CDKL5 e sindrome di Rett: un approccio molecolare per la definizione di una correlazione genotipo/fenotipo.

La sindrome di Rett \ue8 una grave malattia del neurosviluppo legata al cromosoma X che colpisce principalmente individui di sesso femminile. Le bambine affette da sindrome di Rett subiscono uno sviluppo postnatale apparentemente normale fino all'et\ue0 di 6-18 mesi, per poi manifestare un marcato declino neurologico con decorso molto variabile. Circa il 25% delle pazienti sono affette da forme atipiche che si discostano dalla forma classica o per il fatto di essere pi\uf9 blande con un iter meno devastante o per un fenotipo pi\uf9 \u201caggressivo\u201d con insorgenza precoce che pu\uf2 portare anche a crisi epilettiche non trattabili farmacologicamente. La maggior parte dei casi di forma classica di Rett \ue8 causata da mutazioni nel gene MECP2, un repressore trascrizionale espresso maggiormente nel cervello che lega il DNA metilato e che causa la formazione di una struttura cromatinica compatta e trascrizionalmente inerte. Circa solo il 50% delle pazienti con varianti della sindrome di Rett per\uf2 sono portatrici di mutazioni in questo gene. Per questa classe di fenotipi sono state descritte nel 2004 mutazioni a carico del gene CDKL5 codificante per una serin-treonina chinasi e nel 2008 altre a carico del gene FOXG1, un fattore trascrizionale. La ricerca scientifica ha quindi ampliato i propri obbiettivi al fine di comprendere se questi tre geni, apparentemente diversi fra loro, potessero essere accomunati da uno stesso pathway molecolare. A tutt'oggi per\uf2 i risultati sono ancora scarsi e, a volte, contraddittori. Per quanto riguarda gli studi su CDKL5, un aspetto generalmente accettato risiede nel fatto che in tutti i casi l'attivit\ue0 catalitica di CDKL5 appare di estrema importanza. Con questa premessa, sarebbe quindi interessante osservare con quale modalit\ue0 le mutazioni a carico di CDKL5 possano influire sulla sua funzione enzimatica. L'obbiettivo della mia ricerca \ue8 stato quello di analizzare otto mutazioni puntiformi (A40V, N71D, V132G, R178W, W195R, E203D, L220P e T288I) giacenti sul dominio catalitico di CDKL5. Queste mutazioni sono state riscontrate in pazienti con la variante Hanefeld. Per ogni mutazione \ue8 stata valutata la localizzazione cellulare e l'attivit\ue0 chinasica sul motivo TEY. Inoltre, grazie all'ausilio di strumenti bioinformatici, \ue8 stato creato un modello tridimensionale del dominio chinasico di CDKL5 ed \ue8 stato possibile predire l'influenza che ogni mutazione ha sulla struttura della proteina. L'analisi di localizzazione subcellulare ci ha permesso di concludere che in generale le mutazioni a carico del dominio catalitico non influenzano in maniera significativa la distribuzione di CDKL5 all'interno della cellula, a differenza delle mutazioni troncanti sulla coda carbossiterminale, precedentemente analizzate nel nostro laboratorio. Ciononostante per le mutazioni W195R e E203D si \ue8 osservato un accumulo della proteina nel compartimento citoplasmatico. E' stata inoltre osservata la perdita della tipica organizzazione in dots di CDKL5. Le analisi bioinformatiche collocano questi due residui nell' \u3b1-elica F del sottodominio IX del dominio chinasico della proteina. A quest'elica, comune alle MAP chinasi, era gi\ue0 stata precedentemente attribuita una cruciale importanza nell'orchestrazione dell'attivit\ue0 chinasica. E' quindi possibile che una sua precisa conformazione spaziale sia necessaria per una corretta interazione con le altre proteine e per una altrettanto corretta distribuzione della proteina all'interno della cellula. L'analisi dell'attivit\ue0 catalitica invece ha permesso di evidenziare che le mutazioni in esame possono portare a perdita totale di fosforilazione (A40V), a una sua diminuzione (V132G, R178W, W195R, E203D, L220P e T288I) oppure a nessun effetto evidente (N71D). Per questa mutazione perci\uf2 \ue8 stato proposto un saggio di stabilit\ue0 che ha evidenziato un'emivita minore rispetto alla forma canonica, dando un'ulteriore prova di come i livelli di CDKL5 probabilmente debbano essere finemente regolati per una sua corretta funzionalit\ue0 neuronale. Nell'ultimo periodo del mio dottorato ho avuto inoltre la possibilit\ue0 di valutare un ipotetico ruolo di CDKL5 nella maturazione neuronale, in quanto \ue8 stata osservata la sua presenza a livello dei centrosomi in cellule proliferanti fissate in metafase. E' ormai assodato il ruolo del centrosoma nelle tre fasi della maturazione neuronale e perci\uf2 ho approfondito questo aspetto verificando la colocalizzazione di CDKL5 nel centrosoma anche in colture di neuroni corticali in via di maturazione. Questa scoperta non chiarisce con certezza quale sia lo specifico ruolo di CDKL5 in questo fenomeno ma offre sicuramente una nuova chiave di lettura per stabilire quale meccanismo neuronale venga a mancare nelle pazienti portatrici di difetti in questo gene

A phylogenetic analysis of Antrodia s.l. based on nrDNA ITS sequences, with emphasis on rhizomorphic European species

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Getting robots in ‘our own hands’: Structural drivers, spatial dynamics and multi-scalar industrial policy in China

Robots are a key digital production technology of the Fourth Industrial Revolution. In 2020, China accounted for one third of all industrial robots in operation globally. The emerging literature has mainly focused on the effects of robotization, while evidence on its drivers and spatial diffusion remain limited. We address this gap by producing new evidence on the complex mix of structural and policy factors driving fast robotization across China and its regions. We identify three ‘structural drivers’ of robotization – demand pull, supply push and capability preconditions – and study the resulting spatial dynamics of technology adoption. We find significant heterogeneity in robots’ adoption across regions and sectors, in robots manufacturing and technological capabilities. Furthermore, we highlight the key role of a fourth ‘policy driver’ – industrial policy – and conduct an in-depth analysis of robotization policies at the national and province levels since 2016. We identify four main robotizing regional hubs in China – Guangdong, Yangtze-River-Delta, Beijing-Tianjin and Jilin-Liaoning. We finally analyse three emerging policy interfaces linking Made in China 2025 (within which China’s robotization policy is framed) and the Belt and Road Initiative – that is, opening markets, shaping industry and standards, and directing finance. With this new multi-scalar industrial policy configuration, China is further reshaping the domestic and international political economy of robotization, ultimately moving the country ahead in the digital technology race

Structural cycles and industrial policy alignment: the private–public nexus in the Emilian Packaging Valley

The article investigates changes in the interaction between business organisations, local governments and public technology intermediaries resulting from business organisations’ shifts towards higher-value product segment opportunities. Specifically, we analyse how local governments can (or not) align their industrial policies to the industrial transformations—both technological and organisational—underpinning firms’ value creation–capture dynamics. The concept of structural cycle is introduced here to study the two interdependent processes of ‘technology transition’ and ‘organisational reconfiguration’ characterising those firms shifting towards higher-value product segments. This private–public nexus is investigated in the Emilian Packaging Valley context. The mixed-method study focuses on the case of IMA Spa, its shifts from the food to the pharmaceutical value product segment of the packaging machine industry and its changing relationships with regional public policies and institutions. A number of industrial policy implications for sustainable value creation dynamics in local production systems are finally derived

Religion and Political Form: Carl Schmitt’s Genealogy of Politics as Critique of Habermas’s Post-secular Discourse

Jürgen Habermas's post-secular account is rapidly attracting attention in many fields as a theoretical framework through which to reconsider the role of religion in contemporary societies. This work seeks to go beyond Habermas's conceptualisation by placing the post-secular discourse within a broader genealogy of the relationships between space, religion, and politics. Drawing on the work of Carl Schmitt, the aim of this article is to contrast the artificial separation between private and public, religious and secular, state and church, and the logic of inclusion/exclusion on which modernity was established. Revisiting this genealogy is also crucial to illustrating, in light of Schmitt's political theory, the problems underlying Habermas's proposal, emphasising its hidden homogenising and universalist logic in an attempt to offer an alternative reflection on the contribution of religious and cultural pluralism within Western democracies

The cosmic web of dwarf galaxies in a warm versus cold dark matter universe: mock galaxies in CDM and WDM simulations

Using cosmological simulations, we show that the cosmic web of dwarf galaxies in a warm dark matter (WDM) universe, wherein low mass halo formation is heavily suppressed, is nearly indistinguishable to that of a cold dark matter (CDM) universe whose low mass halos are not seen because galaxy formation is suppressed below some threshold mass. Low mass warm dark matter halos are suppressed nearly equally in all environments. For example, WDM voids in the galaxy distribution are neither larger nor emptier than CDM voids, once normalized to the same total galaxy number density and assuming galaxy luminosity scales with halo mass. It is thus a challenge to find hints about the dark matter particle in the cosmic web of galaxies. However, if the scatter between dwarf galaxy luminosity and halo properties is large, low mass CDM halos would sometimes host bright galaxies thereby populating voids that would be empty in WDM. Future surveys that will capture the small scale clustering in the local volume could thus help determine whether the CDM problem of the over-abundance of small halos with respect to the number density of observed dwarf galaxies has a cosmological solution or an astrophysical solution

Probing deformed commutators with macroscopic harmonic oscillators

A minimal observable length is a common feature of theories that aim to merge quantum physics and gravity. Quantum mechanically, this concept is associated to a nonzero minimal uncertainty in position measurements, which is encoded in deformed commutation relations. In spite of increasing theoretical interest, the subject suffers from the complete lack of dedicated experiments and bounds to the deformation parameters are roughly extrapolated from indirect measurements. As recently proposed, low-energy mechanical oscillators could allow to reveal the effect of a modified commutator. Here we analyze the free evolution of high quality factor micro- and nano-oscillators, spanning a wide range of masses around the Planck mass $m_{\mathrm{P}}$ (${\approx 22\,\mu\mathrm{g}}$), and compare it with a model of deformed dynamics. Previous limits to the parameters quantifying the commutator deformation are substantially lowered.Comment: 11 pages, 3 figures, reference adde

EDA2R Is Associated with Androgenetic Alopecia

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Methylenetetrahydrofolate Reductase Gene Polymorphisms in Burkina Faso: Impact on Plasma Fasting Homocysteine and after Methionine Loading Test

SUMMARY In Burkina Faso the levels of plasma homocysteine (Hcy) are lower and the methionine loading tests suggest a more effective Hcy metabolism. The polymorphisms of methylenetetrahydrofolate reductase (MTHFR) showed a relevant difference in the allele frequencies of T MTHFR-677 in young and in old subjects, while the allele frequency of C MTHFR-1298C was comparable in young and old subjects. The aim of this paper was to study the impact of the MTHFR polymorphisms on plasma fasting Hcy and after methionine loading in Burkina Faso. The young subjects with CC MTHFR-677 genotype had levels of Hcy significantly lower than CT and TT subjects. The level of Hcy in subjects who had AA, AC and CC MTHFR-1298 genotypes were comparable. The levels of Hcy after the methionine loading test were significantly higher in CT and TT MTHFR-677 genotype. These results suggest that the genetic situation in Burkina Faso is different from that of other Western countries and this guarantees the maintenance of lower plasma levels of Hcy in young and old Africans. The elevated levels of plasma Hcy in old subjects compared to young subjects, against the low prevalence of the T allele in elderly subjects is discussed. (Clin. Lab. 2007;53:XXX-XXX) KEY WORDS Burkina Faso, homocysteine, methionine loading test, MTHFR, C677T, A1298