Financial Transaction Tax: Small is Beautiful

The case for taxing financial transactions merely to raise more revenues from the financial sector is not particularly strong. Better alternatives to tax the financial sector are likely to be available. However, a tax on financial transactions could be justified in order to limit socially undesirable transactions when more direct means of doing so are unavailable for political or practical reasons. Some financial transactions are indeed likely to do more harm than good, especially when they contribute to the systemic risk of the financial system. However, such a financial transaction tax should be very small, much smaller than the negative externalities in question, because it is a blunt instrument that also drives out socially useful transactions. There is a case for taxing over-the-counter derivative transactions at a somewhat higher rate than exchange-based derivative transactions. More targeted remedies to drive out socially undesirable transactions should be sought in parallel, which would allow, after their implementation, to reduce or even phase out financialtransaction taxes

Validation and reconstruction of flow meter data in the Barcelona water distribution network

12 páginas, 16 figuras, 1 tabla.-- El PDF es la versión pre-print.-- et al.This paper presents a signal analysis methodology to validate (detect) and reconstruct the missing and false data of a large set of flow meters in the telecontrol system of a water distribution network. The proposed methodology is based on two time-scale forecasting models: a daily model based on a ARIMA time series, while the 10-min model is based on distributing the daily flow using a 10-min demand pattern. The demand patterns have been determined using two methods: correlation analysis and an unsupervised fuzzy logic classification, named LAMDA algorithm. Finally, the proposed methodology has been applied to the Barcelona water distribution network, providing very good results.This work is part of a applied research project granted by ADASA and AGBAR companies. The authors also wish to thank the support received by the Research Commission of the Generalitat of Catalunya (Group SAC Ref. 2009 SGR 1491) and by CICYT (Ref. HYFA DPI2008-01996 and WATMAN DPI2009-13744) of Spanish Ministry of Education.Peer reviewe

Validation and reconstruction of flow meter data in the Barcelona water distribution network

This paper presents a signal analysis methodology to validate (detect) and reconstruct the missing and false data of a large set of flow meters in the telecontrol system of a water distribution network. The proposed methodology is based on two time-scale forecasting models: a daily model based on a ARIMA time series, while the 10-min model is based on distributing the daily flow using a 10-min demand pattern. The demand patterns have been determined using two methods: correlation analysis and an unsupervised fuzzy logic classification, named LAMDA algorithm. Finally, the proposed methodology has been applied to the Barcelona water distribution network, providing very good results.Peer ReviewedPostprint (author’s final draft

The materiality of the intangible: Literary metaphor in multimodal texts

Based on a larger practice-based research project in digital writing, this article examines how the materiality of digital media contributes to a layered metaphor that delivers meaning, reflects on the cognitive processes (the writer’s and the reader’s) of navigation and generates a dynamic narrative structure through multimodality, unnatural narration and user interaction. Many writers and artists engage with their chosen medium through an instinctive understanding of the materials at hand, gained through experience; the explicit study of a medium’s materiality is not always required for artistic success, however, that may be judged. This article offers insights into the creative process of creating digital, multimodal fiction, based on a practice-based research project designed to explore the effects of digital media on author and text, and argues that digital media have a significant effect on the outcome of the artefact itself. Awareness of these effects, their variations according to hardware and software, and the affordances of these various materials offer the digital writer greater insight and capability to craft his/her texts for the desired metaphorical meaning

Patient-reported symptom burden of Charcot-Marie-Tooth Disease Type 1A: findings from an observational digital lifestyle study

Objectives: This study aims to explore the impact of Charcot-Marie-Tooth disease type 1A (CMT1A) and its treatment on patients in European (France, Germany, Italy, Spain, and the United Kingdom) and US real-world practice. Methods: Adults with CMT1A (n = 937) were recruited to an ongoing observational study exploring the impact of CMT. Data were collected via CMT&Me, an app through which participants completed patient-reported outcome measures. Results: Symptoms ranked with highest importance were weakness in the extremities, difficulty in walking, and fatigue. Almost half of participants experienced a worsening of symptom severity since diagnosis. Anxiety and depression were each reported by over one-third of participants. Use of rehabilitative interventions, medications, and orthotics/walking aids was high. Conclusions: Patient-reported burden of CMT1A is high, influenced by difficulties in using limbs, fatigue, pain, and impaired quality of life. Burden severity appears to differ across the population, possibly driven by differences in rehabilitative and prescription-based interventions, and country-specific health care variability

Absence of Dystrophin Related Protein-2 disrupts Cajal bands in a patient with Charcot-Marie-Tooth disease

Using exome sequencing in an individual with Charcot-Marie-Tooth disease (CMT) we have identified a mutation in the X-linked dystrophin-related protein 2 (DRP2) gene. A 60-year-old gentleman presented to our clinic and underwent clinical, electrophysiological and skin biopsy studies. The patient had clinical features of a length dependent sensorimotor neuropathy with an age of onset of 50 years. Neurophysiology revealed prolonged latencies with intermediate conduction velocities but no conduction block or temporal dispersion. A panel of 23 disease causing genes was sequenced and ultimately was uninformative. Whole exome sequencing revealed a stop mutation in DRP2, c.805C>T (Q269*). DRP2 interacts with periaxin and dystroglycan to form the periaxin-DRP2-dystroglycan complex which plays a role in the maintenance of the well-characterized Cajal bands of myelinating Schwann cells. Skin biopsies from our patient revealed a lack of DRP2 in myelinated dermal nerves by immunofluorescence. Furthermore electron microscopy failed to identify Cajal bands in the patient's dermal myelinated axons in keeping with ultrastructural pathology seen in the Drp2 knockout mouse. Both the electrophysiologic and dermal nerve twig pathology support the interpretation that this patient's DRP2 mutation causes characteristic morphological abnormalities recapitulating the Drp2 knockout model and potentially represents a novel genetic cause of CMT

Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterised by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and 3 benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness (change in CMTES (ΔCMTES) = 1.3 ± 2.6, p = 0.00016, SRM = 0.50). Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, p = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials

Human Umbilical Cord Blood Cells Restore Brain Damage Induced Changes in Rat Somatosensory Cortex

Intraperitoneal transplantation of human umbilical cord blood (hUCB) cells has been shown to reduce sensorimotor deficits after hypoxic ischemic brain injury in neonatal rats. However, the neuronal correlate of the functional recovery and how such a treatment enforces plastic remodelling at the level of neural processing remains elusive. Here we show by in-vivo recordings that hUCB cells have the capability of ameliorating the injury-related impairment of neural processing in primary somatosensory cortex. Intact cortical processing depends on a delicate balance of inhibitory and excitatory transmission, which is disturbed after injury. We found that the dimensions of cortical maps and receptive fields, which are significantly altered after injury, were largely restored. Additionally, the lesion induced hyperexcitability was no longer observed in hUCB treated animals as indicated by a paired-pulse behaviour resembling that observed in control animals. The beneficial effects on cortical processing were reflected in an almost complete recovery of sensorimotor behaviour. Our results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes. We propose that the intermediate level of cortical processing will become relevant as a new stage to investigate efficacy and mechanisms of cell therapy in the treatment of brain injury

Assessing non-Mendelian inheritance in inherited axonopathies

PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot–Marie–Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance. METHODS: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis. RESULTS: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA. CONCLUSION: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders

Inhibition of CD203c membrane up-regulation in human basophils by high dilutions of histamine: a controlled replication study

none5noPrevious research suggests that human basophil activation may be inhibited by histamine even at extremely low doses (high dilutions). In our experiment, membrane up-regulation of CD203c, which proved to be a more consistent activation marker than CD63, was significantly inhibited in samples treated with histamine at the dilutions of 2C, 12C, 14C, 15C and 16C. Control water dilutions/succussions did not show any significant effect. Therefore, using a strictly standardized flow cytometry protocol and a new dilution/succussion procedure, we have shown that low and high dilution of histamine do inhibit CD203c up-regulation in anti-IgE stimulated basophils.mixedS. Chirumbolo; M. Brizzi; R. Ortolani; A. Vella; P. BellaviteS. Chirumbolo; M. Brizzi; R. Ortolani; A. Vella; P. Bellavit