Governments around the world are responding to the coronavirus disease 2019 (COVID-19) pandemic 1 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with unprecedented policies designed to slow the growth rate of infections. Many policies, such as closing schools and restricting populations to their homes, impose large and visible costs on society; however, their benefits cannot be directly observed and are currently understood only through process-based simulations [2][3][4] . Here we compile data on 1,700 local, regional and national non-pharmaceutical interventions that were deployed in the ongoing pandemic across localities in China, South Korea, Italy, Iran, France and the United States. We then apply reduced-form econometric methods, commonly used to measure the effect of policies on economic growth 5,6 , to empirically evaluate the effect that these anti-contagion policies have had on the growth rate of infections. In the absence of policy actions, we estimate that early infections of COVID-19 exhibit exponential growth rates of approximately 38% per day. We find that anti-contagion policies have significantly and substantially slowed this growth. Some policies have different effects on different populations, but we obtain consistent evidence that the policy packages that were deployed to reduce the rate of transmission achieved large, beneficial and measurable health outcomes. We estimate that across these 6 countries, interventions prevented or delayed on the order of 61 million confirmed cases, corresponding to averting approximately 495 million total infections. These findings may help to inform decisions regarding whether or when these policies should be deployed, intensified or lifted, and they can support policy-making in the more than 180 other countries in which COVID-19 has been reported 7 .The COVID-19 pandemic is forcing societies worldwide to make consequential policy decisions with limited information. After containment of the initial outbreak failed, attention turned to implementing non-pharmaceutical interventions that are designed to slow the contagion of the virus. In general, these policies aim to decrease virus transmission by reducing contact among individuals within or between populations, such as by closing restaurants or restricting travel, thereby slowing the spread of COVID-19 to a manageable rate. These large-scale anti-contagion policies are informed by epidemiological simulations 2,4,8,9 and a small number of natural experiments during past epidemics 10 . However, the actual effects of these policies on infection rates in the ongoing pandemic are unknown. Because the modern world has never confronted this pathogen, nor deployed anti-contagion policies of such scale and scope, it is crucial that direct measurements of the effects of policies are used together with numerical simulations in current decision-making.Societies around the world are considering whether the health benefits of anti-contagion policies are worth their social and economic costs. Many ...

1Governments around the world are responding to the novel coronavirus (COVID-2 19) pandemic 1 with unprecedented policies designed to slow the growth rate of 3 infections. Many actions, such as closing schools and restricting populations to 4 their homes, impose large and visible costs on society, but their benefits cannot 5 be directly observed and are currently understood only through process-based 6 simulations. [2][3][4] Here, we compile new data on 1,717 local, regional, and national 7 non-pharmaceutical interventions deployed in the ongoing pandemic across local-8 ities in China, South Korea, Italy, Iran, France, and the United States (US). We 9 then apply reduced-form econometric methods, commonly used to measure the ef-10 fect of policies on economic growth, 5, 6 to empirically evaluate the effect that these 11 anti-contagion policies have had on the growth rate of infections. In the absence of 12 policy actions, we estimate that early infections of COVID-19 exhibit exponential 13 growth rates of roughly 38% per day. We find that anti-contagion policies have 14 significantly and substantially slowed this growth. Some policies have different 15 impacts on different populations, but we obtain consistent evidence that the pol-16 icy packages now deployed are achieving large, beneficial, and measurable health 17 outcomes. We estimate that across these six countries, interventions prevented 18 or delayed on the order of 62 million confirmed cases, corresponding to averting : medRxiv preprint 23The COVID-19 pandemic is forcing societies worldwide to make consequential policy decisions 24 with limited information. After containment of the initial outbreak failed, attention turned to 25 implementing non-pharmaceutical interventions designed to slow contagion of the virus. In general, 26 these policies aim to decrease virus transmission by reducing contact among individuals within 27 or between populations, such as by closing restaurants or restricting travel, thereby slowing the 28 spread of COVID-19 to a manageable rate. These large-scale anti-contagion policies are informed 29 by epidemiological simulations 2, 4, 8, 9 and a small number of natural experiments in past epidemics. 10 30 However, the actual effects of these policies on infection rates in the ongoing pandemic are unknown. 31Because the modern world has never confronted this pathogen, nor deployed anti-contagion policies 32 of such scale and scope, it is crucial that direct measurements of policy impacts be used alongside 33 numerical simulations in current decision-making. 34Societies around the world are weighing whether the health benefits of anti-contagion policies 35 are worth their social and economic costs. Many of these costs are plainly seen; for example, 36 business restrictions increase unemployment and school closures impact educational outcomes. It is 37 therefore not surprising that some populations have hesitated before implementing such dramatic 38 policies, especially when their costs are visible while their health benefits -infec...

Summary β-adrenergic signaling pathways mediate key aspects of cardiac function. Its dysregulation is associated with a range of cardiac diseases, including dilated cardiomyopathy (DCM). Previously, we established an iPSC model of familial DCM from patients with a mutation in TNNT2, a sarcomeric protein. Here, we found that the β-adrenergic agonist isoproterenol induced mature β-adrenergic signaling in iPSC-derived cardiomyocytes (iPSC-CMs), but that this pathway was blunted in DCM iPSC-CMs. Although expression levels of several β-adrenergic signaling components were unaltered between control and DCM iPSC-CMs, we found that phosphodiesterases (PDE) 2A and PDE3A were upregulated in DCM iPSC-CMs, and that PDE2A was also upregulated in DCM patient tissue. We further discovered increased nuclear localization of mutant TNNT2 and epigenetic modifications of PDE genes in both DCM iPSC-CMs and patient tissue. Notably, pharmacologic inhibition of PDE2A and PDE3A restored cAMP levels and ameliorated the impaired β-adrenergic signaling of in DCM iPSC-CMs, suggesting therapeutic potential.

Summary In familial pulmonary arterial hypertension (FPAH) the autosomal dominant disease-causing BMPR2 mutation is only 20% penetrant, suggesting that genetic variation provides modifiers that alleviate the disease. Here, we used comparison of induced pluripotent stem cell derived endothelial cells (iPSC-ECs) from three families with unaffected mutation carriers (UMCs), FPAH patients, and gender-matched controls to investigate this variation. Our analysis identified features of UMC iPSC-ECs related to modifiers of BMPR2 signaling or to differentially expressed genes. FPAH-iPSC-ECs showed reduced adhesion, survival, migration and angiogenesis compared to UMC-iPSC-ECs and control cells. The ‘rescued’ phenotype of UMC cells was related to an increase in specific BMPR2 activators and/or a reduction in inhibitors, and the improved cell adhesion could be attributed to preservation of related signaling. The improved survival was related to increased BIRC3 and independent of BMPR2. Our findings therefore highlight protective modifiers for FPAH that could help inform development of future treatment strategies.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immaturity and heterogeneity. To characterize the source of this heterogeneity, we applied complementary single-cell RNA-seq and bulk RNA-seq technologies over time during hiPSC cardiac differentiation and in the adult heart. Using integrated transcriptomic and splicing analysis, more than half a dozen distinct single-cell populations were observed, several of which were coincident at a single time-point, day 30 of differentiation. To dissect the role of distinct cardiac transcriptional regulators associated with each cell population, we systematically tested the effect of a gain or loss of three transcription factors (NR2F2, TBX5, and HEY2), using CRISPR genome editing and ChIP-seq, in conjunction with patch clamp, calcium imaging, and CyTOF analysis. These targets, data, and integrative genomics analysis methods provide a powerful platform for understanding in vitro cellular heterogeneity.

Background: Molecular targeted chemotherapies have been shown to significantly improve cancer patient outcomes, but often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype compared to cardiotoxicity induced by conventional chemotherapies. Methods: We employed the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing (RNA-seq) to further examine the effect of trastuzumab on iPSC-CMs. We also generated iPSCs from patients receiving trastuzumab and examined whether patients' phenotype could be recapitulated in vitro using patient-specific iPSC-CMs.

Lamin A/C (LMNA) is one of the most frequently mutated genes in dilated cardiomyopathy (DCM). LMNA-related DCM is a common inherited cardiomyopathy associated with systolic Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Massively parallel, droplet-based scRNA-seq allowed meticulous analysis of thousands of human iPSCs subjected to iPSC-EC differentiation. Results showed inefficiency of the differentiation technique, which can be improved with further studies based on identification of molecular signatures that inhibit expansion of nonendothelial cell types. Subtypes of bona fide human iPSC-ECs were also identified, allowing us to sort for iPSC-ECs with specific biological function and identity.