Mutation profile of BBS genes in patients with Bardet-Biedl syndrome : An Italian study

Background: Bardet-Biedl syndrome (BBS) is a rare inherited multisystemic disorder with autosomal recessive or complex digenic triallelic inheritance. There is currently no treatment for BBS, but some morbidities can be managed. Accurate molecular diagnosis is often crucial for the definition of appropriate patient management and for the development of a potential personalized therapy. Methods: We developed a next-generation-sequencing (NGS) protocol for the screening of the 18 most frequently mutated genes to define the genotype and clarify the mutation spectrum of a cohort of 20 BBS Italian patients. Results: We defined the causative variants in 60% of patients; four of those are novel. 33% of patients also harboured variants in additional gene/s, suggesting possible oligogenic inheritance. To explore the function of different genes, we looked for correlations between genotype and phenotype in our cohort. Hypogonadism was more frequently detected in patients with variants in BBSome proteins, while renal abnormalities in patients with variations in BBSome chaperonin genes. Conclusions: NGS is a powerful tool that can help understanding BBS patients' phenotype through the identification of mutations that could explain differences in phenotype severity and could provide insights for the development of targeted therapy. Furthermore, our results support the existence of additional BBS loci yet to be identified

Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations

Background: Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results: We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients\u2019 biological samples, and a clearly fragmented mitochondrial network was observed in patients\u2019 fibroblasts. Conclusions: This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature

Impact Evaluation of Productive Use – An Implementation Guideline for Electrification Projects

There is a consensus in the international community that rural electrification and, in particular, the productive use of electricity contributes to poverty alleviation. At the same time, efforts to evaluate the impacts of development projects have increased substantially. This paper provides a hands-on guide for designing evaluation studies regarding the impacts of productive electricity usage. Complementary to the existing literature on evaluation methods, this guide familiarizes project managers with the concrete steps that have to be undertaken to plan and implement an evaluation. The guide comprises three modules based on enterprise surveys and on anecdotal case studies. For each module, the implementation is described on a step-by-step basis including conceptual issues as well as logistics and methodological questions

Autoantibodies detection in patients affected by autoimmune retinopathies

Objective: Autoimmune retinopathies (ARs) encompass a spectrum of immune diseases that are characterized by the presence of autoantibodies against retinal proteins in the bloodstream. These autoantibodies (AAbs) lead to a progressive and sometimes rapid loss of vision. ARs commonly affect subjects over 50 years of age, but also rare cases of kids under 3 years of age have been reported. Patients and methods: In this study, 47 unrelated Caucasian patients were enrolled. All subjects showed negative cancer diagnoses and negative results in their genetic screenings. We studied 8 confirmed retinal antigens using Western blotting analysis, with α-enolase followed by carbonic anhydrase II being the two most frequently found in the patients' sera. Results: Nineteen patients were positive (40.4%), thirteen uncertain (27.7%), and fifteen were negative (31.9%). Their gender did not correlate with the presence of AAbs (p=0.409). Conclusions: AAbs are responsible for retinal degeneration in some cases, while in others, they contribute to exacerbating the progression of the disease; however, their detection is crucial to reaching a better diagnosis and developing more effective treatments for these conditions. Moreover, finding good biomarkers is important not only for AR monitoring and prognosis, but also for helping with early cancer diagnosis

A novel, somatic, transforming mutation in the extracellular domain of epidermal growth factor receptor identified in myeloproliferative neoplasm

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFRC329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2V617F-positive clone in this PV patient harbors EGFRC329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2V617F disease clone in MPN.D.A. Casolari, T. Nguyen, C.M. Butcher, D.G. Iarossi, C.N. Hahn, S.C. Bray, P. Neufing, W.T. Parker, J. Feng, K.Z. Y. Maung, A. Wee, L. Vidovic, C.H. Kok, P.G. Bardy, S.Branford, I.D. Lewis, S.W. Lane, H.S. Scott, D.M. Ross, R.J. D’Andre

Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia

The interaction of germline variation and somatic cancer driver mutations is underinvestigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondriallyencoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.Mahmoud A. Bassal, Saumya E. Samaraweera, Kelly Lim, Brooks A. Bernard, Sheree Bailey, Satinder Kaur, Paul Leo, John Toubia, Chloe Thompson-Peach, Tran Nguyen, Kyaw Ze Ya Maung, Debora A. Casolari, Diana G. Iarossi, Ilaria S. Pagani, Jason Powell, Stuart Pitson, Siria Natera, Ute Roessner, Ian D. Lewis, Anna L. Brown, Daniel G. Tenen, Nirmal Robinson, David M. Ross, Ravindra Majeti, Thomas J. Gonda, Daniel Thomas, Richard J. D, Andre

Linee verso il progetto di architettura

Il contributo costituisce una riflessione sul processo di elaborazione del codice grafico, inteso non solo come linguaggio univoco, ma come forma propria della conoscenza in architettura, che ha accompagnato nel suo sviluppo storico, costituendosi, in rapporto dialettico con il modello fisico, come strumento privilegiato di approccio critico al progetto alle diverse scale e nelle sue diverse declinazioni: dalla pianificazione al design, dalla conservazione dell’Heritage fino alla progettazione del nuovo

Ariadne’s Thread. Lines Towards Architectural Project

The process of elaborating a graphic code, not only as a unique language, but as the own form of knowledge in architecture, accompanied its historical development, constituting itself as the par excellence tool for a critical approach to the project, in its different scales and declinations: from urban planning to interior design or heritage preservation project. At the heart of traditional architectural design, today the line seems to be defrauded of its hermeneutic role, supplanted by surfaces and images, often automatically obtained. The contribution proposes a reflection on the use of line drawing and its graphic codes as a knowledge tool aimed at the architectural project in its different fields, exploring its potential also in interaction with other forms of representation, including physical and digital models

Dalle case di carta alle case di pietra.Modulazioni di Pietro Lingeri sul tema della casa per l’artista. / From Paper Houses to Stone Houses. Modulations by Pietro Lingeri on the Theme of the House for the Artist.

La rappresentazione architettonica ha da sempre costituito lo strumento concettuale e operativo del percorso che conduce dalla primigenia formulazione di un’idea formale alla sua materializzazione fisica, in un determinato manufatto. La documentazione grafica custodita negli archivi storici restituisce, nella sequenza cronologica degli elaborati e nella codificazione per linee e tratti delle intenzioni progettuali ad essi sottese, la narrazione di tale processo di affinamento delle forme, in cui tutto un insieme di aspetti e fattori (come le mutate richieste della committenza o delle condizioni di contesto), pur ponendosi come vincoli all’azione progettuale, finiscono per costituirne l’autentico propulsore.Talvolta accade però che lacune nei fondi archivistici disegnino inspiegabili salti logici dell’iter progettuale e solo l’approccio ermeneutico ai materiali grafici disponibili – oggi supportato anche dalle potenzialità del digitale, incluso l’uso della Virtual Reality (VR) – consenta di ricostruire il processo seguito dall’architetto nella definizione e materializzazione delle forme. Il paper documenta l’applicazione di tale metodologia alle tre case per artisti realizzate da Pietro Lingeri sull’Isola Comacina tra il 1937 e il 1940, il cui assetto fisico appare alquanto difforme rispetto a quanto descritto dagli elaborati progettuali conservati negli archivi, facendo emergere quel valore immateriale corrispondente alla cultura del progetto, non riducibile al solo portato patrimoniale del manufatto fisico in cui si è materializzato.Architectural representation has always been the conceptual and operational tool of the path that leads, from the primitive formulation of a formal idea to its physical materialisation in a specific building. The graphic documentation preserved in the historical archives returns, in the chronological se¬quence of the drawings and the coding by lines and strokes of the design intentions underlying them, the narration of this process of refinement of the forms, in which a whole set of aspects and factors (such as the changed requests from the client or the context conditions), while placing themselves as constraints on the design action, end up constituting its authentic propeller. However, sometimes it happens that gaps in the archives draw inexplicable logical leaps in the design process and only the hermeneutic approach to the available graphic materials – today also supported by the digital potential, including the use of Virtual Reality (VR) – allows us to reconstruct the process followed by the architect in the definition and materialisation of forms. The paper documents the application of this methodology to the three houses for artists built by Pietro Lingeri on Comacina Island between 1937 and 1940, whose physical layout appears somewhat different from what is described by the design documents conserved in the archives, bringing out that immaterial value corresponding to the culture of the project, not reducible only to the patrimonial value of the physical artefact in which it is materialised