How Meaningful is the Elite Quality Index Ranking?

The Elite Quality Index (EQx) attempts to measure the propensity of elites-on aggregate-to create value, rather than to rent seek. The index has attracted worldwide media and press attention. In their articles, journalists have based their analyses primarily on their own countries' position in the EQx ranking. But how meaningful is the EQx ranking? How do the uncertainties underlying some of the assumptions made in the index propagate to the country rankings? We conduct a global uncertainty and sensitivity analysis (UA and SA) of the EQx and compute Sobol' first and total order sensitivity indices using state of the art estimators, in order to scrutinise the implications of index assumptions and assess the reliability of the EQx ranking. The UA suggests that the EQx ranking of 2021 (EQx2021) is largely stable for the top 50 countries, but exhibits considerable uncertainties especially for middle and lower performing countries. The SA highlights the handling of missing data, the normalisation process and the weighting scheme as most important methodological choices, while the largest potential for improvement is observed in how raw missing indicator data is handled.

Transcriptional Regulation of the Glutamate/GABA/Glutamine Cycle in Adult Glia Controls Motor Activity and Seizures in Drosophila.

The fruitfly Drosophila melanogaster has been extensively used as a genetic model for the maintenance of nervous system's functions. Glial cells are of utmost importance in regulating the neuronal functions in the adult organism and in the progression of neurological pathologies. Through a microRNA-based screen in adult Drosophila glia, we uncovered the essential role of a major glia developmental determinant, repo, in the adult fly. Here, we report that Repo expression is continuously required in adult glia to transcriptionally regulate the highly conserved function of neurotransmitter recycling in both males and females. Transient loss of Repo dramatically shortens fly lifespan, triggers motor deficits, and increases the sensibility to seizures, partly due to the impairment of the glutamate/GABA/glutamine cycle. Our findings highlight the pivotal role of transcriptional regulation of genes involved in the glutamate/GABA/glutamine cycle in glia to control neurotransmitter levels in neurons and their behavioral output. The mechanism identified here in Drosophila exemplifies how adult functions can be modulated at the transcriptional level and suggest an active synchronized regulation of genes involved in the same pathway. The process of neurotransmitter recycling is of essential importance in human epileptic and psychiatric disorders and our findings may thus have important consequences for the understanding of the role that transcriptional regulation of neurotransmitter recycling in astrocytes has in human disease.SIGNIFICANCE STATEMENT Glial cells are an essential support to neurons in adult life and have been involved in a number of neurological disorders. What controls the maintenance and modulation of glial functions in adult life is not fully characterized. Through a miR overexpression screen in adult glia in Drosophila, we identify an essential role in adult glia of repo, which directs glial differentiation during embryonic development. Repo levels modulate, via transcriptional regulation, the ability of glial cells to support neurons in the glutamate/GABA/glutamine cycle. This leads to significant abnormalities in motor behavior as assessed through a novel automated paradigm. Our work points to the importance of transcriptional regulation in adult glia for neurotransmitter recycling, a key process in several human neurological disorders.

Novel mutants of the aubergine gene.

Aubergine is an RNA-binding protein of the Piwi clade, functioning in germline in the piRNA pathway that silences transposons and repetitive sequences. Several mutations of this gene exist, but they mostly result in truncated proteins or correspond to mutations that also affect neighboring genes. We have generated complete aubergine knock-out mutants that do not disrupt the neighboring genes. These novel mutants are characterized by PCR and sequencing. Their nature is confirmed by female sterility and by the presence of crystals in testes, common to the aubergine loss of function mutations. These mutants provide novel and more appropriate tools for the study of the piRNA pathway that controls genome stability.

The Drosophila fragile X mental retardation protein participates in the piRNA pathway.

RNA metabolism controls multiple biological processes, and a specific class of small RNAs, called piRNAs, act as genome guardians by silencing the expression of transposons and repetitive sequences in the gonads. Defects in the piRNA pathway affect genome integrity and fertility. The possible implications in physiopathological mechanisms of human diseases have made the piRNA pathway the object of intense investigation, and recent work suggests that there is a role for this pathway in somatic processes including synaptic plasticity. The RNA-binding fragile X mental retardation protein (FMRP, also known as FMR1) controls translation and its loss triggers the most frequent syndromic form of mental retardation as well as gonadal defects in humans. Here, we demonstrate for the first time that germline, as well as somatic expression, of Drosophila Fmr1 (denoted dFmr1), the Drosophila ortholog of FMRP, are necessary in a pathway mediated by piRNAs. Moreover, dFmr1 interacts genetically and biochemically with Aubergine, an Argonaute protein and a key player in this pathway. Our data provide novel perspectives for understanding the phenotypes observed in Fragile X patients and support the view that piRNAs might be at work in the nervous system.

Polycomb controls gliogenesis by regulating the transient expression of the Gcm/Glide fate determinant.

The Gcm/Glide transcription factor is transiently expressed and required in the Drosophila nervous system. Threshold Gcm/Glide levels control the glial versus neuronal fate choice, and its perdurance triggers excessive gliogenesis, showing that its tight and dynamic regulation ensures the proper balance between neurons and glia. Here, we present a genetic screen for potential gcm/glide interactors and identify genes encoding chromatin factors of the Trithorax and of the Polycomb groups. These proteins maintain the heritable epigenetic state, among others, of HOX genes throughout development, but their regulatory role on transiently expressed genes remains elusive. Here we show that Polycomb negatively affects Gcm/Glide autoregulation, a positive feedback loop that allows timely accumulation of Gcm/Glide threshold levels. Such temporal fine-tuning of gene expression tightly controls gliogenesis. This work performed at the levels of individual cells reveals an undescribed mode of Polycomb action in the modulation of transiently expressed fate determinants and hence in the acquisition of specific cell identity in the nervous system.

CYFIP dependent actin remodeling controls specific aspects of Drosophila eye morphogenesis.

Cell rearrangements shape organs and organisms using molecular pathways and cellular processes that are still poorly understood. Here we investigate the role of the Actin cytoskeleton in the formation of the Drosophila compound eye, which requires extensive remodeling and coordination between different cell types. We show that CYFIP/Sra-1, a member of the WAVE/SCAR complex and regulator of Actin remodeling, controls specific aspects of eye architecture: rhabdomere extension, rhabdomere terminal web organization, adherens junctions, retina depth and basement membrane integrity. We demonstrate that some phenotypes manifest independently, due to defects in different cell types. Mutations in WAVE/SCAR and in ARP2/3 complex subunits but not in WASP, another major regulator of Actin nucleation, phenocopy CYFIP defects. Thus, the CYFIP-SCAR-ARP2/3 pathway orchestrates specific tissue remodeling processes.

A novel role of the glial fate determinant glial cells missing in hematopoiesis.

Glial cell deficient/Glial cells missing (Glide/Gcm) transcription factor is expressed in all glial precursors of the Drosophila embryo. Gcm is necessary and sufficient to induce glial differentiation but also plays a role in other cell types, by interacting with specific factors. To find potential partners of Gcm which trigger these other pathways, we performed a yeast two-hybrid screen and identified dpias, a gene involved in post-embryonic hematopoiesis. dpias larvae show melanotic tumors due to excess of lamellocytes, a hemocyte lineage that is involved in non-self recognition. We here show that blocking Gcm activity also triggers melanotic tumors and that gcm interacts genetically with dpias. Moreover, the members of the Janus Kinase (JAK)/ Signal Transducer and Activator of Transcription (STAT) pathway, which are known for their role in the vertebrate and invertebrate immune system and are required for dpias-dependent tumor formation, act downstream of Gcm. Altogether, this study identifies an unpredicted role of Gcm, dictated by its cofactor dpias, allowing Gcm to act in a specific pathway. Together with the recent finding that glia act as scavengers during development and in pathological conditions, our data open new perspectives onto the cellular and molecular pathways involved in non-self recognition within and outside the nervous system.

WAVE/SCAR, a multifunctional complex coordinating different aspects of neuronal connectivity.

Although it is well established that the WAVE/SCAR complex transduces Rac1 signaling to trigger Arp2/3-dependent actin nucleation, regulatory mechanisms of this complex and its versatile function in the nervous system are poorly understood. Here we show that the Drosophila proteins SCAR, CYFIP and Kette, orthologs of WAVE/SCAR complex components, all show strong accumulation in axons of the central nervous system and indeed form a complex in vivo. Neuronal defects of SCAR, CYFIP and Kette mutants are, despite the initially proposed function of CYFIP and Kette as SCAR silencers, indistinguishable and are as diverse as ectopic midline crossing and nerve branching as well as synapse undergrowth at the larval neuromuscular junction. The common phenotypes of the single mutants are readily explained by the finding that loss of any one of the three proteins leads to degradation of its partners. As a consequence, each mutant is unambiguously to be judged as defective in multiple components of the complex even though each component affects different signaling pathways. Indeed, SCAR-Arp2/3 signaling is known to control axonogenesis whereas CYFIP signaling to the Fragile X Mental Retardation Protein fly ortholog contributes to synapse morphology. Thus, our results identify the Drosophila WAVE/SCAR complex as a multifunctional unit orchestrating different pathways and aspects of neuronal connectivity.