GLUT-1 deficiency presenting with seizures and reversible leukoencephalopathy on MRI imaging

Glucose transporter type 1 (GLUT1) deficiency syndrome is a well recognised genetic neurometabolic disorder typically presenting with progressive encephalopathy, acquired microcephaly and drug-resistant epilepsy. Imaging is normal in the majority. Here we describe a 5-month-old boy who presented with motor delay, myoclonic jerks and tonic-clonic seizures. His MRI brain scan revealed confluent symmetrical T2 hyperintense signal abnormality in both anterior frontal lobes and delayed myelination. Neurometabolic screen revealed low CSF glucose and lactate levels. A pathogenic de novo heterozygous mutation in SLC2A1 (c.275+1G > A) confirmed the diagnosis of GLUT1 deficiency. Ketogenic diet resulted in a dramatic termination of his seizures at 72 h. At 15 months, he continued to be seizure free with marked developmental catch up. Repeat imaging revealed a significant resolution of the previously seen changes. This case suggests that GLUT1 deficiency should be considered in the differential diagnosis of infants with suspected genetic leukoencephalopathies with important treatment implications

Monitoring T cell-dendritic cell interactions in vivo by intercellular enzymatic labelling

Interactions between different cell types are essential for multiple biological processes, including immunity, embryonic development and neuronal signalling. Although the dynamics of cell-cell interactions can be monitored in vivo by intravital microscopy, this approach does not provide any information on the receptors and ligands involved or enable the isolation of interacting cells for downstream analysis. Here we describe a complementary approach that uses bacterial sortase A-mediated cell labelling across synapses of immune cells to identify receptor-ligand interactions between cells in living mice, by generating a signal that can subsequently be detected ex vivo by flow cytometry. We call this approach for the labelling of 'kiss-and-run' interactions between immune cells 'Labelling Immune Partnerships by SorTagging Intercellular Contacts' (LIPSTIC). Using LIPSTIC, we show that interactions between dendritic cells and CD4+ T cells during T-cell priming in vivo occur in two distinct modalities: an early, cognate stage, during which CD40-CD40L interactions occur specifically between T cells and antigen-loaded dendritic cells; and a later, non-cognate stage during which these interactions no longer require prior engagement of the T-cell receptor. Therefore, LIPSTIC enables the direct measurement of dynamic cell-cell interactions both in vitro and in vivo. Given its flexibility for use with different receptor-ligand pairs and a range of detectable labels, we expect that this approach will be of use to any field of biology requiring quantification of intercellular communication

Anaphora Resolution in Near-Native Speakers of Italian

This study presents data from an experiment on the interpretation of intrasentential anaphora in Italian by native Italian speakers and by English speakers who have learned Italian as adults and have reached a near-native level of proficiency in this language. The two groups of speakers were presented with complex sentences consist-ing of a main clause and a subordinate clause, in which the subor-dinate clause had either an overt pronoun or a null subject pronoun. In half of the sentences the main clause preceded the subordinate clause (forward anaphora) and in the other half the subordinate clause preceded the main clause (backward anaphora). Participants performed in a picture verification task in which they had to indi-cate the picture(s) that corresponded to the meaning of the subor-dinate clause, thus identifying the possible antecedents of the null or overt subject pronouns. The patterns of responses of the two groups were very similar with respect to the null subject pronouns in both the forward and backward anaphora conditions. Compared to native monolingual speakers, however, the near-natives had a significantly higher preference for the subject of the matrix clause as a possible antecedent of overt subject pronouns, particularly in the backward anaphora condition. The results indicate that near-native speakers have acquired the syntactic constraints on pronom-inal subjects in Italian, but may have residual indeterminacy in the interface processing strategies they employ in interpreting pronom-inal forms

Fast Gate-Based Readout of Silicon Quantum Dots Using Josephson Parametric Amplification

Spins in silicon quantum devices are promising candidates for large-scale quantum computing. Gate-based sensing of spin qubits offers a compact and scalable readout with high fidelity, however, further improvements in sensitivity are required to meet the fidelity thresholds and measurement timescales needed for the implementation of fast feedback in error correction protocols. Here, we combine radio-frequency gate-based sensing at 622 MHz with a Josephson parametric amplifier, that operates in the 500–800 MHz band, to reduce the integration time required to read the state of a silicon double quantum dot formed in a nanowire transistor. Based on our achieved signal-to-noise ratio, we estimate that singlet-triplet single-shot readout with an average fidelity of 99.7% could be performed in 1     μ s , well below the requirements for fault-tolerant readout and 30 times faster than without the Josephson parametric amplifier. Additionally, the Josephson parametric amplifier allows operation at a lower radio-frequency power while maintaining identical signal-to-noise ratio. We determine a noise temperature of 200 mK with a contribution from the Josephson parametric amplifier (25%), cryogenic amplifier (25%) and the resonator (50%), showing routes to further increase the readout speed

The iron law of democratic socialism: British and Austrian influences on the young Karl Polanyi

This article has been made available through the Brunel Open Access Publishing Fund.A central thesis of Karl Polanyi's The great transformation concerns the tensions between capitalism and democracy: the former embodies the principle of inequality, while democracy represents that of equality. This paper explores the intellectual heritage of this thesis, in the ‘functional theory’ of G.D.H. Cole and Otto Bauer and in the writings of Eduard Bernstein. It scrutinizes Polanyi's relationship with Bernstein's ‘evolutionary socialism’ and charts his ‘double movement’ vis-à-vis Marxist philosophy: in the 1910s he reacted sharply against Marxism's deterministic excesses, but he then, in the 1920s, engaged in sympathetic dialogue with Austro-Marxist thinkers. The latter, like Bernstein, disavowed economic determinism and insisted upon the importance and autonomy of ethics. Yet they simultaneously predicted a law-like expansion of democracy from the political to the economic arena. Analysis of this contradiction provides the basis for a concluding discussion that reconsiders the deterministic threads in Polanyi's oeuvre. Whereas for some Polanyi scholars these attest to his residual attraction to Marxism, I argue that matters are more complex. While Polanyi did repudiate the more rigidly deterministic of currents in Marxist philosophy, those to which he was attracted, notably Bernstein's ‘revision’ and Austro-Marxism, incorporated a deterministic fatalism of their own, in respect of democratization. Herein lies a more convincing explanation of Polanyi's incomplete escape from a deterministic philosophy of history, as exemplified in his masterwork, The great transformation

Effect of transport-induced charge inhomogeneity on point-contact Andreev reflection spectra at ferromagnet-superconductor interfaces

We investigate the transport properties of a ferromagnet-superconductor interface within the framework of a modified three-dimensional Blonder-Tinkham-Klapwijk formalism. In particular, we propose that charge inhomogeneity forms via two unique transport mechanisms, namely, evanescent Andreev reflection and evanescent quasiparticle transmission. Furthermore, we take into account the influence of charge inhomogeneity on the interfacial barrier potential and calculate the conductance as a function of bias voltage. Point-contact Andreev reflection (PCAR) spectra often show dip structures, large zero-bias conductance enhancement, and additional zero-bias conductance peak. Our results indicate that transport-induced charge inhomogeneity could be a source of all these anomalous characteristics of the PCAR spectra.Comment: 9 pages, 6 figure

An RNAi screen for Aire cofactors reveals a role for Hnrnpl in polymerase release and Aire-activated ectopic transcription

Aire induces the expression of a large set of autoantigen genes in the thymus, driving immunological tolerance in maturing T cells. To determine the full spectrum of molecular mechanisms underlying the Aire transactivation function, we screened an AIRE-dependent gene-expression system with a genome-scale lentiviral shRNA library, targeting factors associated with chromatin architecture/function, transcription, and mRNA processing. Fifty-one functional allies were identified, with a preponderance of factors that impact transcriptional elongation compared with initiation, in particular members of the positive transcription elongation factor b (P-TEFb) involved in the release of "paused" RNA polymerases (CCNT2 and HEXIM1); mRNA processing and polyadenylation factors were also highlighted (HNRNPL/F, SFRS1, SFRS3, and CLP1). Aire's functional allies were validated on transfected and endogenous target genes, including the generation of lentigenic knockdown (KD) mice. We uncovered the effect of the splicing factor Hnrnpl on Aire-induced transcription. Transcripts sensitive to the P-TEFb inhibitor flavopiridol were reduced by Hnrnpl knockdown in thymic epithelial cells, independently of their dependence on Aire, therefore indicating a general effect of Hnrnpl on RNA elongation. This conclusion was substantiated by demonstration of HNRNPL interactions with P-TEFb components (CDK9, CCNT2, HEXIM1, and the small 7SK RNA). Aire-containing complexes include 7SK RNA, the latter interaction disrupted by HNRNPL knockdown, suggesting that HNRNPL may partake in delivering inactive P-TEFb to Aire. Thus, these results indicate that mRNA processing factors cooperate with Aire to release stalled polymerases and to activate ectopic expression of autoantigen genes in the thymu