Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function

Understanding the relation between energy consumption and development during the Global Financial Crisis in Europe

The 28 states of the European Union are addressing considerable effort to reduce their current national energy consumption levels. A new environmental and socially low impact energy system, based on energy consumption reductions, an increase in energy efficiency and reductions of emissions shifting to renewable energy generation are established in all European countries ́ National Energy Efficiency Action Plans. The main goal of country policies to reduce energy consumption, while still increasing the national development level. Within this context, the Global Financial Crisis that especially impacted the European Union in 2009, a new opportunity emerged to analyse the relation between Human Development Index and the energy consumption of a country. In this study, the capacity of the European countries to reduce their energy consumption and the capacity to maintain their development standards have been analysed, based on the Total Primary Energy Supply as well as on the Total Primary Energy Footprint. The former has been provided by the International Energy Agency and the later has been calculated by using Global Multi-Regional Input-Output methodology. The results provide relevant insights towards understanding how a crisis context could be an opportunity in terms of becoming less energy intensive while still maintaining an upward trend for the development indicators of the country

Electricity demand with electric cars in 2030: comparing Great Britain and Spain

The effect of domestic charging of electric vehicles (EVs) on electricity demand at a national level was addressed. A study case was created to investigate how different charging regimes (i.e. control policies) and EV-uptake levels will affect the electricity demand of Great Britain (GB) and Spain in 2030. Charging rates, battery capacities, and battery and charger efficiencies were drawn from literature. Traffic patterns were acquired from the British Department for Transport and the Spanish Ministry of Public Works. Uncontrolled, dual tariff (time-based control), dynamic price (price-based control) domestic charging regimes were defined and applied to both power systems for different EV utilization levels. The results show that for low EV utilization, the GB system would be able to cope with the increased demand that EV domestic charging would create. The Spanish system would need additional generation to cover the EV charging needs. The anticipated high EV utilization would almost double peak the demand in both countries

Contributions of bottom-up energy transitions in Germany: A case study analysis

Within the context of an energy transition towards achieving a renewable low-impact energy consumption system, this study analyses how bottom-up initiatives can contribute to state driven top-down efforts to achieve the sustainability related goals of (1) reducing total primary energy consumption; (2) reducing residential electricity and heat consumption; and (3) increasing generated renewable energy and even attaining self-sufficiency. After identifying the three most cited German bottom-up energy transition cases, the initiatives have been qualitatively and quantitatively analysed. The case study methodology has been used and each initiative has been examined in order to assess and compare these with the German national panorama. The novel results of the analysis demonstrate the remarkable effects of communal living, cooperative investment and participatory processes on the creation of a new sustainable energy system. The study supports the claim that bottom-up initiatives could also contribute to energy sustainability goals together within the state driven plans. Furthermore, the research proves that the analysed bottom-up transitions are not only environmentally and socially beneficial but they can also be economically feasible, at least in a small scale, such as the current German national top-down energy policy panorama

Discovery of a possible Well-being Turning Point within energy footprint accounts which may support the degrowth theory

The former consensus on a link between energy consumption and improved well-being of a country has been scrutinized by scholars for decades and is, succinctly, for the time being a contested thesis. Until the 1970s the relation of energy to well-being was defined as linearly proportional, and in a later period still as an increasing logarithmic function. Recent empirical research falsified the assumption of an overt link between well-being and increased energy consumption in countries with high per-capita energy usage. Going forward, our research shows for the first time a possible proof for a negative correlation between energy consumption and well-being after a Well-being Turning Point (WTP). We used a world data set, not limited to high-income countries but including 176 nations with available data sets. Our findings could support both the logarithmic growth of well-being together with energy, as well as the contradicting saturation theses supporting degrowth, and thus opens the discussion in all directions. In this paper Energy Footprint data within Eora database and Global Multi Regional Input Output methodology have been calculated, which includes also the energy embodied in imported/exported products and services (also known as consumption-based energy accounts). The use of footprint accounts has been demonstrated in our previous research to be necessary when analysing global energy consumption trends; as it records the energy consumption reality better than the usually used Total Primary Energy Supply which is provided by the International Energy Agency. In this paper, we provide in a novel way, some statistical support for an Energy WTP, i.e. a high-energy threshold after which a further consumption increase results in a reduced Human Development Index. We tested our results for possible biases (e.g. excluding outlier countries and including a factor for considering the weight of high population countries) and concluded that a WTP is one possible interpretation of the data. Thus, we would like to open a discussion about how energy consumption could end up having a negative effect on well-being, considering its indirect impacts in citizens of a country

Hidden Energy Flow indicator to reflect the outsourced energy requirements of countries

Globalisation and the outsourcing of industrial manufacturing from developed to less developed countries has an increasing effect on the national energy balances of most developed economies. The current standard metric Total Primary Energy Supply of a country does not take into account the energy embodied in goods and services imported from other countries, leading to the perverse outcome of a country appearing to be more sustainable the more it outsources its energy-intensive industries. Academia has addressed this problem by suggesting the use of the Total Primary Energy Footprint as an additional metric, but there has not been a clear proposal put forward by academia to governments or international institutions about how to officially adopt Consumption-Based Accounting in the field of energy. This article states that acknowledging the existence of embodied energy flows is indispensable when formulating new national and international energy policies for the transition towards energy systems that are socially and environmentally more sustainable. In this study, the Hidden Energy Flow indicator of 44 countries has been quantified using, for the first time, five different Global Multi-Regional Input-Output databases for the latest available year, 2011. The proposed indicator provides a percentage to be added to or subtracted from the Total Primary Energy Used value of a country, provided by the International Energy Agency, to get its real consumption-based energy requirement. This study demonstrates that, from 44 countries analysed, the ten most developed countries demand on average 18.5% more energy than measured by the International Energy Agency; the medium developed 24 countries demand 12.4% more, and the ten least developed countries demand 1.6% less. This means that most developed and medium developed countries displace their indirect energy consumption towards less developed countries in a hidden way. Furthermore, this research supports evidence that direct energy consumption in households is less relevant than the energy embodied in goods and services purchased by households, reaching 59.1% in the case of Switzerland, used as a reference among developed countries. The proposed Hidden Energy Flow indicator supports scientists, policymakers and citizens in the effort to focus the energy transition actions towards conducting the necessary energy consumption and production changes in the most effective way, improving energy justice and energy democracy

PPARβ Interprets a Chromatin Signature of Pluripotency to Promote Embryonic Differentiation at Gastrulation.

Epigenetic post-transcriptional modifications of histone tails are thought to help in coordinating gene expression during development. An epigenetic signature is set in pluripotent cells and interpreted later at the onset of differentiation. In pluripotent cells, epigenetic marks normally associated with active genes (H3K4me3) and with silent genes (H3K27me3) atypically co-occupy chromatin regions surrounding the promoters of important developmental genes. However, it is unclear how these epigenetic marks are recognized when cell differentiation starts and what precise role they play. Here, we report the essential role of the nuclear receptor peroxisome proliferator-activated receptor β (PPARβ, NR1C2) in Xenopus laevis early development. By combining loss-of-function approaches, large throughput transcript expression analysis by the mean of RNA-seq and intensive chromatin immunoprecipitation experiments, we unveil an important cooperation between epigenetic marks and PPARβ. During Xenopus laevis gastrulation PPARβ recognizes H3K27me3 marks that have been deposited earlier at the pluripotent stage to activate early differentiation genes. Thus, PPARβis the first identified transcription factor that interprets an epigenetic signature of pluripotency, in vivo, during embryonic development. This work paves the way for a better mechanistic understanding of how the activation of hundreds of genes is coordinated during early development