Phenotypic definition and genotype-phenotype correlates in pmpca-related disease

Background: Peptidase mitochondrial processing alpha (PMPCA) biallelic mutations cause a spectrum of disorders ranging from severe progressive multisystemic mitochondrial encephalopathy to a milder non-progressive cerebellar ataxia with or without intellectual disability. Recently, we and others described an intermediate phenotype in two unrelated patients. Methods: We report a second Italian patient carrying novel PMPCA variants (p.Trp278Leu; p.Arg362Gly). Molecular modeling, dynamics simulation, RT-qPCR, and Western blotting were performed to predict the pathogenic impact of variants in the two Italian patients and attempt genotype-phenotype correlates. Results: In line with the two patients with intermediate phenotypes, our case presented global psychomotor delay with regression, intellectual disability, spastic-ataxic gait, and hyperkinetic movements, with cerebellar atrophy and bilateral striatal hyperintensities. However, blood lactate, muscle biopsy, and MRI spectroscopy were normal. PMPCA protein levels were significantly higher than controls despite normal cDNA levels. Dynamics simulation of several PMPCA missense variants showed a variable impact on the flexibility of the glycine rich loop and, for some cases, on the overall protein stability, without clear genotype-phenotype correlates. Conclusion: We confirm the expansion of PMPCA phenotypic spectrum including an intermediate phenotype of progressive encephalopathy without systemic involvement. The association of cerebellar atrophy with “Leigh-like” striatal hyperintensities may represent a “red flag” for this condition

SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.

Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies. We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes. Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents. Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk

the effects of climate change on the multifunctional role of basilicata s forests the effects induced on yield and co2 absorption

The first studies on the possible impact of climate change on European forests and the development of adaptation and mitigation strategies began in the 1990s and resulted in the identification of risk assessment models and forest management tools. The prediction of climate change impacts on forests has been based using the evidence theory or Dempster-Shafer (DS)'s theory, appropriately spatialised. The implemented evidence lines refer to the concepts of vulnerability and resilience. The results of the DS model, applied to the Basilicata region, were utilised to assess the loss in biomass production capacity and CO2 absorption ability of different forest-derived biomasses. The loss in stumpage value and in the estimated CO2 absorption shows a reduction over time of forest system's economic value that is basically higher in 2050 than in 2100. The applied methodological approach has shown that the high degree of spatial and information detail may be helpful to produce good predictions to envisage environmental policy strategies for the monitoring and mitigation of the damages caused by the climate change, with a view to ensuring the ecosystems' capacity to produce positive externalities, including air carbon sequestration capacity

John Donne. Poesie.

Tutti i Re e tutti i loro favoriti, tutta la gloria di onori, bellezze e ingegni, il Sole stesso, che crea i tempi com\u2019essi passano, \ue8 pi\uf9 vecchio di un anno, ora, di quando tu e io la prima volta ci vedemmo: tutte le altre cose volgono alla loro distruzione, solo il nostro amore non ha decadimento; questo, domani non ha, n\ue9 ieri; correndo, mai corre via da noi, ma fedele scandisce il suo primo, ultimo, eterno giorno. \u201cPer leggere Donne, misurate il tempo e scoprite il ritmo di ogni parola attraverso il senso della passione.\u201d Samuel Taylor Coleridge L\u2019amore profano e l\u2019amore sacro, le antiche credenze e la nuova scienza, la morte individuale e lo sconvolgimento universale, la societ\ue0 borghese e il mondo della corte sono raccontati nella poesia di John Donne attraverso una fitta trama di storie e di scene, in cui i ritmi drammatici, i sorprendenti parallelismi e le travolgenti arguzie mai si piegano alla concettosit\ue0 di maniera, ma nascono dalla singolarissima passione espressiva di uno dei maggiori poeti di lingua inglese. In questa nuova edizione sono presentate le raccolte complete dei Songs and Sonnets, delle Elegie, degli Epigrammi, delle Satire e dei Sonetti sacri, nonch\ue9 un numero cospicuo di Epistole in versi e Una anatomia del mondo. Chiude il volume l\u2019ultimo sermone dell\u2019autore, Il duello della morte. La raccolta \ue8 corredata da un\u2019ampia introduzione e i testi sono accompagnati da un ricco corpo di apparati critici

Sensitivity of crossflow surfacetransitionroughnessto free-stream conditions and

The present work is an experimental investigation of stationary crossflow (CF) instability-induced transition of the boundary layer over a 45°swept wing, under varying free-stream turbulence, surface roughness, angle of attack and Reynolds number. Key topological features of the transition front, such as the mean transition location and the jaggedness of the front, are retrieved via IR thermography. Linear Stability Theory (LST) is used to extract the N-factor of the most amplified stationary crossflow mode at the transition location, identified experimentally. Results show clear causality between free-stream turbulence, surface roughness, Reynolds number, angle of attack and transition. Large losses of laminarity and a consistent decrease in the transition N-factor are observed with rising turbulence and roughness. Remarkably, N-factor sensitivity to free-stream turbulence is found to vary significantly and non-linearly with angle of attack for the modest levels of turbulence explored in this campaign, whereas the N-factors scale linearly with the log of the surface roughness level, which is consistent with a receptivity mechanism, which is independent of the angle of attack.Aerodynamic

Fundamental solutions for a coupled formulation of porous biphasic media with compressible solid and fluid phases

A general biphasic poroelastic formulation at finite strains with intrinsic compressibility of phases, whose governing equations are inferred on account of a leastaction variational principle, has been recently proposed (TMCPM). Hereby, a theoretical, analytical, and numerical assessment is presented on the capability of linearized TMCPM to recover, in the limit of vanishing porosity, a traditional single phase continuum model

La Qualità rappresentata. Identità e leadership come storie dell'organizzazione.

L'articolo presenta un'esperienza di formazione riflessiva in due scuole elementari di Napoli per rintracciare la qualità organizzativa delle stesse. In termini critici rispetto alle metodologie managerialiste, l'esperienza di ricerca-azione si è mossa lungo le direttrici tracciate dalla letteratura sulle culture organizzativ

Funzioni obiettivo e innovazione delle competenze nella scuola dell'autonomia

L'articolo presenta una ricerca sulle competenze del middle management scolastico rappresentato dalle figure delle funzioni obiettivo alla luce del frame teorico delle competejze istituzionalizzate