On the perception of s and S: considering the effects of phonotactics

The current study explores the interaction between phonological relationships and speech perception. While phonemic status has been thoroughly considered in the speech perception literature, much less research has been devoted to the perception of phones of different phonological status, such as those exhibiting allophony or partial contrast. The goal of the current study was to extend our understanding of partial contrast by considering partial contrast due to phonotactic constraints. Specifically, the research questions were: to what extent do gaps in phonemic distribution affect the perceptual distinctiveness of otherwise contrastive pairs? Within a single language and in a range of environments where a pair of segments differs in degree of contrast, does the degree of perceptual similarity differ, or is perceptual similarity constant no matter the environment?No embarg

SLC26A9 as a Potential Modifier and Therapeutic Target in Cystic Fibrosis Lung Disease

SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins involved in ion transport mechanisms. On the basis of different preliminary findings, including the phenotype of SlC26A9-deficient mice and its possible role as a gene modifier of the human phenotype and treatment response, SLC26A9 has emerged as one of the most interesting alternative targets for the treatment of cystic fibrosis (CF). However, despite relevant clues, some open issues and controversies remain. The lack of specific pharmacological modulators, the elusive expression reported in the airways, and its complex relationships with CFTR and the CF phenotype prevent us from conclusively understanding the contribution of SLC26A9 in human lung physiology and its real potential as a therapeutic target in CF. In this review, we summarized the various studies dealing with SLC26A9 expression, molecular structure, and function as an anion channel or transporter; its interaction and functional relationships with CFTR; and its role as a gene modifier and tried to reconcile them in order to highlight the current understanding and the gap in knowledge regarding the contribution of SLC26A9 to human lung physiology and CF disease and treatment

Romolo divino, Romolo fatto a pezzi. L’uso politico del mito della scomparsa del primo re alla fine della Repubblica

La complessità della tradizione letteraria sui primi secoli della vita di Roma è ormai nota, e proverbiale è quella sulla biografia romulea, imperniata su informazioni ambigue e contrastanti che, tra luci e ombre, rendono affascinante lo studio della sua figura, fin dall’antichità. Non da meno il caso della sua scomparsa, che presenta due varianti principali: in effetti, se in una il primo sovrano di Roma era assunto in cielo tra gli dei, nell’altra era brutalmente smembrato dalla furia dei patres. Nel presente contributo, che si colloca solo in coda a una lunga storia di studi storiografici, attraverso una prospettiva prettamente politica, si è cercato di comprendere le motivazioni sottostanti alla presenza di queste due, non solo diverse, ma diametralmente opposte tradizioni sulla scomparsa di Romolo. Il taglio politico conferito intende giustificare tale doppia esistenza partendo dallo sfruttamento del mito di Romolo all’interno dell’evoluzione e degli sconvolgimenti politici del I secolo a.C., divenendo oggetto centrale nel dibattito politico repubblicano: nella lotta tra le fazioni o negli scontri tra gli imperatores che dominarono la scena.The intricate nature of the literary tradition on the early centuries of the life of Rome is well known, and the one on Romulus’ biography, hinged on ambiguous and contradictory information, between lights and shadows, makes the study of his figure fascinating, since antiquity. No exception is made by his disappearance, which presents two main versions: in one the first king of Rome ascended among the gods, in the other he was brutally dismembered by the fury of the patres. In the work here presented an effort has been made to understand from a political perspective the motivations underlying the presence of these two versions on Romulus’ disappearance, which are not just different, but diametrically opposite. The political slant given, intends to justify this duality by exploiting the myth of Romulus within the political evolution and upheavals of the 1st century BC, which became a central object in the republican political debate, both in the struggle between factions and in the clashes between the imperatores who dominated the scene

Change and Innovation in the Institutional Army from 1860–2020

This article showcases the understudied institutional Army, the generating force, as a critical prerequisite for overall strategic success. Competition, crisis, and conflict require more than the manned, trained, and equipped units that deploy. This article analyzes six case studies of institutional Army reforms over 160 years to examine adaptation in peace and war. The conclusions provide historical insights to inform current practices and fulfill the Army’s articulated 2022 Institutional Strategy

Ruolo della secrezione di bicarbonato nell'iperplasia mucosa dell'epitelio bronchiale

L’iperplasia delle cellule mucipare è una caratteristica di asma e altre patologie dell’apparato respiratorio ed è causata dall’azione delle citochine di tipo Th-2, in particolar modo IL-4 e IL-13. Nello studio oggetto di questa tesi, è stato osservato come, in cellule epiteliali bronchiali umane, la citochina IL-4 induca l’espressione di molti geni codificanti per canali ionici e trasportatori, inclusi TMEM16A, SLC26A4, SLC12A2 e ATP12A. A livello funzionale, il trattamento con IL-4 determina un forte incremento della secrezione di cloruro e bicarbonato dipendente da calcio e AMPc, con conseguente maggiore concentrazione di bicarbonato e pH alcalino nel fluido che riveste la superficie apicale dell’epitelio. Inoltre, il rilascio di muco indotto da stimolazione purinergica richiede la presenza di bicarbonato ed è risultato difettivo in cellule derivanti da pazienti affetti da fibrosi cistica. In conclusione, i risultati di questo studio mostrano che le citochine Th-2 inducono un profondo cambiamento dell’espressione e della funzione di numerosi canali ionici e trasportatori che determina a sua volta un’aumentata capacità di trasporto di bicarbonato. Questo cambiamento è necessario per favorire il rilascio e la clearance del muco

Intermolecular interactions in the TMEM16A dimer controlling channel activity

TMEM16A and TMEM16B are plasma membrane proteins with Ca2+ -dependent Cl- channel function. By replacing the carboxy-terminus of TMEM16A with the equivalent region of TMEM16B, we obtained channels with potentiation of channel activity. Progressive shortening of the chimeric region restricted the "activating domain" to a short sequence close to the last transmembrane domain and led to TMEM16A channels with high activity at very low intracellular Ca2+ concentrations. To elucidate the molecular mechanism underlying this effect, we carried out experiments based on double chimeras, Forster resonance energy transfer, and intermolecular cross-linking. We also modeled TMEM16A structure using the Nectria haematococca TMEM16 protein as template. Our results indicate that the enhanced activity in chimeric channels is due to altered interaction between the carboxy-terminus and the first intracellular loop in the TMEM16A homo-dimer. Mimicking this perturbation with a small molecule could be the basis for a pharmacological stimulation of TMEM16A-dependent Cl- transport

Brain Organoids as Model Systems for Genetic Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) are a group of disorders in which the development of the central nervous system (CNS) is disturbed, resulting in different neurological and neuropsychiatric features, such as impaired motor function, learning, language or non-verbal communication. Frequent comorbidities include epilepsy and movement disorders. Advances in DNA sequencing technologies revealed identifiable genetic causes in an increasingly large proportion of NDDs, highlighting the need of experimental approaches to investigate the defective genes and the molecular pathways implicated in abnormal brain development. However, targeted approaches to investigate specific molecular defects and their implications in human brain dysfunction are prevented by limited access to patient-derived brain tissues. In this context, advances of both stem cell technologies and genome editing strategies during the last decade led to the generation of three-dimensional (3D) in vitro-models of cerebral organoids, holding the potential to recapitulate precise stages of human brain development with the aim of personalized diagnostic and therapeutic approaches. Recent progresses allowed to generate 3D-structures of both neuronal and non-neuronal cell types and develop either whole-brain or region-specific cerebral organoids in order to investigate in vitro key brain developmental processes, such as neuronal cell morphogenesis, migration and connectivity. In this review, we summarized emerging methodological approaches in the field of brain organoid technologies and their application to dissect disease mechanisms underlying an array of pediatric brain developmental disorders, with a particular focus on autism spectrum disorders (ASDs) and epileptic encephalopathies