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

A Bayesian interpretation of the particle swarm optimization and its kernel extension

Particle swarm optimization is a popular method for solving difficult optimization problems. There have been attempts to formulate the method in formal probabilistic or stochastic terms (e.g. bare bones particle swarm) with the aim to achieve more generality and explain the practical behavior of the method. Here we present a Bayesian interpretation of the particle swarm optimization. This interpretation provides a formal framework for incorporation of prior knowledge about the problem that is being solved. Furthermore, it also allows to extend the particle optimization method through the use of kernel functions that represent the intermediary transformation of the data into a different space where the optimization problem is expected to be easier to be resolved–such transformation can be seen as a form of prior knowledge about the nature of the optimization problem. We derive from the general Bayesian formulation the commonly used particle swarm methods as particular cases

Conflict between Genetic and Phenotypic Differentiation: The Evolutionary History of a ‘Lost and Rediscovered’ Shorebird

Understanding and resolving conflicts between phenotypic and genetic differentiation is central to evolutionary research. While phenotypically monomorphic species may exhibit deep genetic divergences, some morphologically distinct taxa lack notable genetic differentiation. Here we conduct a molecular investigation of an enigmatic shorebird with a convoluted taxonomic history, the White-faced Plover (Charadrius alexandrinus dealbatus), widely regarded as a subspecies of the Kentish Plover (C. alexandrinus). Described as distinct in 1863, its name was consistently misapplied in subsequent decades until taxonomic clarification ensued in 2008. Using a recently proposed test of species delimitation, we reconfirm the phenotypic distinctness of dealbatus. We then compare three mitochondrial and seven nuclear DNA markers among 278 samples of dealbatus and alexandrinus from across their breeding range and four other closely related plovers. We fail to find any population genetic differentiation between dealbatus and alexandrinus, whereas the other species are deeply diverged at the study loci. Kentish Plovers join a small but growing list of species for which low levels of genetic differentiation are accompanied by the presence of strong phenotypic divergence, suggesting that diagnostic phenotypic characters may be encoded by few genes that are difficult to detect. Alternatively, gene expression differences may be crucial in producing different phenotypes whereas neutral differentiation may be lagging behind

Geographic variation in breeding system and environment predicts melanin-based plumage ornamentation of male and female Kentish plovers

Sexual selection determines the elaboration of morphological and behavioural traits and thus drives the evolution of phenotypes. Sexual selection on males and females can differ between populations, especially when populations exhibit different breeding systems. A substantial body of literature describes how breeding systems shape ornamentation across species, with a strong emphasis on male ornamentation and female preference. However, whether breeding system predicts ornamentation within species and whether similar mechanisms as in males also shape the phenotype of females remains unclear. Here, we investigate how different breeding systems are associated with male and female ornamentation in five geographically distinct populations of Kentish plovers Charadrius alexandrinus. We predicted that polygamous populations would exhibit more elaborate ornaments and stronger sexual dimorphism than monogamous populations. By estimating the size and intensity of male (n = 162) and female (n = 174) melanin-based plumage ornaments, i.e. breast bands and ear coverts, we show that plumage ornamentation is predicted by breeding system in both sexes. A difference in especially male ornamentation between polygamous (darker and smaller ornaments) and monogamous (lighter and larger) populations causes the greatest sexual dimorphism to be associated with polygamy. The non-social environment, however, may also influence the degree of ornamentation, for instance through availability of food. We found that, in addition to breeding system, a key environmental parameter, rainfall, predicted a seasonal change of ornamentation in a sex-specific manner. Our results emphasise that to understand the phenotype of animals, it is important to consider both natural and sexual selection acting on both males and females

University student engagement inventory (USEI): psychometric properties

Academic engagement describes students’ investment in academic learning and achievement and is an important indicator of students’ adjustment to university life, particularly in the first year. A tridimensional conceptualization of academic engagement has been accepted (behavioral, emotional and cognitive dimensions). This paper tests the dimensionality, internal consistency reliability and invariance of the University Student Engagement Inventory (USEI) taking into consideration both gender and the scientific area of graduation. A sample of 908 Portuguese first-year university students was considered. Good evidence of reliability has been obtained with ordinal alpha and omega values. Confirmatory factor analysis substantiates the theoretical dimensionality proposed (second-order latent factor), internal consistency reliability evidence indicates good values and the results suggest measurement invariance across gender and the area of graduation. The present study enhances the role of the USEI regarding the lack of consensus on the dimensionality and constructs delimitation of academic engagement.Jorge Sinval received funding from the William James Center for Research, Portuguese Science Foundation (FCT UID/PSI/04810/2013). Leandro S. Almeida and Joana R. Casanova received funding from CIEd – Research Centre on Education, projects UID/CED/1661/2013 and UID/CED/1661/2016, Institute of Education, University of Minho, through national funds of FCT/MCTES-PT. Joana R. Casanova received funding from the Portuguese Science Foundation (FCT) as a Doctoral Grant, under grant agreement number SFRH/BD/117902/2016.info:eu-repo/semantics/publishedVersio

Plasma combustion technology for micro gas turbine using Kuwaiti sheep fat biodiesel

The technology of using only fossil fuel in the operation of a gas turbine engine is facing issues that include low thermal efficiency, poor atomization, low vapour pressure, and high greenhouse gases (GHG). Thus the research motivation is to restructure the design principle of gas turbines for enhancing performance, fuel consumption reduction and GHG emission reduction of a gas turbine. Hence the main objective of this research is to investigate the impact assessment of the plasma combustion technology for a micro gas turbine (MGT) using biodiesel fuel. This is achieved through external integration of hybrid plasma-rich mixture injection at the compressor inlet of the engine system for enhanced combustion of biodiesel fuel through improved thermal efficiency by eight percent. In view of this, the specific objectives are (1) To fabricate, develop and assemble a mini gas turbine (MGT) engine system with an external integrated hybrid Plasma-Torch-Ultrasonic atomizer at the compressor inlet point of the 50kW (67hp) MGT engine in the laboratory. (2) To conduct characterization of Kuwaiti sheep fat biodiesel for the MGT engine operation. (3) To evaluate and validate the combustion performance of the fabricated MGT engine and GHG emission reduction. The methodology involved the design, fabricating and assembling of individual systems (turbo charger, compressor system, ignition system, ultrasound-assisted atomizing system, external integration of hybrid plasma-rich fuel injection at the compressor system, inlet air inlet, oil system, and control unit) for the 50 kW (67hp) MGT test bed in the laboratory. The MGT test bed was meticulously designed with an increase in distance between the inlet of the micro gas turbine engine and plasma torch nozzle and tested for stability with the expansion of the inlet to reduce the speed of air entry. This ensures repeatability, reliability, and accurate data acquisition through in-depth experimental design with output data of components consistent with literature thus fulfilling Objective 1 of this thesis. Secondly, fuel characterization (specific gravity, density, kinematic viscosity, total acid number, water content, total sulfur, flash point, lubricity, cloud point, pour point, calcium and magnesium content was according to the American Society for Testing and Materials (ASTM) standards for six fuels (kerosene, diesel, blends of Kuwaiti sheep fat biodiesel (B20, B50, B75 and B100) performed at the Petroleum Research Center, Kuwait Institute for Scientific Research. Results showed biodiesel has higher kinematic viscosity and density than diesel and kerosene; flash point (B75) closest to kerosene and acid number (B20) value 0.03206 mgKOH/gm in compliance to the ASTM D6751 and EN 14214 standard limits of 0.5 mgKOH/gm that indicates minimal nitrogen and sulphur emissions (less soot). These results show that blended biodiesel is suitable for MGT fuel thus Objective 2 of the thesis is achieved. The MGT engine's general performance for all loading conditions when operated under integrated plasma-rich fuel mixture injection with evaluated results (a) fuel consumption was generally 9% lower than normal conditions higher than pledged value of 1.5% (b) thrust value under normal condition is 1.7 - 4.2 kgf and 1.8 - 4.35 with plasma system (c) achieved average thermal efficiency for biodiesels 15 – 18% higher than 8% as pledged. (d) achieved GHG emissions on average 0.07% for CO; 3% for CO2; 5% for NO; and 10% for NO2. (e) B100 exhibits the highest compressor outlet temperature, highest compressor output pressure and best performance in fuel flow rate suggesting unique but desirable features of biodiesel fuel for MGT. Thus the efficacy of integrated plasma-rich fuel mixture assisted combustion operation is presented that fulfils Objective 3 of the thesis. Therefore, Alternative hypothesis H1 (μo ≠ μ1): Intake integration of hybrid plasma-rich fuel mixture at the compressor inlet of mini gas turbine (MGT) engine with assisted ultrasonic atomiser does improve engine performance and exhaust GHG emissions level control is accepted. The findings of this study can serve as a potential technology for improving the efficiency of fuel combustion and ignition in GT engines. It also presents an efficient way of using sustainable renewable sources of energy (animal fat biodiesel) as a means of reducing GHG emissions level