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Mitochondria for Cardiovascular Therapy: A Deep Dive into Drug Targets and Therapeutic Approaches
No full textPurpose: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Mitochondria are central to cardiac physiology, governing energy production, redox signaling, calcium homeostasis, and metabolic adaptation. Given their crucial role, mitochondrial dysfunction is increasingly recognized as a fundamental contributor to CVD progression. This review aims to provide an updated perspective on mitochondrial involvement in cardiovascular health and disease, emphasizing recent therapeutic advances and potential clinical applications. Recent Findings: Mitochondrial dysfunction has been implicated in the pathogenesis of various CVDs, including heart failure, myocardial infarction, and ischemia–reperfusion (I/R) injury. Advances in mitochondrial-targeted drug development have identified novel therapeutic strategies, such as modulation of mitochondrial bioenergetics, dynamics, quality control, and signaling pathways. Additionally, emerging research has expanded our understanding of mitophagy, mitochondrial transfer therapies, and the role of mitochondrial-derived signals in cardiac pathophysiology. Conclusion: Targeting mitochondrial pathways represents a promising therapeutic approach for managing CVDs. However, key challenges remain, including efficient drug delivery, off-target effects, and interpatient variability in response to mitochondrial interventions. This review not only explores these approches but also summarizes compounds currently in preclinical and clinical stages that directly affect mitochondrial function. Additionally, we discuss novel strategies, such as mitochondrial transplantation and advanced drug delivery systems, that may enhance therapeutic efficacy. A deeper understanding of mitochondrial biology and its systemic interactions will be essential for translating these innovations into effective clinical treatments for cardiovascular diseases
MESSIANESIMO POLITICO, DEMOCRAZIA TOTALITARIA E SIONISMO NEL PENSIERO POLITICO DI JACOB TALMON
Full text linkIl presente studio analizza il pensiero politico di Jacob L. Talmon, concentrandosi sui concetti fondamentali di messianesimo politico, democrazia totalitaria e sionismo. Il lavoro di Talmon risulta di fondamentale importanza per comprendere come ideali razionalistici sorti durante l’Illuminismo e solennemente proclamati dalla Rivoluzione Francese abbiano condotto alla nascita di regimi autoritari che, paradossalmente, ambivano a realizzare i concetti di libertà e uguaglianza attraverso metodi coercitivi e di controllo. Viene inoltre analizzato il caso specifico di Israele dalla prospettiva di Talmon, quale case-study di una società imperniata su una mentalità di tipo messianico-politico. Questo lavoro mette in luce come movimenti politici radicali possano condurre a sistemi oppressivi di governo, e analizza i rapporti tra ideali utopici, movimenti rivoluzionari e regimi autoritari
Predicting biomarkers of progressive pulmonary fibrosis: morphological, cytokine profile, and clinical portrait
Full text linkObjective: The term progressive pulmonary fibrosis (PPF) refers to a specific disorder that becomes worse despite optimal treatment. The pathogenic explanation of this progressive worsening is still to be found. In this study, we explored whether any histological, molecular, radiological, or clinical features could predict a progressive phenotype in patients with fibrotic interstitial lung diseases. Methods: Two hundred and fifteen patients with PPF other than idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD) were followed in our ILD clinic between January 2016 and May 2023. Based on tissue block availability, 48 patients were definitively enrolled. Progression was defined according to the most recent guidelines. Clinical, radiological, and functional data were also collected retrospectively and correlated with tissue morphological and molecular cytokine profiles. Results: Fifteen patients were classified as progressors (PPF) and 33 as non-progressors (nPPF) with similar age at diagnosis and gender. PPF showed a higher prevalence of traction bronchiectasis (80% vs. 27%; p=<0.001) at CT scan and lower functional parameters [FVC: 2.42 L vs. 3.37 L; p=0.004; TLC: 3.83 L vs. 4.65 L; p=0.027] at diagnosis. Lung specimens revealed a significant overexpression of IL9 in the PPF compared to the nPPF group (p=0.049). Boruta algorithm analysis showed that lymphoid aggregates and traction bronchiectasis at diagnosis are the most important variables in determining the PPF status. Conclusions: The present results increase the understanding of the pathological mechanisms of PPF, offering potential avenues for improved prognostication and therapeutic intervention
Assessment Of A New 0.2 Hub-To-Tip Ratio Propeller Fan Design With Rigid-Body Blade Loading
Full text linkThis paper presents the numerical assessment of a new 0.2 hub-to-tip ratio propeller fan with specific speed equal to 8.2, by means of an original low-order CFD modelling approach. The fan implements the rigid body blade loading distribution and it was designed by the authors using the classical “Kahane-Wallis” method. First aim of the work is to give a preliminary feedback on the possibility that the new fan improves the aerodynamic performance of a high-efficiency fan, which implements the constant-swirl blade loading. Second aim of the work is to verify the effectiveness of the “Kahane-Wallis” method for the design of very low hub-to-tip ratio fan rotors with rigid-body blade loading. The third aim is to present the new low-order CFD modelling approach that the authors conceived for a low-computational-cost preliminary estimate of the aerodynamic performance expected from ISO 5801 Type-A performance tests.
The results demonstrated that the “Kahane-Wallis” method allows for rigid-body designs with very low hub-to-tip ratio and remarkably high pressure coefficients. However, such designs unlikely exceed the efficiency achieved by constant-swirl designs featuring lower pressure coefficients. Moreover, the successful application of the method is doubtful for designs with flow separation at the blade root or immediately downstream of the rotor. Finally, it is found that the new low-order CFD approach offers potentialities as a tool to support the preliminary fan design and deserves future investigations
Impact of drill bit wear on temperature increase in dental implant osteotomy: an in vitro study
Full text linkObjectives Dental implant surgery relies extensively on bone drilling, a critical procedure with intrinsic challenges. Drill bits show significant wear and are frequently utilized beyond the manufacturer’s recommended limits. Such practices can result in adverse effects, including friction and temperature rise in the surrounding bone area during interventions, with an increased risk of necrosis that can compromise the dental implant osseointegration. This study aimed to compare the quality of osteotomy obtained from two different protocols to determine a possible correlation between the drilling temperature and the tool wear and to evaluate their impact on potential health damage. Materials and methods Experimental evaluations were conducted using synthetic bone that reproduced human bone characteristics. The drilling phase involved real-time temperature acquisition and scanning electron microscopy analysis of tool wear evolution. After the operation, actual hole size and geometry were characterized using a coordinate measuring machine, and temperatures and torques were measured during the subsequent implantation phase. Results The findings revealed a direct correlation between tool wear and the temperature rise during the drilling phase, while a lower correlation was found with the hole profile geometry variation. The implantation phase demonstrated temperature and torque values within acceptable ranges. Conclusions This study highlights the importance of adhering to proper tool maintenance and replacement protocols. By following recommended guidelines, practitioners can minimize adverse effects and enhance the success of dental implant procedures
Thrombotic events after vaccination for covid-19 in Italy: a report from the Italian society on thrombosis and haemostasis registry
No full textSince vaccine induced immune thrombotic thrombocytopenia (VITT) became evident in early 2021, research has focused on characterizing this new pathologic entity. Moreover, data were urgently needed on the association, if any, between all COVID-19 vaccines and thrombotic events (TEs). The study was aimed to collect relevant information on all cases of TEs occurring after COVID-19 vaccination. A national, prospective registry was set up by the Italian Society on Thrombosis and Haemostasis, enrolling consecutive adult patients diagnosed with any TE occurring within 30 days from any COVID-19 vaccine dose, with or without thrombocytopenia. The primary objective was the characterization of TEs and description of its management. The study was approved by the national ethics committee on COVID-19 research and by the participating centers. Among 308 patients included in the registry from February 2021 up to 29 Aug 2022, 276 (89.6%) were diagnosed with venous (266) and/or arterial (33) non-VITT TEs, after a median of 14 days after vaccination. The median age was 60 years, 151 (54.7%) were males, 48 (17.5%) had previous venous or arterial TEs. Within 30 days after diagnosis, 8 (2.9%) patients experienced thrombosis progression/recurrence, 2 (0.7%) major bleeding, 8 (2.9%) died. No differences were found in terms of thrombosis characteristics and progression between non-VITT patients receiving mRNA and adenoviral vector-based vaccines. The remaining 32 patients (10.4%) included in the registry were diagnosed with VITT, after a median of 10 days after vaccination. All of them received adenoviral vector-based vaccines. As compared to non-VITT thrombosis, VITT involved more often both venous and arterial sites (25% vs. 4%, p 0.0002) and unusual sites (62.5% vs. 18.8%, p < 0.0001) and was associated with worse outcomes (thrombosis progression/recurrence 25% vs. 2.9%, major bleeding 34.4% vs. 0.7%, death 18.8% vs. 2.9%, for all comparisons p < 0.0001). Significant differences were found between non-VITT and VITT cases. Non-VITT thromboses occurring after vaccination seem to resemble common thrombosis phenotypes
Trends in background mortality in unmanaged forests across Europe over the last century
Full text linkAnthropogenic climate change has led to increasing background tree mortality rates worldwide. Tree species have different ways of dealing with changing environmental conditions due to their life-history strategies and location within their ecological niche. Trees growing further from the centre of their niche are likely to experience higher levels of climatic stress and potentially higher mortality, whereas trees growing closer to the niche centre may experience higher intraspecific competition. To study the complex interplay of abiotic and biotic factors leading to tree mortality, we used a comprehensive network of permanent plots with repeated censuses spanning from 1936 to 2020 in 299 unmanaged forest reserves across Europe. The database includes 1.5 million stem records covering a total sampled area of 853.7 ha. We (1) calculated background mortality rates, (2) analysed trends in mortality rates and (3) investigated how the trends relate to the location of each tree within its ecological niche. We used Species Distribution Models (SDMs) to locate trees within their niche and generalized linear mixed models (GLMMs) to model mortality. We observed an overall median annual background mortality rate of 1.1%. Spruce-dominated forests had the largest increase in annual mortality from 1.5% to 3%. Similarly, the models showed a significant increase in oak-dominated forests, whereas beech-dominated forests showed a significant decrease in annual mortality rates over time. We identified three distinct mortality responses with respect to the location of trees in their ecological niche. For oak, spruce and mountain pine, higher mortality probabilities occurred when they were located further from their niche centre. Hornbeam, ash and Scots pine showed the opposite pattern and beech and fir featured an almost negligible effect of distance from the niche centre. Synthesis. In contrast to previous studies, our results suggest that dominant tree species in European natural forests have not consistently experienced increasing background mortality under anthropogenic climate change. Conversely, forest reserves dominated by competitive species such as beech may have benefitted from warmer growing conditions. Most studied tree species show no clear effect of distance from the niche centre, indicating high resilience and adaptability to environmental stress
Unlocking the potential of organopalladium complexes for high-grade serous ovarian cancer therapy
No full textHigh-Grade Serous Ovarian Cancer (HGSOC) is the most common and lethal subtype of ovarian cancer, known for its high aggressiveness and extensive genomic alterations. Typically diagnosed at an advanced stage, HGSOC presents formidable challenges in drug therapy. The limited efficacy of standard treatments, development of chemoresistance, scarcity of targeted therapies, and significant tumor heterogeneity render this disease incurable with current treatment options, highlighting the urgent need for novel therapeutic approaches to improve patient outcomes. In this study we report a straightforward and stereoselective synthetic route to novel Pd(ii)-vinyl and -butadienyl complexes bearing a wide range of monodentate and bidentate ligands. Most of the synthesized complexes exhibited good to excellent in vitro anticancer activity against ovarian cancer cells. Particularly promising is the water-soluble complex bearing two PTA (1,3,5-triaza-7-phosphaadamantane) ligands and the Pd(ii)-butadienyl fragment. This compound combines excellent cytotoxicity towards cancer cells with substantial inactivity towards non-cancerous ones. This derivative was selected for further studies on ex vivo tumor organoids and in vivo mouse models, which demonstrate its remarkable efficacy with surprisingly low collateral toxicity even at high dosages. Moreover, this class of compounds appears to operate through a ferroptotic mechanism, thus representing the first such example for an organopalladium compound
Multi-fidelity modelling of a high bypass ratio turbofan engine with variable area nozzle
Full text linkLow pressure ratio fans of modern civil turbofans suffer from reduced stall margin in the take-off operating line and at part-speed, requiring variable geometry devices. Variable area nozzles (VAN) are one of the investigated solutions to control engine operating conditions throughout the mission. In this paper, we present a multi-fidelity modelling approach for an ultra-high bypass ratio turbofan engine with a VAN, combining a zero-dimensional thermodynamic cycle simulator using a realistic fan map with two- and three-dimensional detailed computational fluid dynamics (CFD) simulations for internal/external flow coupling. By adopting a novel algorithm to match the cycle conditions to the CFD solutions, the propulsive performance of the turbofan is analysed in a reference aircraft mission. The numerical method captures the effect on thrust generation and nacelle drag, providing a more reliable estimation of the impact of VAN on engine operation and efficiency. Low-speed mission points are confirmed to be those that benefit the most from an enlarged fan nozzle area, with a possible improvement of 3% in terms of thrust and specific fuel consumption at take-off and approach using a 10% larger area, similarly predicted by both 2D and 3D models. A preliminary acoustic evaluation based on semi-empirical noise models indicates a modest effect on noise emissions, with up to 1 dB reduction in microphone signature at the sideline for a nozzle area increased by 10%. (c) 2025 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/)