Aeroelastic Stability Assessment Of a CS-25 Category Aircraft Equipped With Multi-Modal Wing Morphing Devices

Morphing wing structures have the greatest ambition to dramatically im-prove aircraft aerodynamic performance (less fuel consumption) and reduce aerodynamic noise. Several studies in the literature have shown their potential for increased aerodynamic efficiency across nearly all flight conditions, en-hanced aircraft maneuverability and control effectiveness, decreased take-off/landing length, reduced airframe noise, etc. However, despite a long herit-age of research, morphing wing technology has yet to be approved by the Euro-pean Aviation Safety Authority (EASA) for use in commercial aviation. Models and approaches capable to predict the aeroelastic impact of a morphing wing still need to be matured to safely alter design and operation of future genera-tions of aircraft. Additionally, a number of practical challenges remain to be addressed in the suitable materials, systems reliability, safety and maintenance. Due to the reduced stiffness, increased mass and increased Degree Of Freedom (DOF) with respect to conventional wings, these mechanical systems can cause significant reduction of aircraft flutter margins. This aspect requires dedicated aeroelastic assessments since the early stages of the design process of such an innovative wing. Flutter boundaries predictions need sensitivity anal-yses to evaluate bending/torsional stiffness and inertial distribution variability ranges of the aircraft wing equipped with the morphing wing devices. In such a way, aeroelastic assessments become fundamental to drive a balance between weight and stiffness of the investigated adaptive systems. Furthermore, in pseu-do rigid-body mechanisms-based morphing structures, the inner kinematics is so important that its faults may compromise the general aircraft-level functions. Similarly to the demonstration means of safety compliance, commonly applied to aircraft control surfaces, the novel functions resulting from the integration of adaptive devices into flying aircraft thus impose a detailed examination of the associated risks. In the framework of Clean Sky 2 Airgreen 2 project, the author provides advanced aeroelastic assessments of two adaptive devices enabling the camber morphing of winglets and flaps, conceived for regional aircraft integration (EASA CS-25 category). Segmented ribs architectures ensure the transition from the baseline (or un-morphed) shape to the morphed ones, driven by em-bedded electromechanical actuators. Some of the advantages resulting from the combination of the two aforementioned morphing systems are wing load con-trol, lift-over-drag ratio increase and root bending moment alleviation. The aircraft aeroelastic model was generated by means of the proprietary code SANDY 3.0. Then, the same code was adopted to solve the aeroelastic stability equa-tions through theoretical modes association in frequency domain. To carry out multi-parametric flutter analyses (P-K continuation method), the actuation lines stiffness and winglet/flap tabs inertial parameters were considered in combina-tion each other. Nominal operative conditions as well as systems malfunction-ing or failures were examined as analyses cases of the investigated morphing devices, together with actuators free-play conditions. Proper design solutions were suggested to guarantee flutter clearance in accordance with aircraft stabil-ity robustness with respect to morphing systems integration, evaluated through a combination of “worst cases” simulating the mutual interaction among the adaptive systems. The safety-driven design of the morphing wing devices required also a thorough examination of the potential hazards resulting from operational faults involving either the actuation chain, such as jamming, or the external interfaces, such as loss of power supplies and control lanes, and both. The main goal was to verify whether the morphing flap and winglet systems could comply with the standard civil flight safety regulations and airworthiness requirements (EASA CS25). More in detail, a comprehensive study of systems functions was firstly qualitatively performed at both subsystem and aircraft levels to identify poten-tial design faults, maintenance and crew faults, as well as external environment risks. The severity of the hazard effects was thus determined and then ranked in specific classes, indicative of the maximum tolerable probability of occurrence for a specific event, resulting in safety design objectives. Fault trees were final-ly produced to assess the compliance of the system architectures to the quanti-tative safety requirements resulting from the FHAs

HDAC4 regulates skeletal muscle regeneration via soluble factors

Skeletal muscle possesses a high ability to regenerate after an insult or in pathological conditions, relying on satellite cells, the skeletal muscle stem cells. Satellite cell behavior is tightly regulated by the surrounding microenvironment, which provides multiple signals derived from local cells and systemic factors. Among epigenetic mechanisms, histone deacetylation has been proved to affect muscle regeneration. Indeed, pan-histone deacetylase inhibitors were found to improve muscle regeneration, while deletion of histone deacetylase 4 (HDAC4) in satellite cells inhibits their proliferation and differentiation, leading to compromised muscle regeneration. In this study, we delineated the HDAC4 function in adult skeletal muscle, following injury, by using a tissue-specific null mouse line. HDAC4 resulted crucial for skeletal muscle regeneration by mediating soluble factors that influence muscle-derived cell proliferation and differentiation. These findings add new biological functions to HDAC4 in skeletal muscle that need considering when administering histone deacetylase inhibitors

Growth Factor Receptor-bound Protein 2 Interaction with the Tyrosine-phosphorylated Tail of Amyloid β Precursor Protein Is Mediated by Its Src Homology 2 Domain

The sequential processing of the familial disease gene product amyloid beta precursor protein (AbetaPP) by beta- and gamma-secretases generates amyloid beta, which is considered to be the pathogenic factor of Alzheimer's disease, and the AID peptide (AbetaPP intracellular domain). The AID peptide acts as a positive regulator of apoptosis and modulates transcription and calcium release. To gain clues about the molecular mechanisms regulating the function of AbetaPP and AID, proteins interacting with the AID region of AbetaPP have been isolated using the yeast two-hybrid system. Recent evidence indicates that AbetaPP undergoes post-translational modification events in the AID region and that phosphorylation might regulate its affinity for interacting proteins. To test this possibility and to uncover AbetaPP-binding partners whose interaction depends on AbetaPP phosphorylation, we used a proteomic approach. Here we describe a protein, growth factor receptor-bound protein 2 (Grb2), that specifically binds AbetaPP, phosphorylated in Tyr(682). Furthermore, we show that this interaction is direct and that Grb2 binds to phospho-AbetaPP via its Src homology 2 region. Together with the evidence that Grb2 is in complex with AbetaPP in human brains and that these complexes are augmented in brains from Alzheimer's cases, our data indicate that Grb2 may mediate some biological and possibly pathological AbetaPP-AID function

The Mental Health Index across the Italian Regions in the ESG Context

The following article analyses the relationship between the mental health index and the variables of the Environment, Social and Governance-ESG model in the Italian regions between 2004 and 2023. The econometric analysis is aimed at investigating in detail the relationships between the mental health index and the individual components of the ESG model. The results are critically discussed

The ESG Determinants of Mental Health Index Across Italian Regions: A Machine Learning Approach

The following article analyses the relationship between the mental health index and the variables of the Environment, Social and Governance-ESG model in the Italian regions between 2004 and 2023. First of all, a static analysis is proposed aimed at identifying trends relating to mental health in the Italian regions with indication of the regional gaps. Subsequently, a clustering with k-Means algorithm is proposed. Below is a comparison of 11 machine learning algorithms for predicting the performance of the mental health index. Finally, the article offers some economic policy suggestions. The results are critically discussed in light of the scientific literatur

Histone Deacetylase 4 is crucial for proper skeletal muscle development and disease

Epigenetics plays a pivotal role in modulating gene response to physiological or pathological stimuli. Histone Deacetylase inhibitors (HDACi) have been used in the treatment of various cancers1, are effective in several animal models of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and are currently in clinical trial to promote muscle repair in muscular dystrophies2. However, long-term use of pan-HDAC inhibitors is not tolerated3. The assignment of distinct biological functions to individual HDACs in skeletal muscle is a prerequisite to improve the efficacy of pharmacological treatments based on HDACi. HDAC4 is a member of class II HDACs that mediates many cellular responses. Clinical reports suggest that inhibition of HDAC4 can be beneficial to cancer cachexia, dystrophic or ALS patients. All the above conditions are characterized by progressive muscle wasting and up-regulation of HDAC4 expression in skeletal muscle, suggesting a potential role for this protein in regulating these diseases. To study the role of HDAC4 with a genetic approach, we generated several models of muscle disease in mice lacking HDAC4 in skeletal muscle: cancer cachexia, by implanting Lewis lung carcinoma (LLC), muscular dystrophy, by using mdx mice, or ALS, by using SODG93A mice. Lack of HDAC4 worsens skeletal muscle atrophy induced by both LLC and ALS, demonstrated by a reduction in muscle mass and myofibers size. Conversely, dystrophic mice lacking HDAC4 in skeletal muscle show an increased number of necrotic myofibers and run less efficiently than mdx mice. The aggravation of the dystrophic phenotype may be partially due to the impairment in skeletal muscle regeneration observed in mice lacking HDAC4 in skeletal muscle. Our results indicate that HDAC4 is necessary for maintaining skeletal muscle homeostasis and function. Current studies aim to investigate the molecular mechanisms underlying the role of HDAC4 in skeletal muscle maintenance in response to cancer cachexia, ALS or muscular dystrophy

HDAC4 is necessary for satellite cell differentiation and muscle regeneration

In response to injury, skeletal muscle exhibits high capacity to regenerate and epigenetics controls multiple steps of this process (Giordani et al., 2013). It has been demonstrated in vitro that completion of muscle differentiation requires shuttling of histone deacetylase 4 (HDAC4), a member of class IIa HDACs, from the nucleus to the cytoplasm and consequent activation of MEF2-dependent differentiation genes (McKinsey et al., 2000). In vivo, HDAC4 expression is up-regulated in skeletal muscle upon injury, suggesting a role for this protein in muscle regeneration. With the aim to elucidate the role of HDAC4 in skeletal muscle regeneration, we generate mice lacking HDAC4 in the satellite cells (HDAC4fl/fl;Pax7CE Cre). Lack of HDAC4 inhibits satellite cell differentiation. Despite having similar amount of sorted cells, HDAC4 KO satellite cells proliferate less and have less pax7 than controls. Importantly, muscle regeneration in vivo is impaired in HDAC4fl/fl;Pax7CE Cre mice. These results are confirmed by molecular analyses of the expression of myogenic markers. All together, these data delineate the importance of HDAC4 in muscle regeneration and suggest a protective role in response to muscle damage

Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation

Memory stem T cells (TSCM) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked TSCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived TSCM are highly enriched early after HSCT. We showed at the antigen-specific and clonal level that TSCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of TSCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting TSCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT

Profiling Antibody Response Patterns in COVID-19: Spike S1-Reactive IgA Signature in the Evolution of SARS-CoV-2 Infection

This contribution explores in a new statistical perspective the antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 141 coronavirus disease 2019 (COVID-19) patients exhibiting a broad range of clinical manifestations. This cohort accurately reflects the characteristics of the first wave of the SARS-CoV-2 pandemic in Italy. We determined the IgM, IgA, and IgG levels towards SARS-CoV-2 S1, S2, and NP antigens, evaluating their neutralizing activity and relationship with clinical signatures. Moreover, we longitudinally followed 72 patients up to 9 months postsymptoms onset to study the persistence of the levels of antibodies. Our results showed that the majority of COVID-19 patients developed an early virus-specific antibody response. The magnitude and the neutralizing properties of the response were heterogeneous regardless of the severity of the disease. Antibody levels dropped over time, even though spike reactive IgG and IgA were still detectable up to 9 months. Early baseline antibody levels were key drivers of the subsequent antibody production and the long-lasting protection against SARS-CoV-2. Importantly, we identified anti-S1 IgA as a good surrogate marker to predict the clinical course of COVID-19. Characterizing the antibody response after SARS-CoV-2 infection is relevant for the early clinical management of patients as soon as they are diagnosed and for implementing the current vaccination strategies

Case report: Ponatinib as a bridge to CAR-T cells and subsequent maintenance in a patient with relapsed/refractory Philadelphia-like acute lymphoblastic leukemia

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) constitutes a heterogeneous subset of ALL with a uniformly unfavorable prognosis. The identification of mutations amenable to treatment with tyrosine kinase-inhibitors (TKIs) represents a promising field of investigation. We report the case of a young patient affected by relapsed/refractory Ph-like ALL treated with chimeric antigen receptor T (CAR-T) cells after successful bridging with compassionate-use ponatinib and low-dose prednisone. We restarted low-dose ponatinib maintenance three months later. Twenty months later, measurable residual disease negativity and B-cell aplasia persist. To the best of our knowledge, this is the first case reporting the use of ponatinib in Ph-like ALL as a bridge to and maintenance after CAR-T cell therapy