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6. Imaging the coupling of terahertz radiation to a high electron mobility transistor in the near-field

Author

Ortolani M., Di Gaspare A., Giovine E., Evangelisti F., Foglietti V., Doria A., Gallerano G. P., Giovenale E., Messina G., Spassovsky I., Lanzieri C., Peroni M., and Cetronio A.

Subjects
terahertz, heterostructure, detector, near-field, Applied optics. Photonics, TA1501-1820, Optics. Light, QC350-467
Abstract

We used AlGaN/GaN high electron mobility transistors as room-temperature direct detectors of radiation at 0.15 THz from a free electron laser, hence 5 times higher than their cutoff frequency of 30 GHz. By near-field active mapping we investigated the antenna-like coupling of the radiation to the transistor channel. We formulate a model for the detection based on self-mixing in the transistor channel. The noise equivalent power is found in the range of 10−7 W/Hz0.5 without any optimization of the device responsivity. Present day AlGaN/GaN fabrication technology may provide operation at higher frequency, integration of amplifiers for improved responsivity and fast switches for multiplexing, which make the detector here described the basic element of a monolithic terahertz focal plane array.

Published
2009
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10. Superconducting Cables Characterization with an electrical method

Author

Morici, L., De Bella, E. Tamburo, and Messina, G.

Subjects
Condensed Matter - Superconductivity
Abstract

AC losses in High Temperature Superconductor tapes (HTS) are an important design parameter for large scale power applications. The electrical method is often used for losses measurements on SC tapes and, when the results are to be compared to computed estimations, simple theoretical models like the Norris Brandt are typically used. Electromagnetic dynamic effects are not usually taken into account by the simpler models, but their presence may corrupt the measured data. In this paper, a preliminary study on a conventional copper bar sample has been done to evaluate the effect of the skin currents on the specimen losses measures obtained from the electrical method. The measurement procedure has afterward been applied to a SC YBCO tape (Superpower SCS4050AP), obtaining circuit configuration dependent results. Because the SC losses must obviously be measurement circuit independent, a systematic error due to the skin currents must be playing a role. The skin current induced error is always there and, in order to apply the electrical method for losses estimation, the only possibility is its minimization. The best choice for the measurement circuit to be adopted, in order to minimize the skin current undesired contribution, will finally be proposed., Comment: 12 pages, 11 figures

Published
2018

12. Nitrogen dioxide pollution increases vulnerability to COVID-19 through altered immune function

Author

Di Ciaula, Agostino, Bonfrate, Leonilde, Portincasa, Piero, Appice, C, Belfiore, A, Binetti, M, Cafagna, G, Campanale, G, Carrieri, A, Cascella, G, Cataldi, S, Cezza, A, Ciannarella, M, Cicala, L, D’Alitto, F, Dell’Acqua, A, Dell’Anna, L, Diaferia, M, Erroi, G, Fiermonte, F, Galerati, I, Giove, M, Grimaldi, L, Mallardi, C, Mastrandrea, E, Mazelli, G. D., Mersini, G, Messina, G, Messina, M, Montesano, A, Noto, A, Novielli, M. E., Noviello, M, Palma, M. V., Palmieri, V. O., Passerini, F, Perez, F, Piro, C, Prigigallo, F, Pugliese, S, Rossi, O, Stasi, C, Stranieri, R, and Vitariello, G

Published
2022
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14. Kretzschmaria deusta, a limiting factor for survival and safety of veteran beech trees in Trentino (Alps, Northern Italy)

Author

Cordin G, Messina G, Maresi G, Zottele F, Ferretti F, Montecchio L, and Oliveira Longa CM

Subjects
Fagus sylvatica, Xilariaceae, Brittle Cinder, Soft-rot, Visual Tree Assessment, Veteran Tree Conservation, Forestry, SD1-669.5
Abstract

The importance of veteran trees is well recognised nowadays. The sudden breakage of some of these plants in Trentino (Italy), mainly due to Kretzschmaria deusta, prompted a survey of the veteran beeches reported in this area. Visual tree assessment was carried out in 40 sites with either single trees or groups of beeches, for a total of 115 trees evaluated. Most trees showed serious defects or problems in need of management and 19 had a high level of risk of breakage because of the presence of several structural problems. The presence of K. deusta was recorded on 50.4% of the examined trees. The pathogen was also identified in the proximity of investigated trees at 29 sites. Laboratory tests confirmed the identity of K. deusta by microbiological and molecular approaches and also identified Cosmopora berkeleyana as mycoparasite on K. deusta fruiting bodies. Isolates obtained from declining trees and old stumps showed the same pattern of growth at different temperatures. The risk evaluation emphasised how the fungus could affect the survival and safety of these veteran trees; this was confirmed by the collapse of four of the investigated trees in the last years. Therefore, K. deusta, which has been considered as a facultative parasite up to now, could play a more incisive role both in the decline of old beech trees and the natural evolution of aging beech woods.

Published
2021
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18. An investigation into the magnetic properties of low-dimensional 3D magnets

Author

Messina, G.

Subjects
530
Abstract

This thesis describes investigations of the effects of low dimensionality on two different antiferromagnetic systems. First, coherent spin-density-waves (SDWs) were studied in thin films of epitaxial chromium grown on MgO. This system exhibits antiferromagnetic ground states where the density of the spin of the conduction electrons is spatially modulated with an incommensurate period. The SDW features a wave vector Q and is accompanied by a charge-density-wave (CDW) and a sinusoidal lattice distortion, or strain-wave (SW), whose wave vectors are related by the rule QSW = QCDW = 2QSDW . The CDW and the SW produce satellite peaks around Cr ionic reflections. It is known that the SDW antinodes coincide with the maxima elongation of the lattice constant and by fitting the X-Ray diffraction data collected from our samples we extracted the phase of the SW which implies that the SDW has a node at the interface with non-magnetic MgO and an antinode at the free surface (where a ferromagnetic oxide layer is expected to grow). This confirms the idea that the SW and CDW are consequences of magnetic order. Second, a new technique was designed and implemented to grow single crystals of BaNi2V2O8. This material is a quasi-two-dimensional (2D) antiferromagnet on a honeycomb lattice, made of edge-sharing NiO6 octahedral layers separated by V5+O4 and Ba2+ layers. The only ion carrying a magnetic moment is Ni2+, which in octahedral coordination has an e2 g configuration making BaNi2V2O8 a spin-1 system. Neutron inelastic scattering studies of the magnetic excitations of this compound were conducted, as a detailed investigation is still missing due to the lack of large single crystals. The correlation lengths above TN= 48 K extracted from the analysis of the critical properties are compatible with the Berezinskii-Kosterliz-Thouless behaviour, indicating the presence of vortex-type excitations.

Published
2016

19. Aerobic Exercise and Metabolic Syndrome: The Role of Sympathetic Activity and the Redox System

Author

Monda V, Sessa F, Ruberto M, Carotenuto M, Marsala G, Monda M, Cambria MT, Astuto M, Distefano A, and Messina G

Subjects
metabolic syndrome (mets), orexin a, body mass index (bmi), heart rate (hr), cholesterol, physical activity, Specialties of internal medicine, RC581-951
Abstract

Vincenzo Monda,1 Francesco Sessa,2 Maria Ruberto,3 Marco Carotenuto,4 Gabriella Marsala,5 Marcellino Monda,1 Maria Teresa Cambria,6 Marinella Astuto,7 Alfio Distefano,6 Giovanni Messina2 1Department of Experimental Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Caserta 81100, Italy; 2Department of Clinical and Experimental Medicine, University of Foggia, Foggia 71121, Italy; 3CDR Santa Maria del Pozzo, Naples 80049, Italy; 4Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Caserta 81100, Italy; 5Struttura Complessa di Farmacia, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Foggia, Foggia 71121, Italy; 6Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy; 7Azienda Ospedaliera “Policlinico Vittorio Emanuele”, U.O. di Anestesia e Terapia Intensiva, Catania 95123, ItalyCorrespondence: Francesco SessaDepartment of Clinical and Experimental Medicine, University of Foggia, Foggia 71122, ItalyTel +39 0881 736926Email francesco.sessa@unifg.itBackground: Aerobic exercise can greatly assist in reducing collateral effects of metabolic syndrome (MetS). Moreover, aerobic exercise is associated with sympathetic activation and adaptive responses to sustain muscle engagement, changes in the release of Orexin A, a pleiotropic neuropeptide.Aim: The aim of this study was to analyze the beneficial effects of aerobic exercise without dietary changes, in a cohort of MetS subjects, focusing on the role of sympathetic and orexinergic activity. Several blood parameters linked to MetS ROS production, heart rate, galvanic skin response, d-ROM test, and Orexin A serum levels were evaluated in ten males with MetS (BMI 30– 34.9) before and after a period of 6 months of aerobic exercise compared to ten healthy subjects.Methods: Ten male subjects (aged 54 ± 4.16) with MetS (MetS group) and ten healthy males (aged 49.7 ± 2.79, Healthy group) were told about the study protocol and possible risks, signed the informed consent, and voluntarily participated in the study. Several blood parameters were evaluated in the two tested groups and were re-evaluated in the MetS group after 6 months of training (MetS6M group). The training protocol consisted of more than 30 min/day of walking (average speed of 4.5 km/h) and 3 days/week of aerobic activities (jogging under heart rate control – 120– 140 bpm for 45 min).Results: The results showed that exercise induced a significant increase in GSR and plasma Orexin A but no significant increase in d-ROM values. Significant decreases in the serum ALT enzyme, triglycerides, and total cholesterol were found, while the HDL levels were significantly higher. Finally, a significant reduction of BMI and resting HR were reported.Conclusion: The results of this study confirm that physical activity is associated with sympathetic activation, having a pivotal role against adverse effects linked to MetS. Moreover, this study demonstrates that, in patients with MetS, Orexin A is involved in hormonal adaptations to exercise.Keywords: metabolic syndrome, MetS, Orexin A, body mass index, BMI, heart rate, HR, cholesterol, physical activity

Published
2020

21. Unconventional roles of chromatin remodelers and long non-coding RNAs in cell division

Author

Prozzillo, Y, Santopietro, M, Messina, G, Dimitri, P, Prozzillo Y., Santopietro M. V., Messina G., Dimitri P., Prozzillo, Y, Santopietro, M, Messina, G, Dimitri, P, Prozzillo Y., Santopietro M. V., Messina G., and Dimitri P.

Abstract

The aim of this review article is to focus on the unconventional roles of epigenetic players (chromatin remodelers and long non-coding RNAs) in cell division, beyond their well-characterized functions in chromatin regulation during cell differentiation and development. In the last two decades, diverse experimental evidence has shown that subunits of SRCAP and p400/TIP60 chromatin remodeling complexes in humans relocate from interphase nuclei to centrosomes, spindle or midbody, with their depletion yielding an array of aberrant outcomes of mitosis and cytokinesis. Remarkably, this behavior is shared by orthologous subunits of the Drosophila melanogaster DOM/TIP60 complex, despite fruit flies and humans diverged over 700 million years ago. In short, the available data support the view that subunits of these complexes are a new class of moonlighting proteins, in that they lead a "double life": during the interphase, they function in chromatin regulation within the nucleus, but as the cell progresses through mitosis, they interact with established mitotic factors, thus becoming integral components of the cell division apparatus. By doing so, they contribute to ensuring the correct distribution of chromosomes in the two daughter cells and, when dysfunctional, can cause genomic instability, a condition that can trigger tumorigenesis and developmental diseases. Research over the past few years has unveiled a major contribution of long non-coding RNAs (lncRNAs) in the epigenetics regulation of gene expression which also impacts on cell division control. Here, we focus on possible structural roles of lncRNAs in the execution of cytokinesis: in particular, we suggest that specific classes of lncRNAs relocate to the midbody to form an architectural scaffold ensuring its proper assembly and function during abscission. Drawing attention to experimental evidence for non-canonical extranuclear roles of chromatin factors and lncRNAs has direct implications on important and novel as

Published
2023

28. Paesaggi, territori e immaginari nella transizione digitale

Author

Mercatanti, L, Messina, G, Nicosia, E, Sabato G, Porto, C. M, Lazzeroni, M, Morazzoni, M, Zamperlin, P, Mercatanti, L, Messina, G, Nicosia, E, Sabato G, and Porto, C.M

Subjects
Settore M-GGR/02 - Geografia Economico-Politica, Settore M-GGR/01 - Geografia, Digital transition, Cultural dynamics, landscape
Abstract

Short introduction to the conference session

Published
2023

29. Sviluppo rurale in Italia, una ricognizione sulle prospettive della prossima pianificazione

Author

Cusimano, G, Mercatanti, L, Messina, G, Rocca, L, Castiglioni, B, Lo Presti, L, Cusimano, G, Mercatanti, L, and Messina, G

Subjects
Piano Strategico Nazionale, Politica Agricola Comune, Partenariato, Settore M-GGR/02 - Geografia Economico-Politica
Abstract

This paper intends to represent a preliminary recognition of the programmatic synergies that aim to harmonize, in a cross-scale perspective, the general objectives of the Common Agricultural Policy - CAP - with national and local intervention policies.

Published
2023

37. Design and Feasibility Assessment of an HTS Sector Shaped High-Current Conductor for Fusion Coils

Author

Muzzi, L., primary, Augieri, A., additional, Celentano, G., additional, Chiarelli, S., additional, della Corte, A., additional, De Marzi, G., additional, Di Zenobio, A., additional, Giannini, L., additional, Marchetti, M., additional, Masi, A., additional, Messina, G., additional, Rufoloni, A., additional, Turtu, S., additional, Vannozzi, A., additional, Bragagni, A., additional, Seri, M., additional, Arabi, M., additional, Anemona, A., additional, and Formichetti, A., additional

Published
2023
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40. The endogenous oxytocin after manipulative osteopathic treatment in full-term pregnant women.

Author

RAGUSA, A., SVELATO, A., FOGOLARI, M., FICAROLA, F., PLOTTI, F., DE LUCA, C., D'AVINO, S., DAVINI, F., DE CESARIS, M., MESSINA, G., BERTOLINI, A., MARCI, R., ANGELETTI, S., ANGIOLI, R., and TERRANOVA, C.

Abstract

OBJECTIVE: The aim of this study is to assess whether the touch of osteopathic manipulative treatment (OMT) can affect the endogenous production of oxytocin in fullterm pregnant women and the assessment of well-being following the treatment. PATIENTS AND METHODS: In this study have been enrolled 57 pregnant women at full-term pregnancy (37th-41st week) for evaluation of the concentration of salivary oxytocin 2 minutes before and 2 minutes after a single session of OMT by an osteopath lasting for 30 minutes. Pre-OMT and post-OMT saliva samples were collected with the use of Salivette® salivary swabs. 7 salivary swabs were excluded from the analysis. 50 samples were analyzed with an appropriate ELISA kit. RESULTS: The mean OT salivary concentration pre-OMT was 89.98±16.39, and post-OMT was 100.60±19.13 tends to increase with p=0.0000051. In multivariate analysis, two subgroups show interesting data in the mean difference in OT salivary concentration post-OMT: women with painful contractions (p=0.06) and women under 35 years (p=0.09). CONCLUSIONS: The results of this study demonstrate that the effectiveness of OMT-increasing endogenous oxytocin is statistically significant in full-term pregnant women. The sensation of well-being found in most women indicates that there has been a predominantly central rather than peripheral oxytocin release after OMT. [ABSTRACT FROM AUTHOR]

Published
2024

42. Brain functional integration: an epidemiologic study on stress-producing dissociative phenomena

Author

Sperandeo R, Monda V, Messina G, Carotenuto M, Maldonato NM, Moretto E, Leone E, De Luca V, Monda M, and Messina A

Subjects
mental disorders, personality disorders, amnesia, depersonalization/derealization, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Raffaele Sperandeo,1,2,* Vincenzo Monda,3,* Giovanni Messina,4 Marco Carotenuto,5 Nelson Mauro Maldonato,1,2 Enrico Moretto,1,2 Elena Leone,1,2 Vincenzo De Luca,6 Marcellino Monda,3 Antonietta Messina3 1Department of Human Sciences, Università Della, Basilicata, 2School of Integrated Gestaltic Psychotherapy, Torre Annunziata, 3Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetic and Sport Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, 4Department of Clinical and Experimental Medicine, University of Foggia, Foggia, 5Department of Mental Health, Physical and Preventive Medicine, Clinic of Child and Adolescent Neuropsychiatry, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy; 6Department of Psychiatry, University of Toronto, Toronto, Canada *These authors contributed equally to this work Abstract: Dissociative phenomena are common among psychiatric patients; the presence of these symptoms can worsen the prognosis, increasing the severity of their clinical conditions and exposing them to increased risk of suicidal behavior. Personality disorders as long duration stressful experiences may support the development of dissociative phenomena. In 933 psychiatric outpatients consecutively recruited, presence of dissociative phenomena was identified with the Dissociative Experience Scale (DES). Dissociative phenomena were significantly more severe in the group of people with mental disorders and/or personality disorders. All psychopathologic traits detected with the symptom checklist-90-revised had a significant correlation with the total score on the DES. Using total DES score as the dependent variable, a linear regression model was constructed. Mental and personality disorders which were associated with greater severity of dissociative phenomena on analysis of variance were included as predictors; scores from the nine scales of symptom checklist-90-revised, significantly correlated to total DES score, were used as covariates. The model consisted of seven explanatory variables (four factors and three covariates) explaining 82% of variance. The four significant factors were the presence of borderline and narcissistic personality disorder, substance abuse disorders and psychotic disorders. Significant covariates were psychopathologic traits of anger, psychoticism and obsessiveness. This study, confirming Janet’s theory, explains that, mental disorders and psychopathologic experiences of patients can configure the chronic stress condition that produces functional damage to the adaptive executive system. The symptoms of dissociative depersonalization/derealization and dissociative amnesia can be explained, in large part, through their current and previous psychopathologic experiences. Keywords: mental disorders, personality disorders, amnesia, depersonalization/derealization

Published
2017

43. Obesity and brain illness: from cognitive and psychological evidences to obesity paradox

Author

Monda V, La Marra M, Perrella R, Caviglia G, Iavarone A, Chieffi S, Messina G, Carotenuto M, Monda M, and Messina A

Subjects
Obesity, Cognitive decline, Mood disorders, Obesity paradox, Specialties of internal medicine, RC581-951
Abstract

Vincenzo Monda,1,* Marco La Marra,1,* Raffaella Perrella,2 Giorgio Caviglia,2 Alessandro Iavarone,3 Sergio Chieffi,1 Giovanni Messina,4 Marco Carotenuto,5 Marcellino Monda,1 Antonietta Messina1 1Department of Experimental Medicine, Section of Human Physiology, University of Campania Luigi Vanvitelli, Naples, Italy; 2Neurological and Stroke Unit, CTO Hospital, AORN ‘‘Ospedali dei Colli’’, Naples, Italy; 3Department of Psychology, University of Campania Luigi Vanvitelli, Naples, Italy; 4Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; 5Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy *These authors contributed equally to this work Abstract: Recent findings showed that obesity represents an additional risk factor to developing brain illness such as cognitive impairments and psychopathological disorders. However, some benefits of overweight in the elderly have been identified and an “obesity paradox” has been shown. Currently, it is still unknown how obesity and brain functioning could be linked, and the process by which body fat independently injures cognitive abilities and psychological well-being remains unclear. To establish the independent role of obesity on cognitive abilities and mental health, clarifying the role played by several factors and understanding their interaction is essential. In this review, we discuss the relationship between obesity and brain illness and underline the role played by confounders and other covariates to determine this link. Keywords: obesity, cognitive decline, mood disorders, obesity paradox

Published
2017

44. Quality of life in overweight (obese) and normal-weight women with polycystic ovary syndrome

Author

Panico A, Messina G, Lupoli GA, Lupoli R, Cacciapuoti M, Moscatelli F, Esposito T, Villano I, Valenzano A, Monda V, Messina A, Precenzano F, Cibelli G, Monda M, and Lupoli G

Subjects
Polycystic Ovary Syndrome, Obesity, Normal-weight, Health-related-quality-of-life, Psychological disturbances, Medicine (General), R5-920
Abstract

Annalisa Panico,1 Giovanni Messina,2,3 Gelsy Arianna Lupoli,1 Roberta Lupoli,1 Marianna Cacciapuoti,1 Fiorenzo Moscatelli,2 Teresa Esposito,3 Ines Villano,3 Anna Valenzano,2 Vincenzo Monda,3 Antonietta Messina,3 Francesco Precenzano,4 Giuseppe Cibelli,2 Marcellino Monda,3 Giovanni Lupoli1 1Department of Clinical Medicine and Surgery, University of Napoli Federico II, Naples, Italy; 2Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; 3Department of Experimental Medicine, Second University of Naples, Naples, Italy; 4Department of Mental and Physical Health, and Preventive Medicine, Child and Adolescent Neuropsychiatry Unit, Second University of Naples, Naples, Italy Objective: Polycystic ovary syndrome (PCOS) is characterized by phenotypic heterogeneity and has a wide variety of consequences. Approximately half of women with PCOS are overweight or obese, and their obesity may be a contributing factor to PCOS pathogenesis through different mechanisms. The aim of this study was to evaluate if PCOS alone affects the patients’ quality of life and to what extent obesity contributes to worsen this disease. Design: To evaluate the impact of PCOS on health-related quality-of-life (HRQoL), 100 Mediterranean women with PCOS (group A), 50 with a body mass index (BMI) >25 kg/m2 (group A1) and 50 with BMI 25 (A1) showed a significant and more marked reduction in scores, suggesting a lower quality of life, compared with controls (B) and with normal-weight PCOS patients (A2). Conclusion: PCOS is a complex disease that alone determines a deterioration of HRQoL. The innovative use of these psychometric questionnaires in this study, in particular the PCOS questionnaire, has highlighted that obesity has a negative effect on HRQoL. It follows that a weight decrease is associated to phenotypic spectrum improvement and relative decrement in psychological distress. Keywords: polycystic ovary syndrome, obesity, normal-weight, health-related quality-of-life, psychological disturbances

Published
2017

45. A novel KCNC1 gain-of-function variant causing developmental and epileptic encephalopathy: 'Precision medicine' approach with fluoxetine

Author

Ambrosino, P, Ragona, F, Mosca, I, Vannicola, C, Canafoglia, L, Solazzi, R, Rivolta, I, Freri, E, Granata, T, Messina, G, Castellotti, B, Gellera, C, Soldovieri, M, Difrancesco, J, Taglialatela, M, Ambrosino, Paolo, Ragona, Francesca, Mosca, Ilaria, Vannicola, Chiara, Canafoglia, Laura, Solazzi, Roberta, Rivolta, Ilaria, Freri, Elena, Granata, Tiziana, Messina, Giuliana, Castellotti, Barbara, Gellera, Cinzia, Soldovieri, Maria Virginia, DiFrancesco, Jacopo Cosimo, Taglialatela, Maurizio, Ambrosino, P, Ragona, F, Mosca, I, Vannicola, C, Canafoglia, L, Solazzi, R, Rivolta, I, Freri, E, Granata, T, Messina, G, Castellotti, B, Gellera, C, Soldovieri, M, Difrancesco, J, Taglialatela, M, Ambrosino, Paolo, Ragona, Francesca, Mosca, Ilaria, Vannicola, Chiara, Canafoglia, Laura, Solazzi, Roberta, Rivolta, Ilaria, Freri, Elena, Granata, Tiziana, Messina, Giuliana, Castellotti, Barbara, Gellera, Cinzia, Soldovieri, Maria Virginia, DiFrancesco, Jacopo Cosimo, and Taglialatela, Maurizio

Abstract

Variable phenotypes, including developmental encephalopathy with (DEE) or without seizures and myoclonic epilepsy and ataxia due to potassium channel mutation, are caused by pathogenetic variants in KCNC1, encoding for Kv3.1 channel subunits. In vitro, channels carrying most KCNC1 pathogenic variants display loss-of-function features. Here, we describe a child affected by DEE with fever-triggered seizures, caused by a novel de novo heterozygous missense KCNC1 variant (c.1273G>A; V425M). Patch-clamp recordings in transiently transfected CHO cells revealed that, compared to wild-type, Kv3.1 V425M currents (1) were larger, with membrane potentials between −40 and +40 mV; (2) displayed a hyperpolarizing shift in activation gating; (3) failed to inactivate; and (4) had slower activation and deactivation kinetics, consistent with a mixed functional pattern with prevalent gain-of-function effects. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant Kv3.1 channels. Treatment of the proband with fluoxetine led to a rapid and prolonged clinical amelioration, with the disappearance of seizures and an improvement in balance, gross motor skills, and oculomotor coordination. These results suggest that drug repurposing based on the specific genetic defect may provide an effective personalized treatment for KCNC1-related DEEs.

Published
2023

46. A novel de novo HCN2 loss-of-function variant causing developmental and epileptic encephalopathy treated with a ketogenic diet

Author

Difrancesco, J, Ragona, F, Murano, C, Frosio, A, Melgari, D, Binda, A, Calamaio, S, Prevostini, R, Mauri, M, Canafoglia, L, Castellotti, B, Messina, G, Gellera, C, Previtali, R, Veggiotti, P, Milanesi, R, Barbuti, A, Solazzi, R, Freri, E, Granata, T, Rivolta, I, DiFrancesco, Jacopo C, Ragona, Francesca, Murano, Carmen, Frosio, Anthony, Melgari, Dario, Binda, Anna, Calamaio, Serena, Prevostini, Rachele, Mauri, Mario, Canafoglia, Laura, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Previtali, Roberto, Veggiotti, Pierangelo, Milanesi, Raffaella, Barbuti, Andrea, Solazzi, Roberta, Freri, Elena, Granata, Tiziana, Rivolta, Ilaria, Difrancesco, J, Ragona, F, Murano, C, Frosio, A, Melgari, D, Binda, A, Calamaio, S, Prevostini, R, Mauri, M, Canafoglia, L, Castellotti, B, Messina, G, Gellera, C, Previtali, R, Veggiotti, P, Milanesi, R, Barbuti, A, Solazzi, R, Freri, E, Granata, T, Rivolta, I, DiFrancesco, Jacopo C, Ragona, Francesca, Murano, Carmen, Frosio, Anthony, Melgari, Dario, Binda, Anna, Calamaio, Serena, Prevostini, Rachele, Mauri, Mario, Canafoglia, Laura, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Previtali, Roberto, Veggiotti, Pierangelo, Milanesi, Raffaella, Barbuti, Andrea, Solazzi, Roberta, Freri, Elena, Granata, Tiziana, and Rivolta, Ilaria

Abstract

Missense variants of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels cause variable phenotypes, ranging from mild generalized epilepsy to developmental and epileptic encephalopathy (DEE). Although variants of HCN1 are an established cause of DEE, those of HCN2 have been reported in generalized epilepsies. Here we describe the first case of DEE caused by the novel de novo heterozygous missense variant c.1379G>A (p.G460D) of HCN2. Functional characterization in transfected HEK293 cells and neonatal rat cortical neurons revealed that HCN2 p.G460D currents were strongly reduced compared to wild-type, consistent with a dominant negative loss-of-function effect. Immunofluorescence staining showed that mutant channels are retained within the cell and do not reach the membrane. Moreover, mutant HCN2 also affect HCN1 channels, by reducing the Ih current expressed by the HCN1-HCN2 heteromers. Due to the persistence of frequent seizures despite pharmacological polytherapy, the patient was treated with a ketogenic diet, with a significant and long-lasting reduction of episodes. In vitro experiments conducted in a ketogenic environment demonstrated that the clinical improvement observed with this dietary regimen was not mediated by a direct action on HCN2 activity. These results expand the clinical spectrum related to HCN2 channelopathies, further broadening our understanding of the pathogenesis of DEE.

Published
2023

47. Nuclear elongation during spermiogenesis depends on physical linkage of nuclear pore complexes to bundled microtubules by Drosophila Mst27D

Author

Li, P, Messina, G, Lehner, C, Li, Pengfei, Messina, Giovanni, Lehner, Christian F, Li, P, Messina, G, Lehner, C, Li, Pengfei, Messina, Giovanni, and Lehner, Christian F

Abstract

Spermatozoa in animal species are usually highly elongated cells with a long motile tail attached to a head that contains the haploid genome in a compact and often elongated nucleus. In Drosophila melanogaster, the nucleus is compacted two hundred-fold in volume during spermiogenesis and re-modeled into a needle that is thirty-fold longer than its diameter. Nuclear elongation is preceded by a striking relocalization of nuclear pore complexes (NPCs). While NPCs are initially located throughout the nuclear envelope (NE) around the spherical nucleus of early round spermatids, they are later confined to one hemisphere. In the cytoplasm adjacent to this NPC-containing NE, the so-called dense complex with a strong bundle of microtubules is assembled. While this conspicuous proximity argued for functional significance of NPC-NE and microtubule bundle, experimental confirmation of their contributions to nuclear elongation has not yet been reported. Our functional characterization of the spermatid specific Mst27D protein now resolves this deficit. We demonstrate that Mst27D establishes physical linkage between NPC-NE and dense complex. The C-terminal region of Mst27D binds to the nuclear pore protein Nup358. The N-terminal CH domain of Mst27D, which is similar to that of EB1 family proteins, binds to microtubules. At high expression levels, Mst27D promotes bundling of microtubules in cultured cells. Microscopic analyses indicated co-localization of Mst27D with Nup358 and with the microtubule bundles of the dense complex. Time-lapse imaging revealed that nuclear elongation is accompanied by a progressive bundling of microtubules into a single elongated bundle. In Mst27D null mutants, this bundling process does not occur and nuclear elongation is abnormal. Thus, we propose that Mst27D permits normal nuclear elongation by promoting the attachment of the NPC-NE to the microtubules of the dense complex, as well as the progressive bundling of these microtubules.

Published
2023

48. Epigenetic Silencing of P-Element Reporter Genes Induced by Transcriptionally Active Domains of Constitutive Heterochromatin in Drosophila melanogaster

Author

Messina, G, Celauro, E, Marsano, R, Prozzillo, Y, Dimitri, P, Giovanni Messina, Emanuele Celauro, René Marsano, Yuri Prozzillo, Patrizio Dimitri, Messina, G, Celauro, E, Marsano, R, Prozzillo, Y, Dimitri, P, Giovanni Messina, Emanuele Celauro, René Marsano, Yuri Prozzillo, and Patrizio Dimitri

Abstract

Reporter genes inserted via P-element integration into different locations of the Drosophila melanogaster genome have been routinely used to monitor the functional state of chromatin domains. It is commonly thought that P-element-derived reporter genes are subjected to position effect variegation (PEV) when transposed into constitutive heterochromatin because they acquire heterochromatin-like epigenetic modifications that promote silencing. However, sequencing and annotation of the D. melanogaster genome have shown that constitutive heterochromatin is a genetically and molecularly heterogeneous compartment. In fact, in addition to repetitive DNAs, it harbors hundreds of functional genes, together accounting for a significant fraction of its entire genomic territory. Notably, most of these genes are actively transcribed in different developmental stages and tissues, irrespective of their location in heterochromatin. An open question in the genetic and molecular studies on PEV in D. melanogaster is whether functional heterochromatin domains, i.e., heterochromatin harboring active genes, are able to silence reporter genes therein transposed or, on the contrary, can drive their expression. In this work, we provide experimental evidence showing that strong silencing of the Pw+ reporters is induced even when they are integrated within or near actively transcribed loci in the pericentric regions of chromosome 2. Interestingly, some Pw+ reporters were found insensitive to the action of a known PEV suppressor. Two of them are inserted within Yeti, a gene expressed in the deep heterochromatin of chromosome 2 which carries active chromatin marks. The difference sensitivity to suppressors-exhibited Pw+ reporters supports the view that different epigenetic regulators or mechanisms control different regions of heterochromatin. Together, our results suggest that there may be more complexity regarding the molecular mechanisms underlying PEV.

Published
2023

49. Knockdown of DOM/Tip60 Complex Subunits Impairs Male Meiosis of Drosophila melanogaster

Author

Prozzillo, Y, Fattorini, G, Ferreri, D, Leo, M, Dimitri, P, Messina, G, Prozzillo, Yuri, Fattorini, Gaia, Ferreri, Diego, Leo, Manuela, Dimitri, Patrizio, Messina, Giovanni, Prozzillo, Y, Fattorini, G, Ferreri, D, Leo, M, Dimitri, P, Messina, G, Prozzillo, Yuri, Fattorini, Gaia, Ferreri, Diego, Leo, Manuela, Dimitri, Patrizio, and Messina, Giovanni

Abstract

ATP-dependent chromatin remodeling complexes are involved in nucleosome sliding and eviction and/or the incorporation of histone variants into chromatin to facilitate several cellular and biological processes, including DNA transcription, replication and repair. The DOM/TIP60 chromatin remodeling complex of Drosophila melanogaster contains 18 subunits, including the DOMINO (DOM), an ATPase that catalyzes the exchange of the canonical H2A with its variant (H2A.V), and TIP60, a lysine-acetyltransferase that acetylates H4, H2A and H2A.V histones. In recent decades, experimental evidence has shown that ATP-dependent chromatin remodeling factors, in addition to their role in chromatin organization, have a functional relevance in cell division. In particular, emerging studies suggested the direct roles of ATP-dependent chromatin remodeling complex subunits in controlling mitosis and cytokinesis in both humans and D. melanogaster. However, little is known about their possible involvement during meiosis. The results of this work show that the knockdown of 12 of DOM/TIP60 complex subunits generates cell division defects that, in turn, cause total/partial sterility in Drosophila males, providing new insights into the functions of chromatin remodelers in cell division control during gametogenesis.

Published
2023

50. Mesoangioblasts at 20: From the embryonic aorta to the patient bed

Author

Cossu, G, Tonlorenzi, R, Brunelli, S, Sampaolesi, M, Messina, G, Azzoni, E, Benedetti, S, Biressi, S, Bonfanti, C, Bragg, L, Camps, J, Cappellari, O, Cassano, M, Ciceri, F, Coletta, M, Covarello, D, Crippa, S, Cusella-De Angelis, M, De Angelis, L, Dellavalle, A, Diaz-Manera, J, Galli, D, Galli, F, Gargioli, C, Gerli, M, Giacomazzi, G, Galvez, B, Hoshiya, H, Guttinger, M, Innocenzi, A, Minasi, M, Perani, L, Previtali, S, Quattrocelli, M, Ragazzi, M, Roostalu, U, Rossi, G, Scardigli, R, Sirabella, D, Tedesco, F, Torrente, Y, Ugarte, G, Cossu, Giulio, Tonlorenzi, Rossana, Brunelli, Silvia, Sampaolesi, Maurilio, Messina, Graziella, Azzoni, Emanuele, Benedetti, Sara, Biressi, Stefano, Bonfanti, Chiara, Bragg, Laricia, Camps, Jordi, Cappellari, Ornella, Cassano, Marco, Ciceri, Fabio, Coletta, Marcello, Covarello, Diego, Crippa, Stefania, Cusella-De Angelis, M Gabriella, De Angelis, Luciana, Dellavalle, Arianna, Diaz-Manera, Jordi, Galli, Daniela, Galli, Francesco, Gargioli, Cesare, Gerli, Mattia F M, Giacomazzi, Giorgia, Galvez, Beatriz G, Hoshiya, Hidetoshi, Guttinger, Maria, Innocenzi, Anna, Minasi, M Giulia, Perani, Laura, Previtali, Stefano C, Quattrocelli, Mattia, Ragazzi, Martina, Roostalu, Urmas, Rossi, Giuliana, Scardigli, Raffaella, Sirabella, Dario, Tedesco, Francesco Saverio, Torrente, Yvan, Ugarte, Gonzalo, Cossu, G, Tonlorenzi, R, Brunelli, S, Sampaolesi, M, Messina, G, Azzoni, E, Benedetti, S, Biressi, S, Bonfanti, C, Bragg, L, Camps, J, Cappellari, O, Cassano, M, Ciceri, F, Coletta, M, Covarello, D, Crippa, S, Cusella-De Angelis, M, De Angelis, L, Dellavalle, A, Diaz-Manera, J, Galli, D, Galli, F, Gargioli, C, Gerli, M, Giacomazzi, G, Galvez, B, Hoshiya, H, Guttinger, M, Innocenzi, A, Minasi, M, Perani, L, Previtali, S, Quattrocelli, M, Ragazzi, M, Roostalu, U, Rossi, G, Scardigli, R, Sirabella, D, Tedesco, F, Torrente, Y, Ugarte, G, Cossu, Giulio, Tonlorenzi, Rossana, Brunelli, Silvia, Sampaolesi, Maurilio, Messina, Graziella, Azzoni, Emanuele, Benedetti, Sara, Biressi, Stefano, Bonfanti, Chiara, Bragg, Laricia, Camps, Jordi, Cappellari, Ornella, Cassano, Marco, Ciceri, Fabio, Coletta, Marcello, Covarello, Diego, Crippa, Stefania, Cusella-De Angelis, M Gabriella, De Angelis, Luciana, Dellavalle, Arianna, Diaz-Manera, Jordi, Galli, Daniela, Galli, Francesco, Gargioli, Cesare, Gerli, Mattia F M, Giacomazzi, Giorgia, Galvez, Beatriz G, Hoshiya, Hidetoshi, Guttinger, Maria, Innocenzi, Anna, Minasi, M Giulia, Perani, Laura, Previtali, Stefano C, Quattrocelli, Mattia, Ragazzi, Martina, Roostalu, Urmas, Rossi, Giuliana, Scardigli, Raffaella, Sirabella, Dario, Tedesco, Francesco Saverio, Torrente, Yvan, and Ugarte, Gonzalo

Abstract

In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded in vitro (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration.

Published
2023

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