Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients

Beta-thalassemia is a common monogenic disorder due to mutations in the beta-globin gene and gene therapy, based on autologous transplantation of genetically corrected haematopoietic stem cells (HSCs), holds the promise to treat patients lacking a compatible bone marrow (BM) donor. We recently showed correction of murine beta-thalassemia by gene transfer in HSCs with the GLOBE lentiviral vector (LV), expressing a transcriptionally regulated human beta-globin gene. Here, we report successful correction of thalassemia major in human cells, by studying a large cohort of pediatric patients of diverse ethnic origin, carriers of different mutations and all candidates to BM transplantation. Extensive characterization of BM-derived CD34(+) cells before and following gene transfer shows the achievement of high frequency of transduction, restoration of haemoglobin A synthesis, rescue from apoptosis and correction of ineffective erythropoiesis. The procedure does not significantly affect the differentiating potential and the relative proportion of haematopoietic progenitors. Analysis of vector integrations shows preferential targeting of transcriptionally active regions, without bias for cancer-related genes. Overall, these results provide a solid rationale for a future clinical translation

Functional imaging using fluorine ((19)F) MR methods: basic concepts

Kidney-associated pathologies would greatly benefit from noninvasive and robust methods that can objectively quantify changes in renal function. In the past years there has been a growing incentive to develop new applications for fluorine ((19)F) MRI in biomedical research to study functional changes during disease states. (19)F MRI represents an instrumental tool for the quantification of exogenous (19)F substances in vivo. One of the major benefits of (19)F MRI is that fluorine in its organic form is absent in eukaryotic cells. Therefore, the introduction of exogenous (19)F signals in vivo will yield background-free images, thus providing highly selective detection with absolute specificity in vivo. Here we introduce the concept of (19)F MRI, describe existing challenges, especially those pertaining to signal sensitivity, and give an overview of preclinical applications to illustrate the utility and applicability of this technique for measuring renal function in animal models. This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis

Emergence of criticality through a cascade of delocalization transitions in quasiperiodic chains

Conduction through materials crucially depends on how ordered the materials are. Periodically ordered systems exhibit extended Bloch waves that generate metallic bands, whereas disorder is known to limit conduction and localize the motion of particles in a medium1,2. In this context, quasiperiodic systems, which are neither periodic nor disordered, demonstrate exotic conduction properties, self-similar wavefunctions and critical phenomena3. Here, we explore the localization properties of waves in a novel family of quasiperiodic chains obtained when continuously interpolating between two paradigmatic limits4: the Aubry–André model5,6, famous for its metal-to-insulator transition, and the Fibonacci chain7,8, known for its critical nature. We discover that the Aubry–André model evolves into criticality through a cascade of band-selective localization/delocalization transitions that iteratively shape the self-similar critical wavefunctions of the Fibonacci chain. Using experiments on cavity-polariton devices, we observe the first transition and reveal the microscopic origin of the cascade. Our findings offer (1) a unique new insight into understanding the criticality of quasiperiodic chains, (2) a controllable knob by which to engineer band-selective pass filters and (3) a versatile experimental platform with which to further study the interplay of many-body interactions and dissipation in a wide range of quasiperiodic models.ISSN:1745-2473ISSN:1745-248

Emergence of criticality through a cascade of delocalization transitions in quasiperiodic chains

| openaire: EC/H2020/820392/EU//PhoQuSThe localization properties of waves in the quasiperiodic chains described by the Aubry-Andre model and Fibonacci model are investigated. Passing from one model to the other, the system develops a cascade of delocalization transitions. Conduction through materials crucially depends on how ordered the materials are. Periodically ordered systems exhibit extended Bloch waves that generate metallic bands, whereas disorder is known to limit conduction and localize the motion of particles in a medium(1,2). In this context, quasiperiodic systems, which are neither periodic nor disordered, demonstrate exotic conduction properties, self-similar wavefunctions and critical phenomena(3). Here, we explore the localization properties of waves in a novel family of quasiperiodic chains obtained when continuously interpolating between two paradigmatic limits(4): the Aubry-Andre model(5,6), famous for its metal-to-insulator transition, and the Fibonacci chain(7,8), known for its critical nature. We discover that the Aubry-Andre model evolves into criticality through a cascade of band-selective localization/delocalization transitions that iteratively shape the self-similar critical wavefunctions of the Fibonacci chain. Using experiments on cavity-polariton devices, we observe the first transition and reveal the microscopic origin of the cascade. Our findings offer (1) a unique new insight into understanding the criticality of quasiperiodic chains, (2) a controllable knob by which to engineer band-selective pass filters and (3) a versatile experimental platform with which to further study the interplay of many-body interactions and dissipation in a wide range of quasiperiodic models.Peer reviewe