Should I stay or should I go

Rapid migration flows into urban and peri-urban areas will be an on-going driver of the economic transformation that drives Ghana’s economy forward. Recognising this, policies that support better management of urbanisation will have to ensure improved services, transportation, and housing for growing urban populations

Social Security and Labour Supply: the Italian 1992 Reform as a Natural Experiment

This paper provides new evidence about the effects of economic incentives embedded in the Italian Social Security system on retirement decisions. The 1992 reform is an interesting example since it was implemented when: (a) the system was very generous to retirees; (b) the demographic context was dramatic;(c) an early retirement provision, and no actuarial fairness, distorted retirement choices. I use the reform as a natural experiment and exploit its differential effect on individuals belonging to different groups, namely blue- and white-collar workers. I find evidence that Social Security wealth has a larger impact on retirement choices compared to estimates in previous studies

Pathways from school to work in the developing world

This paper uses novel micro data from the ILO-STWT surveys to provide evidence on the duration, endpoint, and determinants of the transition from school to work in a sample of 23 low- and middle-income countries around the world. The paper analyzes both transition to the first job and to the first stable job. It also illustrates the effects of several correlates, including age of school leaving, gender, work while attending school, and others on the probability of transition and on its duration. The negative effects of low levels of human capital and high levels of population growth on job finding rates are offset by widespread poverty and lack of unemployment insurance, which lead overall to faster transitions in low-income compared to middle-income economies. By lowering reservation wages and speeding transitions, however, these forces lead to worse matches, as measured by the probability of attaining stable employment in the long run, highlighting the trade-off that policy makers face in developing countrie

Social Security and Labour Supply: the Italian 1992 Reform as a Natural Experiment

This paper provides new evidence about the effects of economic incentives embedded in the Italian Social Security system on retirement decisions. The 1992 reform is an interesting example since it was implemented when: (a) the system was very generous to retirees; (b) the demographic context was dramatic;(c) an early retirement provision, and no actuarial fairness, distorted retirement choices. I use the reform as a natural experiment and exploit its differential effect on individuals belonging to different groups, namely blue- and white-collar workers. I find evidence that Social Security wealth has a larger impact on retirement choices compared to estimates in previous studies

An Acidic Loop and Cognate Phosphorylation Sites Define a Molecular Switch That Modulates Ubiquitin Charging Activity in Cdc34-Like Enzymes

E2 ubiquitin-conjugating enzymes are crucial mediators of protein ubiquitination, which strongly influence the ultimate fate of the target substrates. Recently, it has been shown that the activity of several enzymes of the ubiquitination pathway is finely tuned by phosphorylation, an ubiquitous mechanism for cellular regulation, which modulates protein conformation. In this contribution, we provide the first rationale, at the molecular level, of the regulatory mechanism mediated by casein kinase 2 (CK2) phosphorylation of E2 Cdc34-like enzymes. In particular, we identify two co-evolving signature elements in one of the larger families of E2 enzymes: an acidic insertion in β4α2 loop in the proximity of the catalytic cysteine and two conserved key serine residues within the catalytic domain, which are phosphorylated by CK2. Our investigations, using yeast Cdc34 as a model, through 2.5 µs molecular dynamics simulations and biochemical assays, define these two elements as an important phosphorylation-controlled switch that modulates opening and closing of the catalytic cleft. The mechanism relies on electrostatic repulsions between a conserved serine phosphorylated by CK2 and the acidic residues of the β4α2 loop, promoting E2 ubiquitin charging activity. Our investigation identifies a new and unexpected pivotal role for the acidic loop, providing the first evidence that this loop is crucial not only for downstream events related to ubiquitin chain assembly, but is also mandatory for the modulation of an upstream crucial step of the ubiquitin pathway: the ubiquitin charging in the E2 catalytic cleft

Consequences of the 118A>G polymorphism in the OPRMI gene: Translation from bench to bedside?

The 118A>G single nucleotide polymorphism (SNP) in the μ-opioid receptor (OPRM1) gene has been the most described variant in pharmacogenetic studies regarding opioid drugs. Despite evidence for an altered biological function encoded by this variant, this knowledge is not yet utilized clinically. The aim of the present review was to collect and discuss the available information on the 118A>G SNP in the OPRM1 gene, at the molecular level and in its clinical manifestations. In vitro biochemical and molecular assays have shown that the variant receptor has higher binding affinity for β-endorphins, that it has altered signal transduction cascade, and that it has a lower expression compared with wild-type OPRM1. Studies using animal models for 118A>G have revealed a double effect of the variant receptor, with an apparent gain of function with respect to the response to endogenous opioids but a loss of function with exogenous administered opioid drugs. Although patients with this variant have shown a lower pain threshold and a higher drug consumption in order to achieve the analgesic effect, clinical experiences have demonstrated that patients carrying the variant allele are not affected by the increased opioid consumption in terms of side effects

The coding and long noncoding single-cell atlas of the developing human fetal striatum.

Deciphering how the human striatum develops is necessary for understanding the diseases that affect this region. To decode the transcriptional modules that regulate this structure during development, we compiled a catalog of 1116 long intergenic noncoding RNAs (lincRNAs) identified de novo and then profiled 96,789 single cells from the early human fetal striatum. We found that D1 and D2 medium spiny neurons (D1- and D2-MSNs) arise from a common progenitor and that lineage commitment is established during the postmitotic transition, across a pre-MSN phase that exhibits a continuous spectrum of fate determinants. We then uncovered cell type-specific gene regulatory networks that we validated through in silico perturbation. Finally, we identified human-specific lincRNAs that contribute to the phylogenetic divergence of this structure in humans. This work delineates the cellular hierarchies governing MSN lineage commitment

Small-molecule Polθ inhibitors provide safe and effective tumor radiosensitization in preclinical models

Purpose: DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy. Experimental Design: We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo. Results: Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone. Conclusions: These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy

Combinatorial CRISPR screen identifies fitness effects of gene paralogues.

Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. Our studies reveal the fitness effects of FAM50A/FAM50B in cancer cells