On the Proof Theory of Regular Fixed Points

International audienceWe consider encoding finite automata as least fixed points in a proof theoretical framework equipped with a general induction scheme, and study automata inclusion in that setting. We provide a coinductive characterization of inclusion that yields a natural bridge to proof-theory. This leads us to generalize these observations to regular formulas, obtaining new insights about inductive theorem proving and cyclic proofs in particular

Femtosecond photoelectron circular dichroism of chemical reactions

Understanding the chirality of molecular reaction pathways is essential for a broad range of fundamental and applied sciences. However, the current ability to probe chirality on the time scale of chemical reactions remains very limited. Here, we demonstrate time-resolved photoelectron circular dichroism (TRPECD) with ultrashort circularly polarized vacuum-ultraviolet (VUV) pulses from a table-top source. We demonstrate the capabilities of VUV-TRPECD by resolving the chirality changes in time during the photodissociation of atomic iodine from two chiral molecules. We identify several general key features of TRPECD, which include the ability to probe dynamical chirality along the complete photochemical reaction path, the sensitivity to the local chirality of the evolving scattering potential, and the influence of electron scattering off dissociating photofragments. Our results are interpreted by comparison with novel high-level ab-initio calculations of transient PECDs from molecular photoionization calculations. Our experimental and theoretical techniques define a general approach to femtochirality.Comment: 17 pages, 6 figures, 57 references, Accepted in Science Advance

Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease

We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome sequencing in family 1 and exome sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4′,5′-phosphate (cyclic FMN) through an FMN lyase domain. The TKFC homozygous variants reported here are located within the FMN lyase domain. Functional assays in yeast support the deleterious effect of these variants on protein function. Shared phenotypes between affected individuals with TKFC deficiency include cataracts and developmental delay, associated with cerebellar hypoplasia in one case. Further complications observed in two affected individuals included liver dysfunction and microcytic anemia, while one had fatal cardiomyopathy with lactic acidosis following a febrile illness. We postulate that deficiency of TKFC causes disruption of endogenous fructose metabolism leading to generation of by-products that can cause cataract. In line with this, an affected individual had mildly elevated urinary galactitol, which has been linked to cataract development in the galactosemias. Further, in light of a previously reported role of TKFC in regulating innate antiviral immunity through suppression of MDA5, we speculate that deficiency of TKFC leads to impaired innate immunity in response to viral illness, which may explain the fatal illness observed in the most severely affected individual

Reliability of visual assessment of medial temporal lobe atrophy

Background: Medial temporal lobe atrophy (MTA) has been found to be an early sign of Alzheimer’s disease (AD). Visual assessment of MTA (vaMTA) is a rapid, cost-efficient and clinically adaptable visual interpretation method for rating MTA, based on coronal magnetic resonance imaging (MRI) scans. The method was developed by Scheltens et al in the 1990s. Purpose: The aim of this thesis was to investigate the reliability of vaMTA using the Scheltens rating scale: on a long-term basis, compared with volumetric calculation, compared with multivariate analyses and, finally, tested in a clinical situation. In Study I, MRI scans of 100 patients were visually assessed six times over a 1-year period. Two radiologists, with different backgrounds, performed the assessments independently of each other. The results showed a high degree of reproducibility when performed by an experienced investigator. The reproducibility drops when assessment is rarely performed. Study II was a comparison between vaMTA and measurement of hippocampal volume in 544 non-demented elderly individuals from the SwedishNational Study of Ageing and Care in Kungsholmen (SNAC-K). A significant correlation was found between the two methods. Cut-off values for MTA scores in normal ageing were also suggested. In Study III the reliability of Scheltens’ visual assessment rating scale for assessing MTA was compared with that of a multivariate MRI classification method, orthogonal projections to latent structures (OPLS), and manually measured hippocampal volumes to distinguish between subjects with AD and healthy elderly controls (CTL). A comparison between the different techniques was also performed in predicting future developments from mild cognitive impairment (MCI) to AD. The prediction accuracies in distinguishing between AD patients and CTL were high for all three modalities. All three methods were also highly accurate in identifying subjects who converted from MCI to AD at 1-year follow-up. Finally, in Study IV, vaMTA scores were used in a validation study of the proposed new “Dubois criteria” in Alzheimer’s disease, in which MTA is one of four important biomarkers. A retrospective study of 150 patients was carried out to compare the traditional diagnostic criteria for dementia with the new criteria suggested by Dubois et al. The results showed a lack of accuracy for the new AD criteria, as they were valid for only 55% of the clinically diagnosed patients with full-blown AD in this study. Conclusion: Visual assessment of MTA using the MTA scale is reliable when performed on a daily basis. Medial temporal lobe atrophy scores have a significant correlation to hippocampal volume measurements, can predict conversion from MCI to AD with similar accuracy as can volumetric calculations and multivariate analysis, and can be used as supportive biomarker in the work-up of AD

Differential Associations of IL-4 With Hippocampal Subfields in Mild Cognitive Impairment and Alzheimer’s Disease

Background/Aims: We aimed to assess the association between in volumetric measures of hippocampal sub-regions – in healthy older controls (HC), subjects with mild cognitive impairment (MCI) and AD- with circulating levels of IL-4.Methods: From AddNeuroMed Project 113 HC, 101 stable MCI (sMCI), 22 converter MCI (cMCI) and 119 AD were included. Hippocampal subfield volumes were analyzed using Freesurfer 6.0.0 on high-resolution sagittal 3D-T1W MP-RAGE acquisitions. Plasmatic IL-4 was measured using ELISA assay.Results: IL-4 was found to be (a) positively associate with left subiculum volume (β = 0.226, p = 0.037) in sMCI and (b) negatively associate with left subiculum volume (β = -0.253, p = 0.011) and left presubiculum volume (β = -0.257, p = 0.011) in AD.Conclusion: Our results indicate a potential neuroprotective effect of IL-4 on the areas of the hippocampus more vulnerable to aging and neurodegeneration

Noninvasive estimation of tumour viability in a xenograft model of human neuroblastoma with proton magnetic resonance spectroscopy (1H MRS)

The aim of the study was to evaluate proton magnetic resonance spectroscopy (1H MRS) for noninvasive biological characterisation of neuroblastoma xenografts in vivo. For designing the experiments, human neuroblastoma xenografts growing subcutaneously in nude rats were analysed in vivo with 1H MRS and magnetic resonance imaging at 4.7 T. The effects of spontaneous tumour growth and antiangiogenesis treatment, respectively, on spectral characteristics were evaluated. The spectroscopic findings were compared to tumour morphology, proliferation and viable tumour tissue fraction. The results showed that signals from choline (Cho)-containing compounds and mobile lipids (MLs) dominated the spectra. The individual ML/Cho ratios for both treated and untreated tumours were positively correlated with tumour volume (P<0.05). There was an inverse correlation between the ML/Cho ratio and the viable tumour fraction (r=−0.86, P<0.001). Higher ML/Cho ratios concomitant with pronounced histological changes were seen in spectra from tumours treated with the antiangiogenic drug TNP-470, compared to untreated control tumours (P<0.05). In conclusion, the ML/Cho ratio obtained in vivo by 1H MRS enabled accurate assessment of the viable tumour fraction in a human neuroblastoma xenograft model. 1H MRS also revealed early metabolic effects of antiangiogenesis treatment. 1H MRS could prove useful as a tool to monitor experimental therapy in preclinical models of neuroblastoma, and possibly also in children

Excitotoxic cell death induces delayed proliferation of endogenous neuroprogenitor cells in organotypic slice cultures of the rat spinal cord

The aim of the present report was to investigate whether, in the mammalian spinal cord, cell death induced by transient excitotoxic stress could trigger activation and proliferation of endogenous neuroprogenitor cells as a potential source of a lesion repair process and the underlying time course. Because it is difficult to address these issues in vivo, we used a validated model of spinal injury based on rat organotypic slice cultures that retain the fundamental tissue cytoarchitecture and replicate the main characteristics of experimental damage to the whole spinal cord. Excitotoxicity evoked by 1 h kainate application produced delayed neuronal death (40%) peaking after 1 day without further losses or destruction of white matter cells for up to 2 weeks. After 10 days, cultures released a significantly larger concentration of endogenous glutamate, suggesting functional network plasticity. Indeed, after 1 week the total number of cells had returned to untreated control level, indicating substantial cell proliferation. Activation of progenitor cells started early as they spread outside the central area, and persisted for 2 weeks. Although expression of the neuronal progenitor phenotype was observed at day 3, peaked at 1 week and tapered off at 2 weeks, very few cells matured to neurons. Astroglia precursors started proliferating later and matured at 2 weeks. These data show insult-related proliferation of endogenous spinal neuroprogenitors over a relatively brief time course, and delineate a narrow temporal window for future experimental attempts to drive neuronal maturation and for identifying the factors regulating this process. \ua9 2013 Macmillan Publishers Limited. All rights reserved