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Cryptococcus neoformans is an environmental fungus that causes pulmonary and central nervous system infections. It is also responsible for 15% of AIDS-related deaths., The human fungal pathogen Cryptococcus neoformans is intrinsically resistant to the echinocandin antifungal drug caspofungin, which targets the β-1,3-glucan synthase encoded by FKS1. Echinocandins have been on the market for 20 years, yet they are the newest class of antifungal drugs. Analysis of a C. neoformans puf4Δ mutant, lacking the pumilio/FBF RNA binding protein family member Puf4, revealed exacerbated caspofungin resistance. In contrast, overexpression of PUF4 resulted in caspofungin sensitivity. The FKS1 mRNA contains three Puf4-binding elements (PBEs) in its 5′ untranslated region. Puf4 binds with specificity to this region of FKS1. The FKS1 mRNA was destabilized in the puf4Δ mutant, and the abundance of the FKS1 mRNA was reduced compared to wild type, suggesting that Puf4 is a positive regulator of FKS1 mRNA stability. In addition to FKS1, the abundance of additional cell wall biosynthesis genes, including chitin synthases (CHS3, CHS4, and CHS6) and deacetylases (CDA1, CDA2, and CDA3) as well as a β-1,6-glucan synthase gene (SKN1), was regulated by Puf4. The use of fluorescent dyes to quantify cell wall components revealed that the puf4Δ mutant had increased chitin content, suggesting a cell wall composition that is less reliant on β-1,3-glucan. Overall, our findings suggest a mechanism by which caspofungin resistance, and more broadly, cell wall biogenesis, is regulated post-transcriptionally by Puf4.

The rise of large firms in the digital economy, including Amazon, Apple, Facebook, and Google, has rekindled the debate about monopolization law. There are proposals to make finding liability easier against alleged digital monopolists by relaxing substantive standards; to flip burdens of proof; and to overturn broad swaths of existing Supreme Court precedent, and even to condemn a law review article. Frank Easterbrook’s seminal 1984 article, The Limits of Antitrust, theorizes that Type I error costs are greater than Type II error costs in the antitrust context, a proposition that has been woven deeply into antitrust law by the Supreme Court. We consider the implications of this assumption on the standard of proof. We find that, taking variants of the Easterbrook assumption as given, the optimal standard of proof is stronger than the preponderance of the evidence standard. Our conclusion is robust to how one specifies the preponderance of the evidence standard and stands in stark contrast to contemporary proposals to reduce or eliminate the burden of proof facing antitrust plaintiffs in digital markets.

We examine whether the number of lawyers representing a defendant impacts third parties’ moral judgments and recommended punishments for similar offenses. Specifically, we use an experimental survey with a between-subjects design to examine third parties’ perceptions regarding the seriousness of fraud and tax evasion offenses and the punishments they deem appropriate for these offenses. Our benchmark analysis suggests that subjects’ perceived severity and seriousness of both offenses are significantly increasing in the number of lawyers representing the defendant. These results could be driven both by a direct impact of legal representation on third parties’ perceptions and preferences for punishment, or by third parties updating their beliefs regarding the seriousness of these offenses based on the defendant’s legal expenditures. To investigate whether the latter mechanism may be driving results, we conduct a second experimental survey wherein subjects are informed that the number of lawyers has been randomly determined. This causes the significant relationship between the perceived seriousness of the offense and the number of lawyers to vanish. However, for fraud offenses, increasing the number of lawyers from one to more lawyers increases third parties’ recommended sanctions, which is consistent with a psychological phenomenon of ‘luck envy’.

We consider a government’s interrelated decisions of enacting laws prohibiting harmful behavior and choosing how aggressively to enforce those laws. There are three broad policies available to the government in this regard: not prohibiting the act at all, enacting a law and enforcing it, and enacting a law and not enforcing it. When enactment is costly and a fraction of the population reflexively complies with the law once its enactment has been announced (reflecting an expressive function of law), all three policies may be optimal, depending on the severity of the harm from the act and the fraction of reflexive compliers.

The Probabilistic p-Center problem under Pressure (Min PpCP) is a variant of the usual p-Center problem we recently introduced in the context of wildfire management. The problem is to locate p shelters minimizing the maximum distance people will have to cover to reach the closest accessible shelter in case of fire. The landscape is divided into zones and is modeled as an edge-weighted graph with vertices corresponding to zones and edges corresponding to direct connections between two adjacent zones. The risk associated with fire outbreaks is modeled using a finite set of fire scenarios. Each scenario corresponds to a fire outbreak on a single zone (i.e., on a vertex) with the main consequence of modifying evacuation paths in two ways. First, an evacuation path cannot pass through the vertex on fire. Second, the fact that someone close to the fire may not take rational decisions when selecting a direction to escape is modeled using new kinds of evacuation paths. In this paper, for a given instance of Min PpCP defined by an edge-weighted graph G=(V,E,L) and an integer p, we characterize the set of feasible solutions of Min PpCP. We prove that Min PpCP cannot be approximated with a ratio less than 56/55 on subgrids (subgraphs of grids) of degree at most 3. Then, we propose some approximation results for Min PpCP. These results require approximation results for two variants of the (deterministic) Min p-Center problem called Min MAC p-Center and Min Partial p-Center., 40 pages, 10 figures

Many states have responded to the spread of COVID-19 by implementing policies which have led to a dramatic reduction in jail populations. We consider the benefits associated with providing the population of individuals who would, but for these policies, be incarcerated with substance use disorder (SUD) treatment. We discuss problems that may prevent this population from receiving SUD treatment as well as policies which may mitigate these problems., Highlights • Local jails have downsized their population to prevent the spread of COVID-19. • A large proportion of individuals cycling through the criminal justice system have substance use disorders (SUDs). • We discuss the extent of a potential access problem for SUD treatment during COVID-19. • To reduce access problems, we propose facilitating connections to health coverage and medication treatment prior to release. • We also consider the role of telemedicine as an alternative treatment option during the pandemic and onwards.

Echinocandins have been on the market for 20 years, yet they are the newest class of antifungal drugs. The human fungal pathogenCryptococcus neoformansis intrinsically resistant to the echinocandin antifungal drug caspofungin, which targets theβ-1,3-glucan synthase encoded by theFKS1. Analysis of aC. neoformans puf4Δ mutant, lacking the pumilio/FBF RNA binding protein family member Puf4, revealed exacerbated caspofungin resistance. In contrast, overexpression ofPUF4resulted in caspofungin sensitivity. TheFKS1mRNA contains three Puf4-binding elements (PBEs) in its 5’ untranslated region. Puf4 binds with specificity to this region of theFKS1. TheFKS1mRNA was destabilized in thepuf4Δ mutant, and the abundance of theFKS1mRNA was reduced compared to wild type, suggesting that Puf4 is a positive regulatorFKS1mRNA stability. In addition toFKS1, the abundance of additional cell wall biosynthesis genes, including chitin synthases (CHS3,CHS4,CHS6) and deacetylases (CDA1,CDA2,CDA3) as well as aβ-1,6-glucan synthase gene (SKN1) was regulated by Puf4 during a caspofungin time course. The use of fluorescent dyes to quantify cell wall components revealed that thepuf4Δ mutant had increased chitin content, suggesting a cell wall composition that is less reliant onβ-1,3-glucan. Overall, our findings suggest a mechanism by which caspofungin resistance, and more broadly, cell wall biogenesis, is regulated post-transcriptionally by Puf4.ImportanceCryptococcus neoformansis an environmental fungus that causes pulmonary and central nervous system infections. It is also responsible for 15% of AIDS-related deaths. A major contributor to the high morbidity and mortality statistics is the lack of safe and effective antifungal therapies, especially in resource-poor settings. Yet, antifungal drug development has stalled in the pharmaceutical industry. Therefore, it is of importance to understand the mechanism by whichC. neoformansis resistant to caspofungin in order to design adjunctive therapies to potentiate its activity toward this important pathogen.

We analyze the interactions between social norms, the prevalence of regulated acts, and policies. These interactions are impacted by people's inability to directly observe actors' behavior. Norms are ineffective incentivizers when acts are committed either very frequently or very infrequently, because noisy signals of behavior are then too weak to alter people's beliefs about others' behavior. This cuts against the dynamics of the `honor-stigma' model (Benabou and Tirole 2006, 2011) and reverses its implications with even moderately noisy signals. With unobservable acts, the review process through which incentives are provided becomes an additional policy variable whose optima we characterize.

We derive a profit maximizing legislator's decisions to criminalize and punish offenses, and compare them to the optimal scope of criminalization and punishment. A profit maximizing legislator overcriminalizes and overpunishes all criminalized acts when the degree to which it internalizes harms from crimes increases proportionally with the harm from crime until it fully internalizes the harms from the most severe crimes. An analysis of Eighth Amendment review, in the form of an upper bound on the fine that the legislator may impose, reveals that in addition to reducing the fines imposed by the legislator down to optimal levels, there are gains to imposing strict upper bounds for low harm crimes to remove the legislator's incentives to criminalize these acts in the first place. These results provide a rationale for asymmetric judicial review wherein upper bounds are imposed on punishment, but not lower bounds.

We study the interactions between accuracy and standards used in the determination of legal liability. First, we show that accuracy and type-1 errors (wrongful findings of liability) must reduce each other's effectiveness in mitigating optimal type-2 errors (wrongful failures to assign liability) for previous results in the literature to hold. When this condition holds, for major crimes the median voter's tolerance for type-1 errors is reduced as the legal system's accuracy increases. However, this relationship need not hold for minor offenses. Our analysis also reveals that legal processes that emerge under electoral pressures convict more often than is optimal but less often than necessary to maximize deterrence. Moreover, when the median voter's preferences are implemented, an increase in accuracy can counter-intuitively reduce welfare.

In a criminal trial, a jury may observe characteristics about the defendant (or victim) and use them to form a belief on the likelihood of guilt. Many evidentiary rules attempt to limit this inference. If jury beliefs are rational, such rules may be counterproductive. Any prohibition on the use of defendant characteristics as a form of evidence will never simultaneously reduce conviction rates for the innocent and increase conviction rates for the guilty. In fact, the opposite will occur under plausible conditions. However, if juries are sufficiently biased in their beliefs about guilt rates within groups of defendants, an evidentiary rule may simultaneously reduce wrongful convictions and increase rightful convictions.

We revisit the economic theory of exclusionary rules. First, we show that more exclusion may induce enforcers to conduct more searches, contrary to the standard notion that more exclusion leads to fewer searches. Second, we identify and investigate the complexities that arise when enforcers may harass suspects (imposing significant costs without legal proceedings) instead of conducting legal searches. If one attempts to choose the optimal exclusionary rule naively (for example, by ignoring the possibility of harassment by enforcers), the chosen rule will exclude evidence more often than is optimal. We explore social welfare considerations and discuss policy implications based on our formal results.

This paper examines factors affecting the decision of whether or not to make certain harmful acts illegal. It considers factors related both to the cost of law enforcement and to the crime commission decision. On the enforcement side, illegality is limited by the existence of fixed notice and response costs, which are unrelated to the harm from the act, and also by costs of imposing punishment. In addition, illegality is limited by a finite marginal productivity of detection, one cause of which is legal error. On the commission side, illegality is limited if all offenders have strictly positive benefits from committing the act. The paper concludes by examining how the optimal scope of law is affected by its "expressive function," the idea that some people are deterred by the mere fact that an act is illegal. We specifically ask how the scope of law changes if more people behave in this way. The answer depends on whether "efficient" violations of the law are possible, which in turn depends on whether offenders' gains are counted in welfare.

This article shows that regulatory sanctions that fall into an intermediate range can generate subtle problems not apparent in simple enforcement models. Assuming that firms may ultimately face different noncompliance detection probabilities, we highlight that intermediate sanctions may conflict with aspects of both static and dynamic efficiency.

Criminal convictions result in expected losses due to stigmatization. Among other things, the magnitude of these losses depends on the convict’s future expected earnings. People who face larger wag...

We consider a government’s interrelated decisions of enacting laws prohibiting harmful behavior and choosing how aggressively to enforce those laws. There are three broad policies available to the government in this regard: not prohibiting the act at all, enacting a law and enforcing it, and enacting a law and not enforcing it. When enactment is costly and a fraction of the population reflexively complies with the law once its enactment has been announced (reflecting an expressive function of law), all three policies may be optimal, depending on the severity of the harm from the act and the fraction of reflexive compliers.