Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism

Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS

Gender gap in parental leave intentions: Evidence from 37 countries

This is the final version. Available from Wiley via the DOI in this record. Despite global commitments and efforts, a gender-based division of paid and unpaid work persists. To identify how psychological factors, national policies, and the broader sociocultural context contribute to this inequality, we assessed parental-leave intentions in young adults (18–30years old) planning to have children (N = 13,942; 8,880 identified as women; 5,062 identified as men) across 37 countries that varied in parental-leave policies and societal gender equality. In all countries, women intended to take longer leave than men. National parental-leave policies and women’s political representation partially explained cross-national variations in the gender gap. Gender gaps in leave intentions were paradoxically larger in countries with more gender-egalitarian parental-leave policies (i.e., longer leave available to both fathers and mothers). Interestingly, this cross-national variation in the gender gap was driven by cross-national variations in women’s (rather than men’s) leave intentions. Financially generous leave and gender-egalitarian policies (linked to men’s higher uptake in prior research) were not associated with leave intentions in men. Rather, men’s leave intentions were related to their individual gender attitudes. Leave intentions were inversely related to career ambitions. The potential for existing policies to foster gender equality in paid and unpaid work is discussed.SSHRC Insight Development GrantSSHRC Insight GrantEconomic and Social Research CouncilState Research AgencyGuangdong 13th-five Philosophy and Social Science Planning ProjectNational Natural Science Foundation of ChinaSwiss National Science FoundationSwiss National Science FoundationCenter for Social Conflict and Cohesion StudiesCenter for Intercultural and Indigenous ResearchSSHRC Postdoctoral FellowshipSlovak Research and Development AgencySwiss National Science FoundationCanada Research ChairsSocial Sciences and Humanities Research Council of CanadaOntario Ministry of Research and InnovationHSE University, RFFaculty of Arts, Masaryk Universit

A cross-terms geometry based method for components instantaneous frequency estimation using the Cross Wigner-Ville distribution

A novel method for the signal components instantaneous frequency (IF) estimation based on the CrossWigner-Ville distribution (XWVD) is presented. The cross-terms in the XWVD are deliberately formed between the analyzed signal and a reference signal. The proposed method yields a scaled and time shifted image that closely resembles the instantaneous frequency laws of the components present in the signal. As the interferences location follow geometrical rules, and by using a reference signal well localized in time and frequency, the time-frequency coordinates of the analyzed signal components IF can be calculated by an automatic procedure described below. The performance of the method is tested on both synthetic and real-life signals, showing improvements over another recently proposed components extraction method.Scopu

A comparison of quadratic TFDs for entropy based detection of components time supports in multicomponent nonstationary signal mixtures

This paper presents a method for extraction of different signal components from multicomponent mixtures by exploiting the information of the local components Renyi entropy. (Additional details can be found in the comprehensive book on Time-Frequency Signal Analysis and Processing (see http://www.elsevier.com/locate/isbn/0080443354). In addition, the most recent upgrade of the original software package that calculates Time-Frequency Distributions and Instantaneous Frequency estimators can be downloaded from the web site: www.time-frequency.net. This was the first software developed in the field, and it was first released publicly in 1987 at the 1st ISSPA conference held in Brisbane, Australia, and then continuously updated).Separation of different signal components, produced by one or more sources, is a problem encountered in many signal processing applications. This paper proposes a fully automatic undetermined blind source separation method, based on a peak detection and extraction technique from a signal time-frequency distribution (TFD). Information on the local number of components is obtained from the TFD Short-term Rényi entropy. It also allows to detect components time supports in the time-frequency plane, with no need for predefined thresholds on the components amplitude. This approach allows to extract different signal components without prior knowledge about the signal. The method is also used as a quality criterion to compare Quadratic TFDs. Results for synthetic and real data are reported for different TFDs, including the recently introduced Extended Modified B distribution

Umsetzung neuer Konzepte der technischen Gebaeudeausruestung im Wohnungsbau unter Beruecksichtigung von Kosten, Verbraeuchen und Nutzerkomfort Abschlussbericht

The goal of this project was the development of a set of tools for the selection of optimal concepts for HVAC-systems in housing buildings. Several factors are considered. They include technical feasibility, costs for investment, maintenance and operation, energy concumption, environmental impacts and user comfort. It is intended with the help of these tools to identify the most important factors which influence energy consumption and to suggest simple and cost effective measures to reduce energy consumption. Measures include improvements of the envelope, changes in the HVAC-system and its operation according to the needs to the inhabitants of the building. This report describes these components of this tool set which were developed in the frame of the project WohnKomfort. It lists data and rules chosen. In addition we report experiences which we gained with an prototypical implementation. This implementation allows load calculations for more than 60.000 different buildings applying EN 802 (only one zone model) as calculation method. It also supports selection of heating systems for such buildings by offering an evaluation according to user specified criteria including cost, environment and comfort. (orig./MM)Ziel des Vorhabens war die Entwicklung eines Instrumentariums zur Auswahl optimaler Konzepte fuer technische Anlagen in Wohngebaeuden unter Beruecksichtigung der Faktoren technische Machbarkeit, Erstellungs-, Betriebskosten, Energieverbrauch, Umweltbelastung und Nutzerkomfort. Mit Hilfe dieses Instrumentariums soll es moeglich werden, die Haupteinflussfaktoren fuer den Energieverbrauch anzugeben und Vorschlaege fuer einfache und kostenguenstige Massnahmen zu seiner Reduzierung auf der Seite des Gebaeudes (bauliche Massnahmen) und der Anlage (technische Massnahmen, Nutzerverhalten) anzugeben. In diesem Bericht beschreiben wir die im Vorhaben entwickelten Komponenten des Instrumentariums, die zugrundeliegenden Daten und Regeln sowie Erfahrungen, die wir mit dem Instrumentarium anhand einer prototypischen Implementierung erzielen konnten. Die prototypische Implementierung erlaubt thermische Lastberechnungen fuer 60.000 verschiedene Gebaeude nach der EN 802 (allerdings Ein-Zonen-Modell). Darueber hinaus unterstuetzt sie die Auswahl eines Heizsystems entsprechend vom Nutzer vorgegebenen Kriterien. Diese umfassen die Aspekte Kosten, Umweltvertraeglichkeit und Komfort. (orig./MM)SIGLEAvailable from TIB Hannover: RA 607(4-148) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Raumordnung, Bauwesen und Staedtebau, Bonn (Germany)DEGerman

Scientific Reports / STAT3 controls IL6-dependent regulation of serotonin transporter function and depression-like behavior

Experimental evidence suggests a role for the immune system in the pathophysiology of depression. A specific involvement of the proinflammatory cytokine interleukin 6 (IL6) in both, patients suffering from the disease and pertinent animal models, has been proposed. However, it is not clear how IL6 impinges on neurotransmission and thus contributes to depression. Here we tested the hypothesis that IL6-induced modulation of serotonergic neurotransmission through the STAT3 signaling pathway contributes to the role of IL6 in depression. Addition of IL6 to JAR cells, endogenously expressing SERT, reduced SERT activity and downregulated SERT mRNA and protein levels. Similarly, SERT expression was reduced upon IL6 treatment in the mouse hippocampus. Conversely, hippocampal tissue of IL6-KO mice contained elevated levels of SERT and IL6-KO mice displayed a reduction in depression-like behavior and blunted response to acute antidepressant treatment. STAT3 IL6-dependently associated with the SERT promoter and inhibition of STAT3 blocked the effect of IL6 in-vitro and modulated depression-like behavior in-vivo. These observations demonstrate that IL6 directly controls SERT levels and consequently serotonin reuptake and identify STAT3-dependent regulation of SERT as conceivable neurobiological substrate for the involvement of IL6 in depression.(VLID)491089