Search

Insulin-producing cells derived from induced pluripotent stem cells (iPSCs) are promising candidates for β cell replacement in type 1 diabetes. However, the risk of teratoma formation due to residual undifferentiated iPSCs contaminating the differentiated cells is still a critical concern for clinical application. Here, we hypothesized that pretreatment of iPSC-derived insulin-producing cells with an anti-CD30 antibody–drug conjugate could prevent in vivo teratoma formation by selectively killing residual undifferentiated cells. CD30 is expressed in all human iPSCs clones tested by flow cytometry (n = 7) but not in iPSC-derived β cells (iβs). Concordantly, anti-CD30 treatment in vitro for 24 h induced a dose-dependent cell death (up to 90%) in human iPSCs while it did not kill iβs nor had an impact on iβ identity and function, including capacity to secrete insulin in response to stimuli. In a model of teratoma assay associated with iβ transplantation, the pretreatment of cells with anti-CD30 for 24 h before the implantation into NOD-SCID mice completely eliminated teratoma development (0/10 vs. 8/8, p < 0.01). These findings suggest that short-term in vitro treatment with clinical-grade anti-CD30, targeting residual undifferentiated cells, eliminates the tumorigenicity of iPSC-derived β cells, potentially providing enhanced safety for iPSC-based β cell replacement therapy in clinical scenarios.

Reconstructing the evolution of Gramsci’s judgement about the Russian Revolution implies an overall rethinking of his own relation to Marx as well as to Kant. Already in the spring of 1917, Gramsci foresaw that the February Revolution could become a proletarian revolution and that this would realise in fact Kant’s moral: only a society completely freed from oppression and exploitation would allow people to be free and autonomous. After the fall of the Winter Palace, Gramsci wrote that the revolution happened “against Marx’s Capital”, or better, against its literal interpretation as spread by the positivistic Marxism of the Second International. Between the end of the 1910s and the beginning of the 1920s, Gramsci thought it possible for Italy and the whole of Europe “to do as in Russia”; yet, from 1924, he started elaborating a different vision of the revolution in the Western World, which in the Prison Notebooks became a contraposition between a war of movement and a war of position. At the same time, he developed the concepts of caesarism/bonapartism and passive revolution which allowed the analysis of phenomena such as americanism and fascism from the perspective of a conservative modernisation, or revolution without a revolution. Still, and most of all, Gramsci developed the concept of hegemony, highlighting the importance of the moment of consensus in the fight for gaining and maintaining power. This drew Gramsci quite far from the marxism-leninism of his time, both from the political and theoretical point of view; for instance, he rejected the “ingenuous realism” of Lenin’s Materialism and Empiriocriticism in favour of a phenomenalism explicitly drawn by Kant.

Questa sezione non prevede un abstract., ——— Materialismo Storico ——— Rivista di filosofia, storia e scienze umane, V. 13 N. 2 (2022): L’egemonia dopo Gramsci #3: pedagogia, teoria politica e storia (Urbino 2021)

ContextMaturity-onset diabetes of the young (MODY) 8 is a rare form of monogenic diabetes characterized by a mutation in CEL (carboxyl ester lipase) gene, which leads to exocrine pancreas dysfunction, followed by β cell failure. Induced pluripotent stem cells can differentiate into functional β cells. Thus, β cells from MODY8 patients can be generated in vitro and used for disease modelling and cell replacement therapy.MethodsA genetic study was performed in a patient suspected of monogenic diabetes.ResultsA novel heterozygous pathogenic variant in CEL (c.1818delC) was identified in the proband, allowing diagnosis of MODY8. Three MODY8-iPSC (induced pluripotent stem cell) clones were reprogrammed from skin fibroblasts of the patient, and their pluripotency and genomic stability confirmed. All 3 MODY8-iPSC differentiated into β cells following developmental stages. MODY8-iPSC–derived β cells were able to secrete insulin upon glucose dynamic perifusion. The CEL gene was not expressed in iPSCs nor during any steps of endocrine differentiation.ConclusioniPSC lines from a MODY8 patient with a novel pathogenic variant in the CEL gene were generated; they are capable of differentiation into endocrine cells, and β cell function is preserved in mutated cells. These results set the basis for in vitro modelling of the disease and potentially for autologous β cell replacement.

A relação de Gramsci com Nietzsche se articula em dois momentos, aos quais são dedicadas as duas partes em que o ensaio é dividido. Na primeira parte, reconstroem-se as referências e as imagens nieztscheanas presentes em uma série de artigos do biênio 1916-1918. Na segunda parte, enfrenta-se o problema da presença de Nietzsche nos Cadernos do cárcere. Tanto nos anos juvenis como naqueles do cárcere, Gramsci parece estar atento a alguns conceitos-chaves do pensamento do filósofo alemão, começando pelo de super-homem, mas sobretudo parece combater a interpretação nieztschiana, cada vez mais difundida na cultura italiana e européia, com uma chave nacionalista, imperialista e racista. Recebido em 28 de março de 2020Aceito em 13 de maio de 2020Editado em julho de 2020

Electrofluorochromic devices (EFCDs) that allow the modulation of the light emitted by electroactive fluorophores are very attractive in the research field of optoelectronics. Here, the electrofluorochromic behaviour of a series of squaraine dyes was studied for the first time. In solutions, all compounds are photoluminescent with maxima located in the range 665–690 nm, characterized by quantum yields ranging from 30% to 4.1%. Squaraines were incorporated in a polymer gel used as an active layer in all-in-one gel switchable EFCDs. An aggregation induced quenching occurs in the gel phase, causing a significant decrease in the emission quantum yield in the device. However, the squaraines containing the thieno groups (thienosquaraines, TSQs) show a panchromatic emission and their electrofluorochromism allows the tuning of the fluorescence intensity from 500 nm to the near infrared. Indeed, the application of a potential difference to the device induces a reversible quenching of their emission that is significantly higher and occurs at shorter switching times for TSQs-based devices compared to the reference squaraine dye (DIBSQ). Interestingly, the TSQs fluorescence spectral profile becomes more structured under voltage, and this could be explained by the shift of the aggregates/monomer equilibrium toward the monomeric species, due to electrochemical oxidation, which causes the disassembling of aggregates. This effect may be used to modulate the colour of the fluorescence light emitted by a device and paves the way for conceiving new electrofluorochromic materials based on this mechanism.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fondazione Cariplo Caveolae are small-membrane invagination that contribute both to buffering excessive contraction-dependent membrane strain and to initiation of membrane repair. Moreover, they constitute micro-domains where receptors and ion channels are clustered, favouring their functional interaction. Caveolin-3 (Cav3) is the key structural component of muscular caveolae. Mutations in Cav3 gene are associated with alterations of the skeletal muscle architecture leading to some rare forms of hereditary skeletal myopathies and/or cardiomyopathies called caveolinopathies. Notably, skeletal muscle dysfunctions usually precede cardiac dysfunctions, even though the mutated Cav3 is expressed in both cell types. An important difference between skeletal fibers and cardiomyocytes is that in the latter, caveolin-1 (Cav1) participates with Cav3 to form caveolae; skeletal myotubes instead do not express Cav1.The delay or lack of onset of cardiac alterations in caveolinopathies may depend on a preserved micro-domains organization in the heart compared to skeletal muscle, due to Cav1 expression. We decided to focus on a specific mutation T78K found in heterozygous in a patient with Ripple muscle disease and hyperCKemia. We have characterized human cardiomyocytes (CM) differentiated from induced pluripotent stem cells (iPSC) derived from this patient and one healthy control. In particular, we have investigated which caveolin isoforms are expressed at day 30 of differentiation, finding both Cav1 and Cav3, with a significant decrease of Cav3 isoform in T78K-CM. Their different expressions significantly increase T78K membrane resistance (3.27 ± 0.6 GΩ versus 1.64 ± 0.4 GΩ in the CTRL-CM), and consequently membrane excitability. The T78K_CM showed an increase spontaneous beating rate compared to CTRL (1,75± 0,08 Hz and 0,89 ± 0,4 Hz, respectively). Previous laboratory analysis conducted in caveolin-free MEF cells, co-transfected with WT and T78K Cav3 mutation, revealed that the T78K mutant is dominant, inducing the retention of WT Cav3 in the perinuclear areas and causes significant reduction in current density of three ion channels (HCN4, Kv1.5 and Kir2.1) known to interact with caveolins. The dominant decreased in cav3 expression is in line with previous data in skeletal muscle biopsy, however, electrophysiological data would be likely incompatible with life. For this reason, we decided to compare the impact of this mutation in CHO cells that exhibit high levels of Cav1, and in cav-1 expressing MEF line. In these systems, the membrane localization of Cav3 T78K is rescued both in heterozygous and homozygous conditions. In line with caveolin membrane expression, HCN4, Kv1.5 and Kir2.1 density is also rescued to normal levels. These results constitute the first evidence of a possible role of Cav1 in compensating membrane disorganization and disfunction due to Cav3 mutations in the heart, making this organ less susceptible to caveolinopathies.

Observations préliminaires L’objectif des pages qui vont suivre est de présenter et de commenter les multiples images et appréciations des Lumières – françaises en particulier – que l’on trouve dans les écrits de Gramsci, en partant des premiers articles de journaux jusqu’aux écrits de prison. Afin d’éviter les redites avec d’autres contributions de ce volume, nous ne nous arrêterons pas sur les rapports de Gramsci avec des œuvres, des figures particulières ou des courants du xviiie siècle. N...