Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and reroutes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.(F) IF co-staining of distal tubule in MKD patient kidney organoid for MUC1-wt (red), MUC1-fs (green), E-cadherin (blue), and Na + /K + -ATPase (yellow). MUC1-fs localized intracellularly (middle) compared to apical MUC1-wt (left). (G) IF co-staining in P cells for MUC1-fs (green), MUC1-wt (red), and Hoechst (gray). MUC1-fs localized intracellularly (middle) compared to MUC1-wt on the plasma membrane (left). See also Figures S1, S2, and S3 and Table S1.

The Philippines has placed a strong emphasis on achieving Universal Health Coverage. In recent years, earmarked funds from new alcohol and tobacco taxes have substantially increased government funds available for health. This additional funding offers great potential to improve access and health outcomes, as long as the money is well spent. An important pre-requisite for effective spending is a strong budgetary process for health. In terms of budget formulation and planning, the Philippines government has -at the national level -introduced a comprehensive package of public financial management reforms that apply across all sectors. These have helped to measure results better and link the budget formulation process to the Medium-Term Philippine Development Plan. However, the responsibility for health care budgets in the Philippines is largely devolved to local governments and at the local government unit level there is only a weak link between the local health budget, and strategic plans and targets. Further, the complex relationship between national and local government makes aligning planning and budget formulation difficult. The Philippines government also faces important challenges in budget execution, with under-execution a common problem. Finally, several performance monitoring and evaluation mechanisms exist at the national and local levels. While commendable, to maximise their impact these should better feed into the budget decision-making process.

Ecuador became the third largest receiver of the 4.3 million Venezuelans who left their country in the last five years, hosting around 10 per cent of them. Little is known about the characteristics of these migrants and their labor market outcomes. This article fills this gap by analyzing a new large survey (EPEC). On average, Venezuelan workers are highly skilled and have high rates of employment, compared with Ecuadorans. However, their employment is of much lower quality, characterized by low wages, and high rates of informality and temporality. Venezuelans have experienced significant occupational downgrading, relative to their employment prior to emigration. As a result, despite their high educational attainment, Venezuelans primarily compete for jobs with the least skilled and more economically vulnerable Ecuadoran workers. Our simulations suggest that measures that allow Venezuelans to obtain employment that matches their skills, such as facilitating the conversion of education credentials, would increase Ecuador’s GDP between 1.6 and 1.9 per cent and alleviate the pressure on disadvantaged native workers. We also show that providing work permits to Venezuelan workers would substantially reduce their rates of informality and increase their average earnings.