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Post-translational regulation of Cas9 activity may improve the specificity of genomic targeting. A modified version of Cas9 with an insertion of a small molecule–regulated intein allows temporal control of Cas9 activity and reduces off-target activity. Directly modulating the activity of genome-editing proteins has the potential to increase their specificity by reducing activity following target locus modification. We developed Cas9 nucleases that are activated by the presence of a cell-permeable small molecule by inserting an evolved 4-hydroxytamoxifen–responsive intein at specific positions in Cas9. In human cells, conditionally active Cas9s modify target genomic sites with up to 25-fold higher specificity than wild-type Cas9.

Every year, smoking kills more than 5 million people globally, including 440 000 people in the USA, where the long-term decline in smoking prevalence has slowed. The US Centers for Disease Control and Prevention (CDC) delivered a national, 3-month antismoking campaign called Tips From Former Smokers (Tips) that started in March, 2012, in which hard-hitting, emotionally evocative television advertising was featured, depicting smoking-related suffering in real people. We aimed to assess the effects of the Tips campaign. We undertook baseline and follow-up surveys of nationally representative cohorts of adult smokers and non-smokers. The national effect of the Tips campaign was estimated by applying rates of change in the cohort before and after the campaign to US census data. 3051 smokers and 2220 non-smokers completed baseline and follow-up assessments. 2395 (78%) smokers and 1632 (74%) non-smokers recalled seeing at least one Tips advertisement on television during the 3-month campaign. Quit attempts among smokers rose from 31·1% (95% CI 30·3–31·9) at baseline to 34·8% (34·0–35·7) at follow-up, a 12% relative increase. The prevalence of abstinence at follow-up among smokers who made a quit attempt was 13·4% (95% CI 9·7–17·2). Nationally, an estimated 1·64 million additional smokers made a quit attempt, and 220 000 (95% CI 159 000–282 000) remained abstinent at follow-up. Recommendations by non-smokers to quit grew from 2·6% at baseline to 5·1% at follow-up, and the prevalence of people talking with friends and family about the dangers of smoking rose from 31·9% (95% CI 31·3–32·5) to 35·2% (34·6–35·9), resulting in an estimated 4·7 million additional non-smokers recommending cessation services and more than 6 million talking about the dangers of smoking. The high-exposure Tips media campaign was effective at increasing population-level quit attempts. The growth in smokers who quit and became sustained quitters could have added from a third to almost half a million quality-adjusted life-years to the US population. Expanded implementation of similar campaigns globally could accelerate progress on the WHO Framework Convention on Tobacco Control and reduce smoking prevalence globally. CDC, US Department of Health and Human Services.

The use of indicators is a prominent feature of contemporary global governance.Indicators are used to compare and rank states for purposes as varied as deciding how to allocate foreign aid or investment and determining whether states have complied with their treaty obligations. This article defines the concept of an indicator, analyzes distinctive features of indicators as technologies of governance, and identifies various ways in which the use of indicators has the potential to alter the topology and dynamics of global governance.Particular attention is paid to how indicators can affect processes of standard setting, decisionmaking, and contestation in global governance. The World Bank Doing Business indicators and the United Nations Human Development Index are analyzed as case studies.

\"When Nancy Kwan burst onto the scene in the early 1960s, Asian characters in film were portrayed by white actors in makeup playing yellowface, and those minor roles were the stuff of cliché: shopkeepers, maids, prostitutes, servants. When#x14;against all odds#x14;Nancy landedthe lead role in the much-anticipated 1960 film The World of Suzie Wong, she became an international superstar and was celebrated for her beauty, grace, authenticity, and spunk: a Chinese Garbo, the Asian Bardot. From Hong Kong to London, Hollywood and beyond, The World of Nancy Kwan charts Nancy#x19;s journey. The obstacles she faced, the prejudices she overcame, and how her success created paths for others.\"-- Provided by publisher.

Does contract law have any role to play in tackling economic inequality, one of the most pressing problems of our time? The orthodox answer to this question is no: Contract law should promote autonomy, efficiency, and/or justice in exchange, while distributive objectives should be dealt with exclusively through the fiscal system. While scholars have often debated the question of whether contract law should be reformed to address inequality, that question misses the reality that, at least in some contexts, it already does. This Article shows how courts in South Africa, Brazil, and Colombia-prominent developing countries from different legal traditions -have diverged from orthodoxy to embrace the task of using contract law to address inequality. The emergence of contract law heterodoxy in developing countries draws attention to the existing, if more limited, instances of heterodoxy in the contract laws of the United States and Europe and to the stakes of contract law more generally. This analysis highlights how mounting inequality may increase the appeal of contract law heterodoxy and suggests that the present reign of contract law orthodoxy is neither universal nor inevitable.

A potential unintended consequence of legalizing recreational marijuana is increased marijuana-related driving impairment. Some states where recreational marijuana is legal have begun implementing interventions to mitigate driving under the influence (DUI) of marijuana, including media campaigns to increase knowledge about DUI laws. However, little is known about the associations between knowledge of DUI laws and marijuana DUI behavior. In this study, we provide new data from a survey of marijuana users in Colorado and Washington to examine associations between marijuana drugged driving and two potential behavioral precursors of marijuana DUI. We also explore other factors that may influence marijuana DUI. Data are from an online survey of marijuana users in Colorado and Washington. Respondents who reported any marijuana use in the past 30 days (n = 865) served as the analytic sample. We examined prevalence of two behavioral outcomes: (1) any driving of a motor vehicle while high in the past year and (2) driving a motor vehicle within 1 hour of using marijuana 5 or more times in the past month. Additional outcomes measuring willingness to drive while high were also assessed. Logistic regressions were used to estimate each outcome as a function of two multi-item scales measuring knowledge of the legal consequences of driving high and perceptions that driving while high is not safe. Additional covariates for potential confounders were included in each model. Prevalence of past-year driving while under the influence of marijuana was 43.6% among respondents. The prevalence of driving within 1 hour of using marijuana at least 5 times in the past month was 23.9%. Increased perception that driving high is unsafe was associated with lower odds of past-year marijuana DUI (OR = 0.31, P < 0.01) and lower past-month odds of driving 5 or more times within 1 hour of using marijuana (OR = 0.26, P < 0.01). Increased knowledge of marijuana DUI laws was also associated with lower odds of each of these outcomes (OR = 0.63, P < 0.01, OR = 0.69, P = 0.02, respectively). Post-estimation Wald tests confirmed the negative associations with marijuana DUI were greater in magnitude for safety perceptions than knowledge of DUI laws. Increased perceptions that driving while high is unsafe was associated with significantly lower willingness to drive after using marijuana while increased knowledge of marijuana DUI laws was not associated with these outcomes. Despite recent interventions targeting public awareness of the legal consequences of marijuana DUI, our results suggest that knowledge of these laws is a weaker predictor of DUI behavior than perceptions that driving high is unsafe. In addition, safety perceptions predict decreased openness to driving high while knowledge of DUI laws was not associated with openness. These findings suggest that interventions for reducing the incidence of marijuana DUI are likely to be more successful by targeting safety perceptions related to marijuana DUI rather than knowledge of DUI laws. We caution that because these data are limited to an online convenience sample, results may not be generalizable beyond our sample.

Motile cells are capable of sensing the stiffness of the surrounding extracellular matrix through integrin-mediated focal adhesions and migrate towards regions of higher rigidity in a process known as durotaxis. Durotaxis plays an important role in normal development and disease progression, including tumor invasion and metastasis. However, the signaling mechanisms underlying focal adhesion-mediated rigidity sensing and durotaxis are poorly understood. Utilizing matrix-coated polydimethylsiloxane gels to manipulate substrate compliance, we show that cdGAP, an adhesion-localized Rac1 and Cdc42 specific GTPase activating protein, is necessary for U2OS osteosarcoma cells to coordinate cell shape changes and migration as a function of extracellular matrix stiffness. CdGAP regulated rigidity-dependent motility by controlling membrane protrusion and adhesion dynamics, as well as by modulating Rac1 activity. CdGAP was also found to be necessary for U2OS cell durotaxis. Taken together, these data identify cdGAP as an important component of an integrin-mediated signaling pathway that senses and responds to mechanical cues in the extracellular matrix in order to coordinate directed cell motility.