Modeling CRISPR-Cas13d on-target and off-target effects using machine learning approaches

A major challenge in the application of the CRISPR-Cas13d (RfxCas13d, or CasRx) RNA editing system is to accurately predict its guide RNA (gRNA) dependent on-target and off-target effect. Here, we performed CRISPR-Cas13d proliferation screens that target protein-coding genes and long non-coding RNAs (lncRNAs), followed by a systematic modeling of Cas13d on-target efficiency and off-target viability effect. We first designed a deep learning model, named DeepCas13, to predict the on-target activity of a gRNA with high accuracy from its sequence and secondary structure. DeepCas13 outperforms existing methods and accurately predicts the efficiency of guides targeting both protein-coding and non-coding RNAs (e.g., circRNAs and lncRNAs). Next, we systematically studied guides targeting non-essential genes, and found that the off-target viability effect, defined as the unintended effect of guides on cell viability, is closely related to their on-target RNA cleavage efficiency. This finding suggests that these gRNAs should be used as negative controls in proliferation screens to reduce false positives, possibly coming from the unwanted off-target viability effect of efficient guides. Finally, we applied these models to our screens that included guides targeting 234 lncRNAs, and identified lncRNAs that affect cell viability and proliferation in multiple cell lines. DeepCas13 is freely accessible via http://deepcas13.weililab.org.

Punching Below Its Weight: The Role of the European Parliament in Politicised Consultation Procedures

With Lisbon, the European Parliament formally acquired an equal standing to that of the Council of the EU in the making of policies in the AFSJ (area of freedom, security and justice). However, the growing political salience of policy issues at stake and bottom-up politicisation in the AFSJ has had the unintended effect of undermining the European Parliament’s internal unity even under consultation procedures. To show how this played out in practice during Europe’s migration and refugee crisis, this article analyses the European Parliament’s role, preferences, and bargaining position in the making of two Refugee Relocation Decisions (Council Decisions 2015/1523 and 2015/1601) under consultation procedure. To do so, this article exploits Putnam’s two-level framework (level I and II politics throughout the policy-making process) to explore early agenda-setting attempts and groups’ positions on issues of refugee relocation and burden-sharing, as they were formally stated in their position papers and expressed at the LIBE Committee and at plenary. This article shows that the high domestic salience and politicization of the issues at stake left MEPs torn between competing principals at home and within their European Parliament political groups and had the effect of weakening overall unity on the issue of refugee relocation.

Perceptions of minimum age at marriage laws and their enforcement: qualitative evidence from Malawi

Background Child marriage in Malawi is a significant problem with 42.1% of women 20–24 married by age 18. In 2017 the Malawi government formalized legislation to make marriage under age 18 illegal; violators are subject to fines. While leveraging laws to reduce child marriage is common, the enactment of laws and their enforcement has led to some novel practices. One such practice observed in Malawi is marriage withdrawal, where the community intervenes when a child marriage has taken place to force the girl to return to her natal home. Methods This paper is a qualitative analysis of perceptions regarding marriage withdrawal. We conducted focus group discussions and in-depth interviews with married and unmarried adolescents, parents of adolescents, and key community members in Mangochi and Nkhata Bay. Data were collected as part of an evaluation of the More Than Brides Alliance program aimed at delaying marriage and improving access to sexual and reproductive health services in Malawi. Results The knowledge that violation of marriage laws entails substantial fines is widespread and marriage withdrawals are seen by some respondents as a way of enforcing the spirit of child marriage laws while avoiding fines. Some respondents suggest that enforcement of marriage laws has an unintended effect of driving marriages underground. One important disconnect between the laws and the realities of child marriage practices in these communities is that the law holds parents responsible for the marriage and for preventing it, while parents do not necessarily exercise control, particularly when the marriage is precipitated by pregnancy. While parents and other adults view withdrawals as an acceptable resolution of a problematic child marriage, girls noted many drawbacks for withdrawn girls such as stigma and limited education and livelihood opportunities once withdrawn. Conclusions Our exploration of perceptions about marriage laws suggest that the imposition of fines may have some unintended consequences, both driving the practice underground and encouraging practices to evade fines, and may be associated with unintended consequences for adolescent girls. Programs to address child marriage should include other approaches that address more distal drivers including poverty and lack of alternatives to child marriage. Trial registration This work is part of an RCT registered August 4, 2016 in the AEA RCT registry identified as: AEARCTR-0001463. See: https://www.socialscienceregistry.org/trials/1463

Can Appeals For Peace Promote Tolerance and Mitigate Support for Extremism? Evidence from an Experiment with Adolescents in Burkina Faso

Recent efforts to improve attitudes toward outgroups and reduce support for extremists in violent settings report mixed results. Donors and aid organizations have spent millions of dollars to amplify the voices of moderate religious figures to counter violent extremism in West Africa, the Middle East, and South Asia. Despite this investment, we know little about whether such messaging persuades the primary recruits of violent extremist organizations: at-risk youth in fragile settings. In this paper, we consider whether pro-peace religious messaging can promote social cohesion among school-age respondents in Burkina Faso. Using a survey experiment, we find little evidence that such messages affect reported attitudes or behaviors towards religious extremism and find instead that it can have the unintended effect of increasing intolerance towards ethnic others. Our findings carry lessons about the inadvertent priming of ethnic identities that can result in a backlash effect among certain societal segments.

Locked in the Home: A Critique of House Arrest as an Alternative to Imprisonment for Women Sentenced for Drug-Related Crimes

This article addresses the unintended consequences of using house arrest for female offenders as an alternative to prison for drug-related crimes. We propose that in patriarchal societies, locking women at home could imply moving them to another control device that may be as harmful as prison. Thereby, house arrest creates an unintended effect in which domestication in traditional gender roles ends up being the primary target of female offender punishment.

The unintended benefit of the risk factor mandate of 2005

In 2005, the SEC mandated that firms disclose risk factors to provide useful information about firm risk. An unintended effect of the mandate is that mandatory risk factor (RF) disclosure may constitute “meaningful cautionary language” as defined in the Private Securities Litigation Reform Act, and may therefore provide legal protection for forward-looking statements (FLSs). Using both a difference-in-differences design and a two-stage least squares approach, we find that, following the mandate, firms that had not previously disclosed risk factors (late RF disclosers) became more willing to provide qualitative FLSs, particularly positive ones, than other firms. This finding is consistent with our prediction that, for late RF disclosers, the mandate reduces managers’ perceived litigation risk. We also find that these firms experience improvement in their information environment. A path analysis reveals that the mandate improves firms’ information environment not only directly but also indirectly by prompting more disclosure of positive FLSs, illustrating an unintended benefit of the 2005 RF mandate. Cross-sectional tests show that the RF mandate induces a larger increase in positive FLSs for firms whose managers perceive a higher level of benefit from safe harbor protection arising from meaningful cautionary statements.

Striking Decrease of Enteroviral Meningitis in Children During the COVID-19 Pandemic

We report the unprecedented complete absence of pediatric enteroviral meningitis in 2020 in the area of Bern, Switzerland. Presumably an unintended effect of COVID-19 public health measures, this finding highlights the potential of community-wide non-pharmaceutical interventions (NPI) for controlling the circulation of a major pediatric pathogen, which is mainly transmitted by the fecal-oral route.

Performance and Regeneration of Methane Oxidation Catalyst for LNG Ships

Liquefied natural gas (LNG) use as marine fuel is increasing. Switching diesel to LNG in ships significantly reduces air pollutants but the methane slip from gas engines can in the worst case outweigh the CO2 decrease with an unintended effect on climate. In this study, a methane oxidation catalyst (MOC) is investigated with engine experiments in lean-burn conditions. Since the highly efficient catalyst needed to oxidize methane is very sensitive to sulfur poisoning a regeneration using stoichiometric conditions was studied to reactivate the catalyst. In addition, the effect of a special sulfur trap to protect the MOC and ensure long-term performance for methane oxidation was studied. MOC was found to decrease the methane emission up to 70–80% at the exhaust temperature of 550 degrees. This efficiency decreased within time, but the regeneration done once a day was found to recover the efficiency. Moreover, the sulfur trap studied with MOC was shown to protect the MOC against sulfur poisoning to some extent. These results give indication of the possible use of MOC in LNG ships to control methane slip emissions.

Trading off wage for workplace safety? Gaps between immigrants and natives in Italy

We employ Italian administrative data to analyze the differentials in wages and workplace injuries between immigrants and natives over the 1994–2012 period. Via propensity score reweighting, we construct the factual and counterfactual, marginal and joint distributions of wages and workplace injuries. Examining the differentials along the entire distributions, our approach yields novel insights on their potential drivers. Our findings confirm that immigrants face lower wages and a substantially higher injury risk than natives; futhermore, they highlight that foreign-born workers display a disproportionate concentration of injuries around the minimum contractual wages. Our results show that the latter can be interpreted as an unintended effect of minimum contractual wages. Indeed, if wages are downward rigid and workplace safety investments are costly, firms employing low-wage workers may reallocate their savings away from wages onto safety. Over time, the gap is found to shrink. Our analysis suggests that, beyond the reduction in workplace intensity during recessions, this may be due to destruction of marginal jobs. Being disproportionally concentrated in marginal occupations, then, lower-skilled migrant workers are more vulnerable to downturns in the economic cycle. Overall, our results highlight that labour market segmentation may co-exist with wage regulations.