer excellent fluorescence properties and the ability to carry multiple drugs simultaneously through covalent bonding. In this work, CDs with carbonyl groups on the surface were prepared by aldol condensation and reacted with amine groups in the structure of doxorubicin (DOX) through Schiff base reaction to generate pH-responsive CDs-DOX. On the other hand, cubosomes with three-dimensional lattice structures formed by lipid bilayers have advantageous capabilities of encapsulating various hydrophilic, amphiphilic, and hydrophobic substances. The pH-responsive CDs-DOX are subsequently loaded into cubosomes to form an anticancer therapeutic nanosystem, CDs-DOX@cubosome. Leveraging the unique properties of CDs-DOX and cubosomes, our CDs-DOX@cubosome can enter tumor tissue through the enhanced permeation and retention effect first and conduct membrane fusion with tumor cells to intracellularly release CDs-DOX. Then, the imine bond in CDs-DOX breaks under acidic conditions within human cancer cell lines (HeLa and HepG-2 cells), releasing DOX and achieving enhanced treatment of tumors. Additionally, fluorescent CDs can synchronously achieve real-time in situ diagnosis of tumor tissue. We demonstrate that our CDs-DOX@cubosome works as an excellent drug delivery system with therapeutic efficiency enhancement to the tumor and reduced side effects.

Dietary change influences the composition of the fecal microbiota in two rescued wild raccoon dogs (Nyctereutes procyonoides).

The gut microbiota of wild animals, influenced by various factors including diet, nutrition, gender, and age, plays a critical role in their health and disease status. This study focuses on raccoon dogs (Nyctereutes procyonoides), a commonly found wild animal, and its gut microbiota composition in response to dietary shifts. The study aimed to compare the fecal bacterial communities and diversity of rescued raccoon dogs fed three different diet types (fish and amphibians, mixed protein with maize, and solely maize) using high-throughput sequencing. Results indicated that the dietary composition significantly influenced the gut microbiota, with notable differences in the abundance of several key phyla and genera. The study identified Firmicutes as the dominant phylum in all diet groups, with notable variations in the relative abundances of Bacteroidota, Proteobacteria, and Verrucomicrobiota. Notably, the group solely fed maize exhibited a significant increase in Proteobacteria, potentially linked to dietary fiber and lignin degradation. The genus-level analysis highlighted significant differences, with Lactobacillus and Bifidobacterium responding to dietary shifts. The genus Akkermansia in Verrucomicrobiota can be identified as a marker for assessing the health of the gut and deserves further investigation. Gender-specific differences in the gut microbiota were observed, highlighting the influence of individual variation. Furthermore, the analysis of bacterial functions suggested a connection between diet and host metabolism, emphasizing the need for further research to understand the complex mechanisms underlying the relationship between dietary composition and gut microbiota in wild animals. These findings provide crucial insights into conservation and rescue efforts for wild animals.

Fibrous dysplasia with aneurysmal bone cyst-like change occurring in pediatric orbit: case report and literature review.

PURPOSE: We report a case of fibrous dysplasia (FD) with aneurysmal bone cyst (ABC)-like change in a child with orbital involvement, review the related cases, and discuss clinical features, therapy, and prognosis of this disease. CASE PRESENTATION: A 10-year-old girl had right proptosis (degree of exophthalmos: OD 16 mm, OS 13 mm) and limited vision (visual acuity: OD 1.0, OS 0.8) without trauma. Preoperative CT showed a 5.0*4.3 cm right-sided crania-orbital communicating tumor. MRI indicated a well-defined multicystic mass with scattered fluid levels and soap bubble-like alterations. The child underwent total tumor resection and orbital parietal titanium mesh reconstruction. At 20 months of follow-up, the child has recovered from ocular problems, and the tumor has not recurred. CONCLUSION: FD combined with ABC rarely occurs in orbit and generally begins with ocular symptoms. The etiology is uncertain. Early diagnosis and surgery are essential. Complete resection is suggested whenever possible because residual lesions may recur.

Roles, underlying mechanisms and clinical significances of LINC01503 in human cancers.

Long intergenic non-coding RNA 01503 (LINC01503) is a long non-coding RNA (lncRNA) located on human chromosome 9q34.11. There is compelling evidence indicating that LINC01503 is upregulated in multiple types of tumors and functions as a tumor stimulator. The upregulation of LINC01503 was significantly associated with the risk of 12 tumors and showed a strong correlation with clinicopathological characteristics and poor prognosis in 9 tumors. The expression of LINC01503 is regulated by transcription factors such as TP63, EGR1, c-MYC, GATA1 and AR. The downstream regulatory mechanisms of LINC01503 are complex and multifaceted. LINC01503, as a competing endogenous RNA (ceRNA), regulates gene expression by competitively inhibiting miRNA. LINC01503 may also regulate gene expression via interacting with biomolecules or recruiting chromatin-modifying complexes. In addition, LINC01503 can abnormally activate the ERK/MAPK, PI3K/AKT and Wnt/ß-catenin signaling pathways to enhance tumor progression. Here, this review presents an overview of the latest research progress of LINC01503 in the field of oncology, summarizes its comprehensive network involved in multiple cancer molecular mechanisms, and explores its potential applications in cancer diagnosis, prognosis, and treatment.

Integrated RNA expression and alternative polyadenylation analysis identified CPSF1-CCDC137 oncogenic axis in lung adenocarcinoma.

This study aims to analyze the RNA expression and alternative polyadenylation (APA) events and identify APA tuned genes with prognostic significance in lung adenocarcinoma (LUAD). Genome-wide RNA expression profile and APA events were acquired in LUAD cancer and normal samples in GSE197346. Comparative analysis screened common deregulated genes and transcripts. All 11 and 19 transcripts were up and down expressed and polyadenylated in cancer samples, respectively. Clinical analysis found eight genes with prognostic significance, such as coiled-coil domain containing 137 (CCDC137). Role of CCDC137 in LUAD was first reported in this study. The cellular and animal experiments indicated that downregulated CCDC137 suppressed the malignant tumor phenotype and tumor growth in LUAD. Then, to identify APA regulators for elevated CCDC137, we analyzed the expression of 26 APA regulators in GSE197346 and The Cancer Genome Atlas (TCGA), and found 4 differential regulators: CPSF1, CELF2, NUDT21, and ELAVL1. At last, the correlation of eight genes with four differential APA regulators was analyzed, and CPSF1 showed a strong positive correlation with CCDC137. Based on the above results, we propose an oncogenic axis of CPSF1-CCDC137 in LUAD. This study first constructed a polyadenylation tuned RNA expression map in LUAD, and the proposed oncogenic axis of CPSF1-CCDC137 would shed light on the pathogenesis of LUAD.

DBU-catalyzed diastereoselective 1,3-dipolar [3+2] cycloaddition of trifluoroethyl amine-derived isatin ketimines with chalcones: synthesis of 5'-CF3-substituted 3,2'-pyrrolidinyl spirooxindoles.

A diastereoselective 1,3-dipolar cycloaddition reaction between trifluoroethyl amine-derived isatin ketimines and chalcones was successfully achieved in the presence of DBU. A series of 5'-CF3-substituted 3,2'-pyrrolidinyl spirooxindoles were efficiently synthesized with high yields and excellent diastereoselectivities (up to 89% yield, and >99 : 1 dr). The in vitro anticancer activities of these highly functionalized spiro[pyrrolidin-3,2'-oxindole] derivatives were evaluated.

Hub gene ELK3-mediated reprogramming lipid metabolism regulates phenotypic switching of pulmonary artery smooth muscle cells to develop pulmonary arterial hypertension induced by PM2.5.

Fine particulate matter (PM2.5) as an environmental pollutant is related with respiratory and cardiovascular diseases. Pulmonary arterial hypertension (PAH) was characterized by incremental pulmonary artery pressure and pulmonary arterial remodeling, leading to right ventricular hypertrophy, and finally cardiac failure and death. The adverse effects on pulmonary artery and the molecular biological mechanism underlying PM2.5-caused PAH has not been elaborated clearly. In the current study, the ambient PM2.5 exposure mice model along with HPASMCs models were established. Based on bioinformatic methods and machine learning algorithms, the hub genes in PAH were screened and then adverse effects on pulmonary artery and potential mechanism was studied. Our results showed that chronic PM2.5 exposure contributed to increased pulmonary artery pressure, pulmonary arterial remodeling and right ventricular hypertrophy in mice. In vitro, PM2.5 induced phenotypic switching in HPASMCs, which served as the early stage of PAH. In mechanism, we investigated that PM2.5-mediated mitochondrial dysfunction could induce phenotypic switching in HPASMCs, which was possibly through reprogramming lipid metabolism. Next, we used machine learning algorithm to identify ELK3 as potential hub gene for mitochondrial fission. Besides, the effect of DNA methylation on ELK3 was further detected in HPASMCs after PM2.5 exposure. The results provided novel directions for protection of pulmonary vasculature injury, against adverse environmental stimuli. This work also provided a new idea for the prevention of PAH, as well as provided experimental evidence for the targeted therapy of PAH.