Low Levels of Genetic Divergence across Geographically and Linguistically Diverse Populations from India

Ongoing modernization in India has elevated the prevalence of many complex genetic diseases associated with a western lifestyle and diet to near-epidemic proportions. However, although India comprises more than one sixth of the world's human population, it has largely been omitted from genomic surveys that provide the backdrop for association studies of genetic disease. Here, by genotyping India-born individuals sampled in the United States, we carry out an extensive study of Indian genetic variation. We analyze 1,200 genome-wide polymorphisms in 432 individuals from 15 Indian populations. We find that populations from India, and populations from South Asia more generally, constitute one of the major human subgroups with increased similarity of genetic ancestry. However, only a relatively small amount of genetic differentiation exists among the Indian populations. Although caution is warranted due to the fact that United States–sampled Indian populations do not represent a random sample from India, these results suggest that the frequencies of many genetic variants are distinctive in India compared to other parts of the world and that the effects of population heterogeneity on the production of false positives in association studies may be smaller in Indians (and particularly in Indian-Americans) than might be expected for such a geographically and linguistically diverse subset of the human population

Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Untangling the knotty web of Al

Thesis: S.M., Massachusetts Institute of Technology, School of Architecture and Planning, Program in Media Arts and Sciences, 2019Cataloged from PDF version of thesis.Includes bibliographical references (pages 73-82).Artificial intelligence systems (Al) have become a ubiquitous part of modern life. Yet their complexity has prevented a concrete conceptualization that correctly map the web of human actors and computational processes involved in Al. This opaque representation of AI poses questions for accountability and governance, such as who is responsible when an Al makes a moral transgression? This thesis takes a discursive and empirical approach to reifying Al as a specific network of human actors with real world outcomes. It explores the phenomenon of anthropormophization, by which Al is endowed with human-like characteristics, and shows how the extent to which a Al system is anthropomorphized can affect the attribution of responsibility to human actors. This thesis does not offer a normative suggestion for whom society should blame when Al make moral transgressions, but rather offers a view into human folk intuitions.by Ziv Epstein.S.M.S.M. Massachusetts Institute of Technology, School of Architecture and Planning, Program in Media Arts and Science

Risking your life without a second thought: intuitive decision-making and extreme altruism.

When faced with the chance to help someone in mortal danger, what is our first response? Do we leap into action, only later considering the risks to ourselves? Or must instinctive self-preservation be overcome by will-power in order to act? We investigate this question by examining the testimony of Carnegie Hero Medal Recipients (CHMRs), extreme altruists who risked their lives to save others. We collected published interviews with CHMRs where they described their decisions to help. We then had participants rate the intuitiveness versus deliberativeness of the decision-making process described in each CHMR statement. The statements were judged to be overwhelmingly dominated by intuition; to be significantly more intuitive than a set of control statements describing deliberative decision-making; and to not differ significantly from a set of intuitive control statements. This remained true when restricting to scenarios in which the CHMRs had sufficient time to reflect before acting if they had so chosen. Text-analysis software found similar results. These findings suggest that high-stakes extreme altruism may be largely motivated by automatic, intuitive processes

Distribution of ratings of CHMR statements (A), intuitive control statements (B) and deliberative control statements (C) in Study 2.

<p>Distribution of ratings of CHMR statements (A), intuitive control statements (B) and deliberative control statements (C) in Study 2.</p

Median rating of number of seconds CHMRs had in which to act for each CHMR scenario.

<p>Median rating of number of seconds CHMRs had in which to act for each CHMR scenario.</p

Digital literacy is associated with more discerning accuracy judgments but not sharing intentions

It has been widely argued that social media users with low digital literacy—who lack fluency with basic technological concepts related to the internet—are more likely to fall for online misinformation, but surprisingly little research has examined this association empirically. In a large survey experiment involving true and false news posts about politics and COVID-19, we found that digital literacy is indeed an important predictor of the ability to tell truth from falsehood when judging headline accuracy. However, digital literacy is not a robust predictor of users’ intentions to share true versus false headlines. This observation resonates with recent observations of a substantial disconnect between accuracy judgments and sharing intentions. Furthermore, our results suggest that lack of digital literacy may be useful for helping to identify people with inaccurate beliefs, but not for identifying those who are more likely to spread misinformation online.</jats:p

Developing an accuracy-prompt toolkit to reduce COVID-19 misinformation online

Recent research suggests that shifting users’ attention to accuracy increases the quality of news they subsequently share online. Here we help develop this initial observation into a suite of deploy-able interventions for practitioners. We ask (i) how prior results generalize to other approaches for prompting users to consider accuracy, and (ii) for whom these prompts are more versus less effec-tive. In a large survey experiment examining participants’ intentions to share true and false head-lines about COVID-19, we identify a variety of different accuracy prompts that su¬ccessfully increase sharing</jats:p

Understanding and Combating Misinformation Across 16 Countries on Six Continents

The spread of misinformation online is a global problem that requires global solutions. To that end, we conducted an experiment in 16 countries across 6 continents (N = 33,480) to investigate predictors of susceptibility to misinformation and interventions to combat misinformation. In every country, participants with a more analytic cognitive style and stronger accuracy-related motivations were better at discerning truth from falsehood; valuing democracy was also associated with greater truth discernment whereas political conservatism was negatively associated with truth discernment in most countries. Subtly prompting people to think about accuracy was broadly effective at improving the veracity of news that people were willing to share, as were minimal digital literacy tips. Finally, crowdsourced accuracy evaluation was able to differentiate true from false headlines with high accuracy in all countries. The consistent patterns we observe suggest that the psychological factors underlying the misinformation challenge are similar across the globe, and that similar solutions may be broadly effective