The era of cryptic exons: implications for ALS-FTD

TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer's disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g., STMN2), as well as being able to modify disease progression (e.g., UNC13A). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies

H-Bridge Converter as Basic Switching Topology Workbench in Power Electronics Teaching

This article deals with an effective power electronics learning setup based on a Full-Bridge converter used to teach electrical energy conversion experimentally. In the proposed learning by doing methodology, the hardware and the software are properly mixed in order to obtain an easy-to-use experimental learning environment. In this paper, the H-Bridge is the fundamental brick to build students’ knowledge on the main topics of power electronics converter circuit in different operative conditions. This H-Bridge comes with a reconfigurable output LCL to achieve several basic DC-DC powerconverters topologies. Converter current and voltage switching behavior can be investigated using the proposed setup. Furthermore, the friendly hardware and software set-up allows studying the converter modulation and control techniques of the different power electronics circuits

Interleukin-1 receptor antagonist gene (IL-1RN) polymorphism is a predictive factor of clinical pregnancy after IVF

BACKGROUND Only 25% of IVF transfer cycles lead to a clinical pregnancy, calling for continued technical progress but also more in depth analysis of patients' individual characteristics. The interleukin-1 (IL-1) system and matrix metalloproteinases (MMPs) are strongly implicated in embryo implantation. The genes coding for IL-1Ra (gene symbol IL-1RN), IL-1β, MMP2 and MMP9 bear functional polymorphisms. We analysed the maternal genetic profile at these polymorphic sites in IVF patients, to determine possible correlations with IVF outcome. METHODS One hundred and sixty women undergoing an IVF cycle were enrolled and a buccal smear was obtained. The presence of IL-1RN variable number of tandem repeats and IL-1B + 3953, MMP2-1306 and MMP9-1562 single nucleotide substitutions were determined. Patients were divided into pregnancy failures (119), biochemical pregnancies (8) and clinical pregnancies (33). RESULTS There was a 40% decrease in IL-1RN*2 allele frequency (P = 0.024) and a 45% decrease in IL-1RN*2 carrier status in the clinical pregnancy group as compared to the pregnancy failure group (P = 0.017). This decrease was still statistically significant after a multivariate logistic regression analysis. The likelihood of a clinical pregnancy was decreased accordingly in IL-1RN*2 carriers: odds ratio = 0.349, 95% confidence interval = 0.2-0.8, P = 0.017. The IL-1B, MMP2 and MMP9 polymorphisms showed no correlation with IVF outcome. CONCLUSIONS IL-1RN*2 allele carriage is associated with a poor prognosis of achieving a pregnancy after IV

A note on boundedness of operators in Grand Grand Morrey spaces

In this note we introduce grand grand Morrey spaces, in the spirit of the grand Lebesgue spaces. We prove a kind of \textit{reduction lemma} which is applicable to a variety of operators to reduce their boundedness in grand grand Morrey spaces to the corresponding boundedness in Morrey spaces. As a result of this application, we obtain the boundedness of the Hardy-Littlewood maximal operator and Calder\'on-Zygmund operators in the framework of grand grand Morrey spaces.Comment: 8 page

Editorial: Epigenetic insights into diagnostic and therapeutic applications

Studies of the heredity and variation in DNA sequence that directs normal development of all living organisms has fundamentally reshaped our understanding of human disease. However, a greater focus on an additional layer of information that does not depend on the underlying DNA sequence referred to as “epigenetics”, has emerged. Epigenetic processes have been recognized as critical for refining DNA-encoded instructions that direct cellular function, and there is increasing evidence that epigenetic dysregulation plays a central role in human disease. In contrast to irreversible genetic mutations, alterations to epigenetic pathways are dynamic, making them attractive therapeutic targets

Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration

The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the beta2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different alpha subunit partners of beta2 (i.e., alpha4 and alpha6), the homo-pentameric alpha7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 microg free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the beta2, alpha4, alpha6 and alpha7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice, beta2-VEC mice with the beta2 subunit re-expressed exclusively in the VTA, alpha4-VEC mice with selective alpha4 re-expression in the VTA, alpha6-VEC mice with selective alpha6 re-expression in the VTA, and alpha7-KO mice promptly self-administer nicotine intravenously, whereas beta2-KO, beta2-VEC in the substantia nigra, alpha4-KO and alpha6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of alpha4beta2- and alpha6beta2-subunit containing nicotinic receptors (alpha4beta2*- and alpha6beta2*-nAChRs), but not alpha7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mic

Distribution and ecology of calanoid species in relation to morphometric and chemical characteristics of lakes and ponds of the Northern Apennines (Italy)

In 1999 a limnological campaign was carried out in 89 water bodies located in 8 valleys of the Northern Apennines (provinces of Genua, Piacenza, Parma and Reggio Emilia) at an altitude between 877 and 1772 m a.s.l. This survey took into account permanent lakes, but also temporary and ephemeral water bodies which had been scarcely considered in hydrobiological studies previously carried out in this area. Most of the biotopes were visited seasonally during the ice-free period (May - November). The aim of this research was to define the relationships between morphometric features, lithology, hydroperiod and chemical characteristics of the biotopes and the distribution of the three species of calanoid copepods reported in the Northern Apennines, i.e. Mixodiaptomus kupelwieseri, M. tatricus and Eudiaptomus intermedius. The two most common species, M. kupelwieseri and E. intermedius, show an overlap in their altitudinal distribution. However, the former species widely occurs in very shallow, temporary or ephemeral water bodies and the latter clearly prefers permanent, relatively deep waters. Also the water inonic concentration influences the distribution of these two diaptomids, while concentrations of dissolved inorganic nutrients seem to have a negligible effect. Mixodiaptomus tatricus was found only in two shallow ponds beyond 1700 m a.s.l. Co-occurrence of E. intermedius and M. kupelwieseri has been observed only in a pond, but the two species are not found at the same time. The proportion of subitaneous and resting eggs laid in different seasons was analysed in populations of E. intermedius. The voltinism of this species varies according to the duration of the filling period and the productivity of the water bodies. The persistence of diaptomids in the study area has been evaluated through the comparison with distributional data available from the 1950s for most of the permanent lakes and some temporary habitats. Populations appear to be stable over time also in scarcely predictable environments as temporary pools, although in some cases calanoids have disappeared from biotopes severely affected by anthropogenic impacts

Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disease of the human motor neuron system, where variability in progression rate limits clinical trial efficacy. Therefore, better prognostication will facilitate therapeutic progress. In this study, we investigated the potential of plasma cell-free microRNAs (miRNAs) as ALS prognostication biomarkers in 252 patients with detailed clinical phenotyping. First, we identified, in a longitudinal cohort, miRNAs whose plasma levels remain stable over the course of disease. Next, we showed that high levels of miR-181, a miRNA enriched in neurons, predicts a greater than two-fold risk of death in independent discovery and replication cohorts (126 and 122 patients, respectively). miR-181 performance is similar to neurofilament light chain (NfL), and when combined together, miR-181 + NfL establish a novel RNA–protein biomarker pair with superior prognostication capacity. Therefore, plasma miR-181 alone and a novel miRNA–protein biomarker approach, based on miR-181 + NfL, boost precision of patient stratification. miR-181-based ALS biomarkers encourage additional validation and might enhance the power of clinical trials