Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations

Mfn2, an oligomeric mitochondrial protein important for mitochondrial fusion, is mutated in Charcot-Marie-Tooth disease (CMT) type 2A, a peripheral neuropathy characterized by axonal degeneration. In addition to homooligomeric complexes, Mfn2 also associates with Mfn1, but the functional significance of such heterooligomeric complexes is unknown. Also unknown is why Mfn2 mutations in CMT2A lead to cell type–specific defects given the widespread expression of Mfn2. In this study, we show that homooligomeric complexes formed by many Mfn2 disease mutants are nonfunctional for mitochondrial fusion. However, wild-type Mfn1 complements mutant Mfn2 through the formation of heterooligomeric complexes, including complexes that form in trans between mitochondria. Wild-type Mfn2 cannot complement the disease alleles. Our results highlight the functional importance of Mfn1–Mfn2 heterooligomeric complexes and the close interplay between the two mitofusins in the control of mitochondrial fusion. Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients

Electromagnetic transitions of the helium atom in superstrong magnetic fields

We investigate the electromagnetic transition probabilities for the helium atom embedded in a superstrong magnetic field taking into account the finite nuclear mass. We address the regime \gamma=100-10000 a.u. studying several excited states for each symmetry, i.e. for the magnetic quantum numbers 0,-1,-2,-3, positive and negative z parity and singlet and triplet symmetry. The oscillator strengths as a function of the magnetic field, and in particular the influence of the finite nuclear mass on the oscillator strengths are shown and analyzed.Comment: 10 pages, 8 figure

Security and confidentiality approach for the Clinical E-Science Framework (CLEF)

CLEF is an MRC sponsored project in the E-Science programme that aims to establish policies and infrastructure for the next generation of integrated clinical and bioscience research. One of the major goals of the project is to provide a pseudonymised repository of histories of cancer patients that can be accessed by researchers. Robust mechanisms and policies are needed to ensure that patient privacy and confidentiality are preserved while delivering a repository of such medically rich information for the purposes of scientific research. This paper summarises the overall approach adopted by CLEF to meet data protection requirements, including the data flows and pseudonymisation mechanisms that are currently being developed. Intended constraints and monitoring policies that will apply to research interrogation of the repository are also outlined. Once evaluated, it is hoped that the CLEF approach can serve as a model for other distributed electronic health record repositories to be accessed for research

Security and confidentiality approach for the Clinical E-Science Framework (CLEF)

Objectives: CLEF is an MRC sponsored project in the E-Science programme that aims to establish methodologies and a technical infrastructure for the next generation of integrated clinical and bioscience research. Methods: The heart of the CLEF approach to this challenge is to design and develop a pseudonymised repository of histories of cancer patients that can be accessed by researchers. Robust mechanisms and policies have been developed to ensure that patient privacy and confidentiality are preserved while delivering a repository of such medically rich information for the purposes of scientific research. Results: This paper summarises the overall approach adopted by CLEF to meet data protection requirements, including the data flows, pseudonymisation measures and additional monitoring policies that are currently being developed. Conclusion: Once evaluated, it is hoped that the CLEF approach can serve as a model for other distributed electronic health record repositories to be accessed for research

Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development

Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and Mfn2, have been shown to affect mitochondrial morphology when overexpressed. We find that mice deficient in either Mfn1 or Mfn2 die in midgestation. However, whereas Mfn2 mutant embryos have a specific and severe disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells are normal. Embryonic fibroblasts lacking Mfn1 or Mfn2 display distinct types of fragmented mitochondria, a phenotype we determine to be due to a severe reduction in mitochondrial fusion. Moreover, we find that Mfn1 and Mfn2 form homotypic and heterotypic complexes and show, by rescue of mutant cells, that the homotypic complexes are functional for fusion. We conclude that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion. Strikingly, a subset of mitochondria in mutant cells lose membrane potential. Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population

Highlighting the learning in project-based undergraduate engineering education: pedagogical and methodological considerations

This paper presents a discussion of findings in relation to the pedagogy of Project Based Learning (PjBL) from a collaborative learning and teaching research project at UCL Engineering. It highlights the importance of adopting a) an understanding learning as a social practice in PjBL, and b) developing valid methodological approaches when capturing student learning experiences

Fitness for purpose? project-based, collaborative learning in engineering undergraduate education

In response to evolving work practices in engineering (Royal Academy of Engineering 2010) and the ever-changing nature of vocational and professional knowledge (Broad, 2016), attention has rightly turned to the development of innovative pedagogies to facilitate the entry of graduates to the employment market. Project-based Learning (PjBL) is an example of such an innovative pedagogy and has been developed in some HE contexts to provide students with authentic learning experiences which are designed to embed team working and collaboration; problem solving and solution-finding alongside the development of technical knowledge and skills (Mills and Treagust, 2003). Yet despite the introduction of collaborative inquiry-based curricula in engineering, comprehensive understanding of the pedagogical practices that these innovative practices require has not yet emerged (Damşa & Nerland, 2016). At UCL Engineering, PjBL has been an integral feature of the Integrated Engineering Programme (IEP) undergraduate curriculum since 2014. Drawing upon an on-going collaborative Institute of Education/UCL ‘seed corn’ funded project, this paper will present data collected through observation of project-based learning scenarios and discussion with engineering undergraduates in situ. It will identify and discuss the nature of student learning and engagement in project-based learning activities, with particular attention to disciplinary issues and the development of student disciplinary knowledge. In so doing, it will assess whether PjBL is, indeed, ‘fit for purpose’

Helium in superstrong magnetic fields

We investigate the helium atom embedded in a superstrong magnetic field gamma=100-10000 au. All effects due to the finite nuclear mass for vanishing pseudomomentum are taken into account. The influence and the magnitude of the different finite mass effects are analyzed and discussed. Within our full configuration interaction approach calculations are performed for the magnetic quantum numbers M=0,-1,-2,-3, singlet and triplet states, as well as positive and negative z parities. Up to six excited states for each symmetry are studied. With increasing field strength the number of bound states decreases rapidly and we remain with a comparatively small number of bound states for gamma=10^4 au within the symmetries investigated here.Comment: 16 pages, including 14 eps figures, submitted to Phys. Rev.