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Abstract Early metastatic disease development is one characteristic that defines triple-negative breast cancer (TNBC) as the most aggressive breast cancer (BC) subtype. Numerous studies have identified long non-coding RNAs (lncRNA) as critical players in regulating tumor progression and metastasis formation. Here, we show that MALAT1, a long non-coding RNA known to promote various features of BC malignancy, such as migration and neo angiogenesis, regulates TNBC cell response to hypoxia. By profiling MALAT1-associated transcripts, we discovered that lncRNA MALAT1 interacts with the mRNA encoding WTAP protein, previously reported as a component of the N6-methyladenosine (m6A) modification writer complex. In hypoxic conditions, MALAT1 positively regulates WTAP protein expression, which influences the response to hypoxia by favoring the transcription of the master regulators HIF1α and HIF1β. Furthermore, WTAP stimulates BC cell migratory ability and the expression of N-Cadherin and Vimentin, hallmarks of epithelial-to-mesenchymal transition (EMT). In conclusion, this study highlights the functional axis comprising MALAT1 and WTAP as a novel prognostic marker of TNBC progression and as a potential target for the development of therapeutic approaches for TNBC treatment.

Increasing construction land demands and population growth within urban agglomerations have led to increasingly prominent landscape ecological risk (LER) issues. However, the multi-scale nature and spatial non-stationarity characteristics of the driving patterns have not been fully investigated. In this study, taking the Xiamen-Zhangzhou-Quanzhou Urban Agglomeration (XZQUA) as a case, we analyzed the spatio-temporal evolution characteristics of LER utilizing the long time series land use data from 1980 to 2020; then, the Exploratory Regression Analysis (ERA) was employed to investigate the optimal combination of key influential elements affecting LER. Finally, the Multiscale Geographically Weighted regression (MGWR) model was applied to explore the spatial non-stationarity effects of the key driving elements. The results reveal that: (1) The LER of the XZQUA has shown a declining trend from 1980 to 2020, characterized with significantly and increasingly spatial autocorrelation as well. (2) The optimal variable combination is the temperature, distance from roads, elevation, and construction land area. (3) The MGWR model results reveal that the impact of various factors on LER demonstrates significant spatial non-stationarity. The mechanisms and intensity of these influences change depending on geographical location. The negative proportion of regression coefficients for construction land area (−0.203 to −0.002) and elevation (−0.046 to −0.001) all exceeded 80%, indicating a high negative effect on LER; The positive proportion of the regression coefficient for distance from roads (−0.026 to 0.042) exceeded 60%, indicating a predominantly positive effect on LER. Our findings provide guidance for regional policymakers to adopt targeted ecological risk intervention measures, thus reducing LER in the urban agglomeration.

Numerous ecological issues will arise from the expansion of tourism-related infrastructure and activities, potentially having a major effect on the ecosystem. However, its impact on landscape ecological risk (LER) is still poorly understood. Taking the Min River Basin as an example, an improved LER evaluation method was adopted in this study, which uses landscape disturbance based on landscape pattern and incorporates ecosystem services (ESs) represent landscape vulnerability. On this basis, the impacts of tourism-related infrastructure and activities on ecology environment were comprehensively considered, and buffer zone analysis, scenario analysis, response index (RI), and the bivariate Moran’s I approaches were applied to identify the spatio-temporal evolution characteristics of LER under tourism interference. The results show that: (1) The Min River Basin’s LER from 2000 to 2020 demonstrates a trend of gradually decreased, primarily in the middle and low risk areas. Most of the areas where scenic spots and roads are located are high risk areas, suggesting that tourism disturbances negatively affect LER. (2) There is a spatial gradient effect associated with the influence of tourism infrastructure on LER, and the impact degree varies throughout different tourism infrastructure. (3) The difference of scenic spots causes diverse degrees of LER. Through comparison, it is found that the LER of high-grade and cultural scenic spots is larger than that of low-grade and natural scenic spots. The quantitative results of the RI show that the values inside the influence zones of scenic spots and roads are 5 times and 9 times more than the values outside, respectively. This suggests that tourism infrastructure increases LER. (4)There is a spatial correlation between LER and tourism activities intensity. In order to offer a scientific reference for balancing local tourism development and ecological environmental conservation, this study develops a more thorough and rigorous research framework of the impact of tourism on LER.

Abstract Artificial Intelligence has the potential to reshape the landscape of clinical trials through innovative applications, with a notable advancement being the emergence of synthetic patient generation. This process involves simulating cohorts of virtual patients that can either replace or supplement real individuals within trial settings. By leveraging synthetic patients, it becomes possible to eliminate the need for obtaining patient consent and creating control groups that mimic patients in active treatment arms. This method not only streamlines trial processes, reducing time and costs but also fortifies the protection of sensitive participant data. Furthermore, integrating synthetic patients amplifies trial efficiency by expanding the sample size. These straightforward and cost‐effective methods also enable the development of personalized subject‐specific models, enabling predictions of patient responses to interventions. Synthetic data holds great promise for generating real‐world evidence in clinical trials while upholding rigorous confidentiality standards throughout the process. Therefore, this study aims to demonstrate the applicability and performance of these methods in the context of onco‐hematological research, breaking through the theoretical and practical barriers associated with the implementation of artificial intelligence in medical trials.

Background: Spontaneous ventilation, essential for human life, is addressed by the nursing diagnosis “Ineffective Spontaneous Ventilation” which requires strong scientific support. Aim: This revision study aimed to elevate this nursing diagnosis to a higher level of evidence by clarifying its definition, clinical indicators, and differentiation from other diagnoses. The diagnosis is crucial for identifying patients with compromised breathing who may require respiratory support. Methods: Researchers searched the PubMed medical literature database for studies (2006-2021) on the "Ineffective Spontaneous Ventilation" diagnosis. Results: The search identified 45 studies, but after applying pre-defined criteria, only 10 articles were included in the final analysis. These articles mainly focused on the accuracy of defining characteristics for the diagnosis. Despite limitations of individual defining characteristics, Impaired Spontaneous Ventilation remains a valuable nursing diagnosis for patients with respiratory issues. Utilizing clusters of these characteristics and considering the specific context can significantly enhance the accuracy of ISV diagnosis. Conclusion: The findings unequivocally corroborate the definition of Impaired Spontaneous Ventilation, with eight out of ten articles providing validation. Moreover, the analysis proposes additional defining characteristics, namely dyspnea and cyanosis, to further refine the diagnosis. The clinical applicability of Impaired Spontaneous Ventilation extends to a wide range of patient populations and conditions. It serves as a critical marker for premature infants grappling with respiratory and cardiac challenges, trauma victims battling life-threatening injuries, and patients relying on mechanical ventilation in intensive care settings.

Abstract Phosphodiesterase 2A (Pde2A) is a dual-specific PDE that breaks down both cAMP and cGMP cyclic nucleotides. We recently highlighted a direct relationship between Pde2A impairment, a consequent increase of cAMP, and the appearance of mouse congenital heart defects (CHDs). Here we aimed to characterize the pathways involved in the development of CHDs and in their prevention by pharmacological approaches targeting cAMP and cGMP signaling. Transcriptome analysis revealed a modulation of more than 500 genes affecting biological processes involved in the immune system, cardiomyocyte development and contractility, angiogenesis, transcription, and oxidative stress in hearts from Pde2A −/− embryos. Metoprolol and H89 pharmacological administration prevented heart dilatation and hypertabeculation in Pde2A −/− embryos. Metoprolol was also able to partially impede heart septum defect and oxidative stress at tissue and molecular levels. Amelioration of cardiac defects was also observed by using the antioxidant NAC, indicating oxidative stress as one of the molecular mechanisms underpinning the CHDs. In addition, Sildenafil treatment recovered cardiac defects suggesting the requirement of cAMP/cGMP nucleotides balance for the correct heart development.

Abstract Understanding the mechanisms of breast cancer cell communication underlying cell spreading and metastasis formation is fundamental for developing new therapies. ID4 is a proto-oncogene overexpressed in the basal-like subtype of triple-negative breast cancer (TNBC), where it promotes angiogenesis, cancer stem cells, and BRACA1 misfunction. Here, we show that ID4 expression in BC cells correlates with the activation of motility pathways and promotes the production of VEGFA, which stimulates the interaction of VEGFR2 and integrin β3 in a paracrine fashion. This interaction induces the downstream focal adhesion pathway favoring migration, invasion, and stress fiber formation. Furthermore, ID4/ VEGFA/ VEGFR2/ integrin β3 signaling stimulates the nuclear translocation and activation of the Hippo pathway member’s YAP and TAZ, two critical executors for cancer initiation and progression. Our study provides new insights into the oncogenic roles of ID4 in tumor cell migration and YAP/TAZ pathway activation, suggesting VEGFA/ VEGFR2/ integrin β3 axis as a potential target for BC treatment.

Natural products are thoroughly studied as valuable alternatives to synthetic insecticides. Heracleum persicum Desf. ex Fisch. (Apiaceae), commonly known as Golpar, is an Iranian medicinal plant largely employed as a spice, which has previously revealed insecticidal potential. The chemical composition of H. persicum essential oil (EO) was investigated by GC-MS and was mainly dominated by hexyl butyrate (36.1%) and octyl acetate (23.7%). The EO and its main esters were tested on three mosquito species. Aedes aegypti (L.) larvae were the most sensitive to all tested products. Lethal concentrations (LC50) of 59.09, 53.59, and 47.05 ppm were recorded for the EO, hexyl butyrate, and octyl acetate, respectively. Aedes albopictus (Skuse) and Anopheles gambiae Giles demonstrated comparable sensitivity to the EO, with LC50 values of 102.97 and 97.91 ppm, respectively, whereas the isolated constituents appeared more active on An. gambiae (LC50 of hexyl butyrate and octyl acetate of 70.97 and 60.71 ppm, respectively) with respect to Ae. albopictus (LC50 of hexyl butyrate and octyl acetate of 85.40 and 91.38 ppm, respectively). Low toxicity was registered for both EO and single components against human embryonic kidney (HEK293) cells. Overall, the H. persicum EO, hexyl butyrate, and octyl acetate could be further considered for larvicide development.

The Bagno dell'Acqua lake is characterized by CO2 emissions, alkaline waters (pH = 9) and Eh values which indicate strongly oxidizing conditions. A typical feature of the lake is the presence of actively growing microbialites rich in calcium carbonates and silica precipitates. Mineralogy, petrography and morphology analyses of the microbialites were coupled with the analysis of the microbial community, combining molecular and cultivation approaches. The DNA sequencing revealed distinct patterns of microbial diversity, showing pronounced differences between emerged and submerged microbialite, with the upper layer of emerged samples exhibiting the most distinctive composition, both in terms of prokaryotes and eukaryotes. In particular, the most representative phyla in the microbial community were Proteobacteria, Actinobacteriota, and Bacteroidota, while Cyanobacteria were present only with an average of 5%, with the highest concentration in the submerged intermediate layer (12%). The role of microorganisms in carbonate mineral formation was clearly demonstrated as most of the isolates were able to precipitate calcium carbonate and five of them were characterized at molecular level. Interestingly, when microbial isolates were cultivated only in filtered water, the precipitation of hazenite was observed (up to 85%), opening new prospective in P (phosphate) recovery from P depleted environments.

Abstract Background Central retinal artery occlusion (CRAO) is an ophthalmic emergency, and its etiology is generally ascribed to vessel occlusion by a thrombus or embolus, eventually due to a hypercoagulable state. CRAO occurrence is described even in the pediatric population, but its incidence is very rare. SARS-CoV-2 infection has a multitude of presentations, and almost any organ may be involved including the ocular district. Cases of CRAO in patients affected by COVID-19 are reported in the literature in the adult population, but not in the pediatric one. Case presentation We describe the case of a six-year-old otherwise healthy girl, who presented a sudden and complete bilateral vision loss after a one-day fever. All the clinical, ophthalmological, laboratory and instrumental investigations led to the diagnosis of a right CRAO and the suspicion of a contralateral posterior optic nerve affection. These manifestations could not be ascribed to any etiological condition apart from the documented ongoing mild SARS-CoV-2 infection. Treatment with anticoagulants and steroids was tried but the visual outcome was poor during the one-month hospitalization and at the last follow-up. Conclusions To the best of our knowledge, this is the first report of CRAO in the course of SARS-CoV-2 infection in the pediatric age. In our review of the literature, we found few cases of CRAO in adults with COVID-19; we highlighted differences in anamnestic, clinical, and interventional aspects and therefore we tried to summarize the state of the art on this topic to facilitate further studies. Even if rare, the prognosis of CRAO is poor and the thrombolytic treatment could be effective only if rapidly administered, so the disease suspicion should be high in a patient with sudden vision loss, also in pediatric age.

Organogenesis occurs in the uterus under low oxygen levels (4%). Preterm birth exposes immature newborns to a hyperoxic environment, which can induce a massive production of reactive oxygen species and potentially affect organ development, leading to diseases such as necrotizing enterocolitis. The β3-adrenoreceptor (β3-AR) has an oxygen-dependent regulatory mechanism, and its activation exerts an antioxidant effect. To test the hypothesis that β3-AR could protect postnatal ileal development from the negative impact of high oxygen levels, Sprague–Dawley rat pups were raised under normoxia (21%) or hyperoxia (85%) for the first 2 weeks after birth and treated or not with BRL37344, a selective β3-AR agonist, at 1, 3, or 6 mg/kg. Hyperoxia alters ileal mucosal morphology, leading to increased cell lipid oxidation byproducts, reduced presence of β3-AR-positive resident cells, decreased junctional protein expression, disrupted brush border, mucin over-production, and impaired vascularization. Treatment with 3 mg/kg of BRL37344 prevented these alterations, although not completely, while the lower 1 mg/kg dose was ineffective, and the higher 6 mg/kg dose was toxic. Our findings indicate the potential of β3-AR agonism as a new therapeutic approach to counteract the hyperoxia-induced ileal alterations and, more generally, the disorders of prematurity related to supra-physiologic oxygen exposure.

Abstract Background Acute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A). Methods We treated FLT3-ITD+ AML cells with low doses of the aforementioned drugs, used alone or in combinations and we investigated the induction of ER and oxidative stress. We then performed the same experiments in an in vitro co-culture system of FLT3-ITD+ AML cells and bone marrow stromal cells (BMSCs) to assess the protective role of the niche on AML blasts. Eventually, we tested the combination of drugs in an orthotopic murine model of human AML. Results The combination RBA exerts strong cytotoxic activity on FLT3-ITD+ AML cell lines and primary blasts isolated from patients, due to ER homeostasis imbalance and generation of oxidative stress. AML cells become completely resistant to the combination RBA when treated in co-culture with BMSCs. Nonetheless, we could overcome such protective effects by using high doses of ascorbic acid (Vitamin C) as an adjuvant. Importantly, the combination RBA plus ascorbic acid significantly prolongs the life span of a murine model of human FLT3-ITD+ AML without toxic effects. Furthermore, we show for the first time that the cross-talk between AML and BMSCs upon treatment involves disruption of the actin cytoskeleton and the actin cap, increased thickness of the nuclei, and relocalization of the transcriptional co-regulator YAP in the cytosol of the BMSCs. Conclusions Our findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD+ AML therapy and open to the possibility of identifying new therapeutic targets in the crosstalk between AML and BMSCs, involving mechanotransduction and YAP signaling.

The scientific assessment of tourism ecological security holds significant theoretical and practical importance in promoting the sustainable development of the tourism economy and the ecological environment in the region. This study focuses on 84 counties within Fujian Province as its research scope. By utilizing the DPSIR model and integrating the remote sensing ecological index (RSEI), we have established an evaluation index system for assessing tourism ecological security in the region. The tourism ecological security index was quantitatively determined using the SBM-DEA model. Subsequently, a combination of methods, including spatial autocorrelation, exploratory regression analysis, and the GWR model, was employed to explore the spatial and temporal evolution patterns, as well as driving factors affecting tourism ecological security from 2010 to 2019. The findings reveal the following insights: (1) Overall, the level of tourism ecological security within Fujian Province is low, with a decreasing disparity in the security index across different regions. The tourism ecological security mainly falls within the “unsafe” and “relatively unsafe” categories; however, regions with higher security levels are exhibiting an expanding trend. Moreover, the tourism ecological security of each county is improving, with Southern and Central Fujian outperforming other regions. (2) Notably, there is significant spatial correlation among the tourism ecological security of each county in Fujian Province, indicating pronounced agglomeration characteristics. (3) Key drivers contributing to the spatial–temporal disparities in tourism ecological security encompass tourist-related disturbances, income levels of local farmers and herders, tourism-generated income, and government interventions. Among these factors, higher income levels for farmers and herders, increased tourism income, and proactive government intervention have a positive impact on tourism ecological security, whereas tourist disturbances exert a negative influence. Additionally, the impact of each factor on tourism ecological security displays noticeable spatial heterogeneity.

Abstract Background To evaluate by means of profilometric analysis and scanning electronic microscope (SEM) the effects on enamel surfaces of oscillating mechanical systems for interproximal enamel reduction (IPR). Fifteen complete (Group 1) oscillating IPR sequence and 15 single metallic strips (Group 2) for active IPR phase of 0.2 mm were selected and tested on 30 freshly extracted teeth by means of tribological tests with alternative dry-sliding motion (Linear Reciprocating Tribometer, C.S.M. Instruments, Peseaux, Switzerland). Enamel surface roughness and waviness measurements were assessed by contact probe surface profiler (TalySurf CLI 2000; Taylor Hobson, Leicester, UK) and a TayMap software for the 3D analysis. Statistical analysis was performed with independent samples t-test. Significance was established at the P

The development of coatings for accident-tolerant fuels (ATFs) for light water reactor (LWR) applications promises improved corrosion resistance under accident conditions and better performances during operation. CrN and TiN coatings are characterized by high wear resistance coupled with good corrosion resistance properties. They are generally used to protect materials in applications where extreme conditions are involved and represent promising candidates for ATF. Zr cladding tubes coated with 5 µm-thick CrN or TiN, exposed in an autoclave to simulated PWR chemistry and BWR chemistry, were characterized with SEM, EDS, and STEM. The investigation focused on the performance and oxidation mechanisms of the coated claddings under simulated reactor chemistry. Both coatings provided improved oxidation resistance in a simulated PWR environment, where passivating films of Cr2O3 and TiO2, less than 1 µm-thick, formed on the CrN and TiN outer surfaces, respectively. Under the more challenging BWR conditions, any formed Cr2O3 dissolved into the oxidizing water, resulting in the complete dissolution of the CrN coating. For the TiN coating, the formation of a stable TiO2 film was observed under BWR conditions, but the developed oxide film was unable to stop the flux of oxygen to the substrate, causing the oxidation of the substrate.

In this study, neutron diffraction and transmission electron microscopy (TEM) have been implemented to study the crystallographic structure of the ternary phase U2CrN3 from pellet to nano scale respectively. Recently microstructural evaluation of this ternary phase has been performed for the first time in pellet condition, overcoming the Cr evaporation issue during the conventional sintering process. In this work for the first time, the crystallographic structure of the ordered ternary U2CrN3 phase, stabilized in pellet condition, has been obtained by implementing neutron diffraction. For this study, pellets of the composite material UN with 20 vol% CrN were fabricated by powder metallurgy by mixing UN and CrN powders followed by Spark Plasma Sintering (SPS). TEM was used to investigate the nanoscale structure with a thin lamella of the order of 100–140 nm produced by focused ion beam (FIB). The neutron data revealed the phase composition of the pellet to be primarily 54(8) wt.% U2CrN3, in good agreement with the stoichiometry of starting reagents (UN and CrN powder) and metallographic analysis. Neutron data analysis confirms that all the crystallographic sites in U2CrN3 phase are fully occupied reinforcing the fully stoichiometric composition of this phase, however, the position of the N at the 4i site was found to be closer to the Cr than previously thought. TEM and selected area electron diffraction rendered nano-level information and revealed the presence of nano domains along grain boundaries of UN and U2CrN3, indicating a formation mechanism of the ternary phase, where the phase likely nucleates as nano domains in UN grains from migration of Cr.

Oxygen level is a key regulator of organogenesis and its modification in postnatal life alters the maturation process of organs, including the intestine, which do not completely develop in utero. The β3-adrenoreceptor (β3-AR) is expressed in the colon and has an oxygen-dependent regulatory mechanism. This study shows the effects of the β3-AR agonist BRL37344 in a neonatal model of hyperoxia-driven colonic injury. For the first 14 days after birth, Sprague–Dawley rat pups were exposed to ambient oxygen levels (21%) or hyperoxia (85%) and treated daily with BRL37344 at 1, 3, 6 mg/kg or untreated. At the end of day 14, proximal colon samples were collected for analysis. Hyperoxia deeply influences the proximal colon development by reducing β3-AR-expressing cells (27%), colonic length (26%) and mucin production (47%), and altering the neuronal chemical coding in the myenteric plexus without changes in the neuron number. The administration of BRL37344 at 3 mg/kg, but not at 1 mg/kg, significantly prevented these alterations. Conversely, it was ineffective in preventing hyperoxia-induced body weight loss. BRL37344 at 6 mg/kg was toxic. These findings pave the way for β3-AR pharmacological targeting as a therapeutic option for diseases caused by hyperoxia-impaired development, typical prematurity disorders.

Abstract Malignant mesothelioma (MM) is a rare orphan aggressive neoplasia with low survival rates. Among the other signaling pathways, ErbB receptors and Hh signaling are deregulated in MM. Thus, molecules involved in these signaling pathways could be used for targeted therapy approaches. The aim of this study was to evaluate the effects of inhibitors of Hh- (GANT-61) and ErbB receptors (Afatinib)-mediated signaling pathways, when used alone or in combination, on growth, cell cycle, cell death and autophagy, modulation of molecules involved in transduction pathways, in three human MM cell lines of different histotypes. The efficacy of the combined treatment was also evaluated in a murine epithelioid MM cell line both in vitro and in vivo. This study demonstrated that combined treatment with two inhibitors counteracting the activation of two different signaling pathways involved in neoplastic transformation and progression, such as those activated by ErbB and Hh signaling, is more effective than the single treatments in reducing MM growth in vitro and in vivo. This study may have clinical implications for the development of targeted therapy approaches for MM.

The circular isoform of VEGFA mRNA (circ_0076611), associated with size and pathogenesis of triple-negative breast tumors, is produced via back splicing of exon-7 by a RNP complex comprising lncRNA-MALAT1, ID4 and SRSF1, and secreted through exosomes.

Abstract Background The nucleolus is a subnuclear, non-membrane bound domain that is the hub of ribosome biogenesis and a critical regulator of cell homeostasis. Rapid growth and division of cells in tumors are correlated with intensive nucleolar metabolism as a response to oncogenic factors overexpression. Several members of the Epidermal Growth Factor Receptor (EGFR) family, have been identified in the nucleus and nucleolus of many cancer cells, but their function in these compartments remains unexplored. Results We focused our research on the nucleolar function that a specific member of EGFR family, the ErbB3 receptor, plays in glioblastoma, a tumor without effective therapies. Here, Neuregulin 1 mediated proliferative stimuli, promotes ErbB3 relocalization from the nucleolus to the cytoplasm and increases pre-rRNA synthesis. Instead ErbB3 silencing or nucleolar stress reduce cell proliferation and affect cell cycle progression. Conclusions These data point to the existence of an ErbB3-mediated non canonical pathway that glioblastoma cells use to control ribosomes synthesis and cell proliferation. These results highlight the potential role for the nucleolar ErbB3 receptor, as a new target in glioblastoma.