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

CK2 Phosphorylates Sec31 and Regulates ER-To-Golgi Trafficking

Protein export from the endoplasmic reticulum (ER) is an initial and rate-limiting step of molecular trafficking and secretion. This is mediated by coat protein II (COPII)-coated vesicles, whose formation requires small GTPase Sar1 and 6 Sec proteins including Sec23 and Sec31. Sec31 is a component of the outer layer of COPII coat and has been identified as a phosphoprotein. The initiation and promotion of COPII vesicle formation is regulated by Sar1; however, the mechanism regulating the completion of COPII vesicle formation followed by vesicle release is largely unknown. Hypothesizing that the Sec31 phosphorylation may be such a mechanism, we identified phosphorylation sites in the middle linker region of Sec31. Sec31 phosphorylation appeared to decrease its association with ER membranes and Sec23. Non-phosphorylatable mutant of Sec31 stayed longer at ER exit sites and bound more strongly to Sec23. We also found that CK2 is one of the kinases responsible for Sec31 phosphorylation because CK2 knockdown decreased Sec31 phosphorylation, whereas CK2 overexpression increased Sec31 phosphorylation. Furthermore, CK2 knockdown increased affinity of Sec31 for Sec23 and inhibited ER-to-Golgi trafficking. These results suggest that Sec31 phosphorylation by CK2 controls the duration of COPII vesicle formation, which regulates ER-to-Golgi trafficking

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

Heart Sound Analysis Using MFCC and Time Frequency Distribution

This paper presents heart sound analysis method based on Time-Frequency Distribution (TFD) analysis and Mel Frequency Cepstrum Coefficient (MFCC). TFD represents the heart sound in term of time and frequency simultaneously which while the MFCC defines a signal in term of frequency coefficient corresponding to the Mel filter scale. There are 100 normal data and 100 data with disease obtained from the hospital which consists of various kinds of problems including mitral regurgitation and stenosis, tricuspid regurgitation and stenosis, ventricular septal defect and other structural related disease. B-Distribution is chosen from a number of time-frequency analysis methods due its capability to represent the signal in the most efficient way in term of noise and cross term reduction. The advantage of MFCC is that it is good in error reduction and able to produce a robust feature when the signal is affected by noise. SVD/PCA technique is used to extract the important features out of the B-Distribution representation. The coefficient obtained from SVD-PCA and MFCC is later used for classification Artificial Neural Network. The results show that the system is able to produce the accuracy up to 90.0% using the TFD and 80.0% using the MFCC

Renyi entropy of quadratic time-frequency distributions: effects of signal’s parameters

The Renyi Entropy (ER) of a time-frequency distribution (TFD) has been used for estimating the signal information content and the TFD complexity in the time-frequency (TF) plane. In this paper we provide an experimental comparison of the performance of ER obtained from Wigner-Ville distribution (WVD), Spectrogram (SP), Choi-William Distribution (CWD), Born-Jordan Distribution (BJD) and Modified B Distribution (MBD). The performances are tested on two component Gabor logon and LFM signals with the goal of illustrating the effects on ER obtained from different TFDs when signalpsilas TF parameters varies. The presented analysis shows that high-resolution TFDs, such as the MBD, result into consistent ER measures

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