Determining countries’ tax effort.

This paper presents a model to determine the tax effort and tax capacity of 96 countries and the main variables from which they depend. The results and the model allow us to clearly determine which countries are near their tax capacity and which are some way from it, and therefore, could increase their tax revenue. Our study corroborates previous analysis inasmuch as the positive and significant relationship between tax revenue as percent of GDP and the level of development (per capita GDP), trade (imports and exports as percent of GDP) and education (public expenditure on education as percent of GDP). The study also demonstrates the negative relationship between tax revenue and inflation (CPI), income distribution (GINI coefficient), the ease of tax collection (agricultural sector value added as GDP percent), and corruption.tax effort, tax frontier, tax capacity, tax revenue, stochastic tax frontier, inefficiency.

Asparaginase-based antibody Drug Conjugates

L-Asparaginase (ASNase, EC 3.5.1.1) is a key component of the established combined chemotherapy used for the treatment of pediatric acute lymphoblastic leukemia, having significantly increased the percentage of complete remissions in patients since its introduction in 1970s. The benefit of ASNase treatment is supported by extensive clinical data, while resistance to asparaginase is correlated with poor prognosis. ASNase is an amidohydrolase which shows a prevalent asparaginolytic and a secondary glutaminolytic activity; its therapeutic benefit comes from the depletion of asparagine from the blood stream, on which leukemic cells depends, given their absent or compromised capability to express asparagine synthetase (EC 6.3.5.4) under stress conditions. The ASNase molecules currently used in the clinics are derived from either E. coli (EcAII) or E. chrysanthemi, with the first line drug being PEG-Asparaginase (Oncaspar ®). However, most of the available ASNase products lack optimal pharmaceutical features, in particular because of ASNase high toxicity, due to its untargeted activity; high immunogenicity, due to its bacterial origin and large size; short blood serum half-life, and poor efficacy in specific sub-classes of patients (high risk). The aim of this work was to address these limitations, in order to improve EcAII efficacy, and in particular its high toxicity, on one side, by targeting the drug onto leukemic cells, and its high immunogenicity, on the other side, by miniaturizing the drug. It is expected that tackling these two points should also help to increase the drug efficacy in the treatment of high-risk patients. The adopted strategy consisted in the design of a radically new, anti-CD19 Asparaginase-based Antibody Drug Conjugate (ADC), which was conceived by our research group after the successful engineering of a single domain antibody (sdAb) with asparagynolitic activity, obtained through the rational transfer of E. coli type II asparaginase catalytic residues onto a camelid sdAb backbone (sdASNase) (PATENT# E0115946). The addition of a targeting domain nanobody to the catalytic sdASNase lead to the new concept of Targeted Catalytic Nanobodies (TCANs).In particular, the molecule designed in this work (TCAN3) was composed by a newly selected anti-CD19 nanobody (targeting domain) and by the catalytic sdASNase nanobody (catalytic domain). In order to produce such molecule, several steps were followed. Firstly, the extracellular domain of CD19 was expressed as a C-terminal fusion with the human Fc fragment. For the selection of targeting nanobodies, the Phage Display technique was set up in house, but, due to obstacles encountered in both recombinant CD19 purification and classical Phage Display selection, the Yeast Two Hybrid system was chosen as an alternative strategy for the screening of anti-CD19 intracellular nanobodies. The collaboration with the group of Prof. Cattaneo (SNS, Pisa) resulted in the successful isolation of a nanobody, whose binding to CD19 was confirmed through ELISA tests. The TCAN3 was then assembled joining the selected anti-CD19 nanobody targeting domain to the available sdASNase nanobody through a linker. The TCAN3 was then expressed and purified, and its binding to CD19 was confirmed through ELISA tests. In the meantime, preliminary tests for co-localization studies of CD19 and lysosomes were set up. In conclusion, in this work, TCAN3, a promising targeted asparaginase-based molecule which could help in leukemia therapy, and especially in high-risk forms, was designed and expressed. TCANs, focusing for the first time on the specificity of the metabolic traits of a given tumor and coupling the correct catalytic activity to the appropriate target specificity,might potentially represent a novel general approach to tackle any type of cancer which shows sensitivity to a specific metabolite deprivation

Improved split fluorescent proteins for endogenous protein labeling.

Self-complementing split fluorescent proteins (FPs) have been widely used for protein labeling, visualization of subcellular protein localization, and detection of cell-cell contact. To expand this toolset, we have developed a screening strategy for the direct engineering of self-complementing split FPs. Via this strategy, we have generated a yellow-green split-mNeonGreen21-10/11 that improves the ratio of complemented signal to the background of FP1-10-expressing cells compared to the commonly used split GFP1-10/11; as well as a 10-fold brighter red-colored split-sfCherry21-10/11. Based on split sfCherry2, we have engineered a photoactivatable variant that enables single-molecule localization-based super-resolution microscopy. We have demonstrated dual-color endogenous protein tagging with sfCherry211 and GFP11, revealing that endoplasmic reticulum translocon complex Sec61B has reduced abundance in certain peripheral tubules. These new split FPs not only offer multiple colors for imaging interaction networks of endogenous proteins, but also hold the potential to provide orthogonal handles for biochemical isolation of native protein complexes.Split fluorescent proteins (FPs) have been widely used to visualise proteins in cells. Here the authors develop a screen for engineering new split FPs, and report a yellow-green split-mNeonGreen2 with reduced background, a red split-sfCherry2 for multicolour labeling, and its photoactivatable variant for super-resolution use

La efectividad de las redes de protección social: El rol de los sistemas integrados de información social en Argentina

Este trabajo es parte de una serie de estudios realizados en el marco del proyecto: “La efectividad de las redes de protección social: El rol de los sistemas integrados de información social”. Los estudios de caso fueron realizados en el período 2007-08. Se agradecen los comentarios de Ignacio Irarrázaval y Viviane Azevedo.

Functional selectivity of GPCR-directed drug action through location bias.

G-protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The β 2 -adrenergic GPCR can activate G s -linked cyclic AMP (G s -cAMP) signaling from endosomes. We show here that the homologous human β 1 -adrenergic receptor initiates an internal G s -cAMP signal from the Golgi apparatus. By developing a chemical method to acutely squelch G-protein coupling at defined membrane locations, we demonstrate that Golgi activation contributes significantly to the overall cellular cAMP response. Golgi signaling utilizes a preexisting receptor pool rather than receptors delivered from the cell surface, requiring separate access of extracellular ligands. Epinephrine, a hydrophilic endogenous ligand, accesses the Golgi-localized receptor pool by facilitated transport requiring the organic cation transporter 3 (OCT3), whereas drugs can access the Golgi pool by passive diffusion according to hydrophobicity. We demonstrate marked differences, among both agonist and antagonist drugs, in Golgi-localized receptor access and show that β-blocker drugs currently used in the clinic differ markedly in ability to antagonize the Golgi signal. We propose \u27location bias\u27 as a new principle for achieving functional selectivity of GPCR-directed drug action

Fiscal policy, income redistribution, and poverty reduction in Latin America

This paper uses standard fiscal incidence analysis to study how much income redistribution and poverty reduction are accomplished through the fiscal system in eighteen Latin American and Caribbean (LAC) countries. We show there is considerable heterogeneity in the income inequality and poverty-reducing power of LAC fiscal systems. While all LAC fiscal systems reduce income inequality, fiscal systems in nine LAC countries are poverty-increasing, and this startling characteristic has not improved over time. When analyzing specific fiscal elements, we find that direct taxes, direct transfers, and in-kind transfers are all equalizing, and spending on education and health is often pro-poor. Moreover, contrary to expectations, indirect taxes and subsidies are more frequently equalizing than unequalizing

Distributional effects of taxation in Latin America

This chapter analyzes the incidence on income distribution by a comprehensive array of direct and indirect taxes in ten Latin American countries circa 2018. The study finds that although there is a significant heterogeneity, the redistributive impact is equalizing for direct taxes and unequalizing for indirect taxes. Overall, redistribution through taxes, without accounting for spending effects and interactions, is slightly equalizing for some countries and unequalizing for others, but the burden on the poor is high and even higher than on the rich. This is mainly a consequence of the high share of indirect taxes in the tax structures, and of low personal income tax collection and coverage. The inclusion of the redistributive effect of the corporate income tax contributes to improve redistribution and accounts for better comparison with the redistributive impact in more developed countries, where dividends are taxed heavily with personal income taxes rather than corporate income taxes as in Latin America. High levels of evasion and informality make payroll taxes more regressive in integrated labor markets with high informality, but make indirect taxes less regressive, since the poor pay little or no indirect taxes on some of their purchases