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Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases. A structure-based design allows the development of a potent PROTAC to degrade BAF ATPase subunits SMARCA2 and SMARCA4 via recruitment of E3 ubiquitin ligase VHL and induce cancer cell death.

Esta investigación estima el peso de los sobrecargos que el Fondo Monetario Internacional (FMI) espera cobrar a los países deudores de medianos ingresos durante 2023-2033. La evidencia indica que los sobrecargos no logran su supuesto objetivo de incentivar el pago anticipado de las deudas; en cambio, incrementan el peso de la deuda de los prestatarios de medianos ingresos que precisamente enfrentan los problemas más graves de balanza de pago, mientras que el FMI se beneficia de estas crisis.

On June 30, President Trump signed an executive order terminating the majority of US sanctions on Syria. The move, which would have been unthinkable mere months ago, fulfilled a promise he made at an investment forum in Riyadh in May. \"The sanctions were brutal and crippling,\" he had declared to an audience of primarily Saudi businessmen. Lifting them, he said, will \"give Syria a chance at greatness.\" The significance of this statement lies not solely in the relief that it will bring to the Syrian people. His remarks revealed an implicit but rarely admitted truth: sanctions--often presented as a peaceful alternative to war--have been harming the Syrian people all along. It is difficult to deny the extent of Syria's economic devastation. The size of Syria's economy more than halved between 2010 and 2022. Around 70 percent of Syrians live in poverty, and half the population is food insecure.

This research estimates the weight of surcharges that the International Monetary Fund (IMF) expects to levy on middle-income borrowing countries during the 2023-2033 period. The evidence indicates that surcharges do not achieve their alleged objective of encouraging early debt repayment; rather, they increase debt burdens for those middle-income borrowers facing the most acute balance of payment problems, while the IMF profits from these crises. Esta investigación estima el peso de los sobrecargos que el Fondo Monetario Internacional (FMI) espera cobrar a los países deudores de medianos ingresos durante 2023-2033. La evidencia indica que los sobrecargos no logran su supuesto objetivo de incentivar el pago anticipado de las deudas; en cambio, incrementan el peso de la deuda de los prestatarios de medianos ingresos que precisamente enfrentan los problemas más graves de balanza de pago, mientras que el FMI se beneficia de estas crisis.

In the version of this article originally published, several lines of text in the last paragraph of the right column on page 1 of the PDF were transposed into the bottom paragraph of the left column. The affected text of the left column should read “The ATP-dependent activities of the BAF (SWI/SNF) chromatin remodeling complexes affect the positioning of nucleosomes on DNA and thereby many cellular processes related to chromatin structure, including transcription, DNA repair and decatenation of chromosomes during mitosis 12,13 .” The affected text of the right column should read “SMARCA2/4 BD inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers but could provide attractive ligands for PROTAC conjugation. Small molecules binding to other bromodomains have been successfully converted into PROTACs by conjugating them with structures capable of binding to the E3 ligases von Hippel−Lindau (VHL) or cereblon 5,6,10,11,25,26,27 .” The errors have been corrected in the PDF version of the paper.

The global economy is collapsing. When the pandemic began, experts at the International Monetary Fund predicted that we would see the worst economic downturn since the Great Depression. This week, they announced that it will be even worse than they thought.This disaster comes into a world already facing record inequality, desperate poverty, and a growing climate crisis. The COVID-19 pandemic has pushed a precarious world economy over the edge. This moment offers a rare opportunity to rethink the path that led us here and chart a new course out: a Global Green New Deal.We have a tendency to treat the global economy as something natural - beyond our control. We understand that poverty, epidemics, and environmental destruction within the United States are not inevitable. There are certain rules in place that benefit some over others. People are not poor because they fail to liftthemselves up by their bootstraps. People are poor because wages are too low, because we don't invest in public goods, because the wealthy are too powerful.

The International Labor Organization adopted a new Convention on workplace harassment. It's time for the United States to ratify.The #MeToo movement started with a single tweet - now, it has produced an international treaty.One in three women have experienced physical or sexual violence in their lifetimes, while close to three in four report having been sexually harassed. Much of this violence occurs in the workplace, where power imbalances and economic pressures increase the risk of abuse. Yet 59 countries have no legislation specifically addressing workplace harassment.This June, the International Labor Organization (ILO) - the United Nations agency for workers' rights - took a historic step to close this gap. In a landslide vote of 439 to 7, the ILO adopted the legally binding Convention Concerning the Elimination of Violence and Harassment in the World of Work, as well as a non-binding recommendation that builds out the details.

The International Labour Organization (ILO) is celebrating its 100th anniversary this June. In the wake of a devastating world war, its mission was transformational: to realize social justice and the rights of workers everywhere.But now, 100 years later, exploitative working conditions remain the norm, more people than ever live in poverty, and the richest 1 percent are on track to own two-thirds of all global wealth in a decade. While no single policy could solve these problems entirely, one in particular would be a decisive step forward.At its centenary conference, the ILO should call for a global minimum wage.A recent global poll from the International Trade Union Confederation found that an overwhelming 84 percent of all respondents judged their national minimum wage to be insufficient for a decent life. A global minimum wage - not uniform across countries, but based on a common formula for a living wage - would raise millions out of poverty by ensuring all workers the resources necessary for a decent quality of life. But the real potential of a global minimum wage lies in its capacity to correct a dynamic that has, for decades, been eating away at the power and wellbeing of workers everywhere: the global race to the bottom.

One year ago, the UK Labour party released its guiding manifesto on international development.Written by then Shadow Secretary of State for International Development Kate Osamor, the brief, accessible manifesto overturns the dominant neoliberal development model and replaces it with a bold, progressive vision of \"A World For The Many, Not The Few.\"Though far from perfect, A World For The Many is an extraordinary document to come from the largest political party in western Europe. As Democratic presidential hopefuls stake out their own policy positions and fight to prove their progressive credentials, they would do well to consult the Labour manifesto.There has long been a bipartisan consensus on international development. Development policy is about stimulating private sector-led economic growth. This is achieved through private investment, charitable aid, and pressure to adopt \"Washington Consensus\" policies of austerity, privatization, and market fundamentalism.