Systematic Discovery of Short Linear Motifs Decodes Calcineurin Phosphatase Signaling.

Short linear motifs (SLiMs) drive dynamic protein-protein interactions essential for signaling, but sequence degeneracy and low binding affinities make them difficult to identify. We harnessed unbiased systematic approaches for SLiM discovery to elucidate the regulatory network of calcineurin (CN)/PP2B, the Ca2+-activated phosphatase that recognizes LxVP and PxIxIT motifs. In vitro proteome-wide detection of CN-binding peptides, in vivo SLiM-dependent proximity labeling, and in silico modeling of motif determinants uncovered unanticipated CN interactors, including NOTCH1, which we establish as a CN substrate. Unexpectedly, CN shows SLiM-dependent proximity to centrosomal and nuclear pore complex (NPC) proteins-structures where Ca2+ signaling is largely uncharacterized. CN dephosphorylates human and yeast NPC proteins and promotes accumulation of a nuclear transport reporter, suggesting conserved NPC regulation by CN. The CN network assembled here provides a resource to investigate Ca2+ and CN signaling and demonstrates synergy between experimental and computational methods, establishing a blueprint for examining SLiM-based networks.

Perspectives on the Use of Proprietary Blends in Dietary Supplements.

This paper discusses the rationale for use of proprietary blends on dietary supplement labels, and their implications for researchers and consumers. The Dietary Supplement Health Education Act of 1994 allows the listing of nonnutrient dietary ingredients as proprietary blends on dietary supplement labels for companies to protect their unique formulas. The weight of the blend and names of the ingredients within the blends must be declared, but not the amounts of the individual ingredients within the proprietary blend. Thus, from label information, the amount of a dietary ingredient in a proprietary blend is not available for calculating exposures in assessments of intakes or for determining doses in clinical trials.

Reconsidering scarce drug rationing: implications for clinical research.

Hospital systems commonly face the challenge of determining just ways to allocate scarce drugs during national shortages. There is no standardised approach of how this should be instituted, but principles of distributive justice are commonly used so that patients who are most likely to benefit from the drug receive it. As a result, clinical indications, in which the evidence for the drug is assumed to be established, are often prioritised over research use. In this manuscript, we present a case of a phase II investigational trial of intravenous thiamine for delirium prevention in patients undergoing haematopoietic stem cell transplantation to emphasise several shortcomings in the overarching prioritisation of clinical over research uses of scarce drugs. Specifically, we present the following considerations: (1) clinical use may not have stronger evidence than research use; (2) a strong scientific rationale for research use may outweigh the claim for clinical indications in which there is weak evidence; (3) treatment within the context of a clinical trial may be the standard of care; and (4) research use may not only benefit patients receiving the treatment but also offers the prospect of improving future clinical care. In summary, we argue against allocation schemes that prohibit all research uses of scarce drugs and instead recommend that allocation schemes include a balanced approach that weighs risks and benefits of access to scarce drugs irrespective of the research versus clinical use designation.

Four Faces of Fair Subject Selection.

Although the principle of fair subject selection is a widely recognized requirement of ethical clinical research, it often yields conflicting imperatives, thus raising major ethical dilemmas regarding participant selection. In this paper, we diagnose the source of this problem, arguing that the principle of fair subject selection is best understood as a bundle of four distinct sub-principles, each with normative force and each yielding distinct imperatives: (1) fair inclusion; (2) fair burden sharing; (3) fair opportunity; and (4) fair distribution of third-party risks. We first map out these distinct sub-principles, and then identify the ways in which they yield conflicting imperatives for the design of inclusion and exclusion criteria, and the recruitment of participants. We then offer guidance for how decision makers should navigate these conflicting imperatives to ensure that participants are selected fairly.

Selecting participants fairly for controlled human infection studies.

Controlled human infection (CHI) studies involve the deliberate exposure of healthy research participants to infectious agents to study early disease processes and evaluate interventions under controlled conditions with high efficiency. Although CHI studies expose participants to the risk of infection, they are designed to offer investigators unique advantages for studying the pathogenesis of infectious diseases and testing potential vaccines or treatments in humans. One of the central challenges facing investigators involves the fair selection of research subjects to participate in CHI studies. While there is widespread agreement that investigators have a duty to select research participants fairly, this principle also yields conflicting ethical imperatives, for example requiring investigators to both exclude potential participants with co-morbidities since they face increased risks, but also to include them in order to ensure generalizability. In this paper we defend an account of fair subject selection that is tailored to the context of CHI studies. We identify the considerations of fairness that bear directly on selecting participants for CHI studies and provide investigators and members of IRBs and RECs with a principled way to navigate the conflicting imperatives to which these considerations give rise.

Nup153 and Nup50 promote recruitment of 53BP1 to DNA repair foci by antagonizing BRCA1-dependent events.

DNA double-strand breaks are typically repaired through either the high-fidelity process of homologous recombination (HR), in which BRCA1 plays a key role, or the more error-prone process of non-homologous end joining (NHEJ), which relies on 53BP1. The balance between NHEJ and HR depends, in part, on whether 53BP1 predominates in binding to damage sites, where it protects the DNA ends from resection. The nucleoporin Nup153 has been implicated in the DNA damage response, attributed to a role in promoting nuclear import of 53BP1. Here, we define a distinct requirement for Nup153 in 53BP1 intranuclear targeting to damage foci and report that Nup153 likely facilitates the role of another nucleoporin, Nup50, in 53BP1 targeting. The requirement for Nup153 and Nup50 in promoting 53BP1 recruitment to damage foci induced by either etoposide or olaparib is abrogated in cells deficient for BRCA1 or its partner BARD1, but not in cells deficient for BRCA2. Together, our results further highlight the antagonistic relationship between 53BP1 and BRCA1, and place Nup153 and Nup50 in a molecular pathway that regulates 53BP1 function by counteracting BRCA1-mediated events.

Douglas MacKay, ND: Defining the Regulatory Landscape for Hemp-based Supplements.

No Abstract Available.

Weighing obligations to home care workers and Medicaid recipients.

In June 2016, a US Department of Labor rule extending minimum wage and overtime pay protections to home care workers such as certified nursing assistants and home health aides survived its final legal challenge and became effective. However, Medicaid officials in certain states reported that during the intervening decades when these protections were not in place, their states had developed a range of innovative services and programs providing home care to people with disabilities-services and programs that would be at risk if workers were newly owed minimum wage and overtime pay. In this article, we examine whether the Department of Labor was right to extend these wage protections to home care workers even at the risk of a reduction in these home care services to people with disabilities. We argue that it was right to do so. Home care workers are entitled to these protections, and, although it is permissible under certain conditions for government to infringe workers' occupational rights and entitlements, these conditions are not satisfied in this case.

The ethics of public policy RCTs: The principle of policy equipoise.

In this article, I ask whether a principle analogous to the principle of clinical equipoise should govern the design and conduct of RCTs evaluating the effectiveness of policy interventions. I answer this question affirmatively, and introduce and defend the principle of policy equipoise. According to this principle, all arms of a policy RCT must be, at minimum, in a state of equipoise with the best proven policy that is also morally and practically attainable and sustainable. For all arms of a policy RCT, policy experts must either (1) reasonably disagree about whether the trial arms are more effective than this policy, or (2) know that they are.

The Duty to Rescue and Investigators' Obligations.

We examine current applications of the moral duty to rescue to justify clinical investigators' duties of ancillary care and standard of care to subjects in resource-poor settings. These applications fail to explain why investigators possess obligations to research participants, in particular, and not to people in need, in general. Further, these applications fail to recognize the normative significance of the institutional role of the investigators. We offer a positive account of the duty to rescue for investigators as institutional agents, with duties to populations rather than merely individuals.

Fair subject selection in clinical research: formal equality of opportunity.

In this paper, I explore the ethics of subject selection in the context of biomedical research. I reject a key principle of what I shall refer to as the standard view According to this principle, investigators should select participants so as to minimise aggregate risk to participants and maximise aggregate benefits to participants and society. On this view, investigators should exclude prospective participants who are more susceptible to risk than other prospective participants. I argue instead that investigators should select subjects in accordance with an alternative principle: formal equality of opportunity. According to this principle, investigators must treat all prospective participants the same unless differential treatment is warranted by the scientific goals of the study or the need to promote participants' medically related interests. All prospective participants (1) who meet the scientifically defined eligibility criteria and (2) for whom participation is consistent with their medically related interests should have an equal, formal opportunity to participate in the study. Prospective participants should not be excluded simply because they are more susceptible to risk than others.

The Ethics of Organ Donor Registration Policies: Nudges and Respect for Autonomy.

Governments must determine the legal procedures by which their residents are registered, or can register, as organ donors. Provided that governments recognize that people have a right to determine what happens to their organs after they die, there are four feasible options to choose from: opt-in, opt-out, mandated active choice, and voluntary active choice. We investigate the ethics of these policies' use of nudges to affect organ donor registration rates. We argue that the use of nudges in this context is morally problematic. It is disrespectful of people's autonomy to take advantage of their cognitive biases since doing so involves bypassing, not engaging, their rational capacities. We conclude that while mandated active choice policies are not problem free-they are coercive, after all-voluntary active choice, opt-in, and opt-out policies are potentially less respectful of people's autonomy since their use of nudges could significantly affect people's decision making.

Consumer attitudes about the role of multivitamins and other dietary supplements: report of a survey.

BACKGROUND: U.S. nutrition surveys find that intakes of many nutrients fall short of recommendations. The majority of U.S. adults use multivitamins and other dietary supplements as one means of improving nutrient intakes. Some policy makers and health professionals appear reluctant to recommend routine use of dietary supplements to fill nutrient gaps in the diet, in part because they are concerned that people will view the supplements as a substitute for dietary improvement and that the use of supplements may lead to overconsumption of micronutrients. Surveys find that in fact users of dietary supplements tend to have better diets and adopt other healthy habits, suggesting that the supplements are viewed as one aspect of an overall effort to improve wellness. Furthermore, evidence demonstrates that the incidence of excess micronutrient intake is low. We report the results of a survey probing consumer attitudes about the role of dietary supplements. METHODS: The Council for Responsible Nutrition funded a survey to measure consumer attitudes about the role of multivitamins, calcium and/or vitamin D supplements, and other supplements in improving dietary intakes. The research was designed and analyzed by FoodMinds and was fielded using Toluna's On-line Omnibus. The weighted sample of 2159 respondents is representative of U.S. adults. RESULTS: Nearly 90% of the survey respondents agreed that multivitamins and supplements of calcium and/or vitamin D can help meet nutrient needs when desirable intakes are not achieved through food alone. At the same time, 80% agreed that dietary supplements should not be used to replace healthy dietary or lifestyle habits, and 82% agreed that people considering taking a high dose, single nutrient supplement should talk with their physician. CONCLUSIONS: These results provide additional support for the conclusion that the vast majority of consumers recognize that multivitamins and other supplements can help fill nutrient gaps but should not be viewed as replacements for a healthy diet. This suggests that policy makers and health professionals could feel comfortable recommending rational dietary supplementation as one means of improving nutrient intakes, without being unduly concerned that such a recommendation would lead consumers to discount the importance of good dietary habits.

Opt-out and consent.

A chief objection to opt-out organ donor registration policies is that they do not secure people's actual consent to donation, and so fail to respect their autonomy rights to decide what happens to their organs after they die. However, scholars have recently offered two powerful responses to this objection. First, Michael B Gill argues that opt-out policies do not fail to respect people's autonomy simply because they do not secure people's actual consent to donation. Second, Ben Saunders argues that opt-out policies do secure people's actual-if not explicit-consent, provided that certain conditions are satisfied. I argue that Gill and Saunders' arguments are not successful. My conclusion does not imply that jurisdictions should not implement opt-out policies-their failure to secure people's actual consent may be outweighed by other considerations. But, my conclusion does imply that Gill and Saunders are mistaken to claim that opt-out policies are respectful of people's autonomy.

Standard of care, institutional obligations, and distributive justice.

The problem of standard of care in clinical research concerns the level of treatment that investigators must provide to subjects in clinical trials. Commentators often formulate answers to this problem by appealing to two distinct types of obligations: professional obligations and natural duties. In this article, I investigate whether investigators also possess institutional obligations that are directly relevant to the problem of standard of care, that is, those obligations a person has because she occupies a particular institutional role. I examine two types of institutional contexts: (1) public research agencies - agencies or departments of states that fund or conduct clinical research in the public interest; and (2) private-for-profit corporations. I argue that investigators who are employed or have their research sponsored by the former have a distinctive institutional obligation to conduct their research in a way that is consistent with the state's duty of distributive justice to provide its citizens with access to basic health care, and its duty to aid citizens of lower income countries. By contrast, I argue that investigators who are employed or have their research sponsored by private-for-profit corporations do not possess this obligation nor any other institutional obligation that is directly relevant to the ethics of RCTs. My account of the institutional obligations of investigators aims to contribute to the development of a reasonable, distributive justice-based account of standard of care.

Health habits and other characteristics of dietary supplement users: a review.

Dietary supplements are used by half to two-thirds of American adults, and the evidence suggests that this usage is one component of a larger effort to develop a healthier lifestyle. Dietary supplement users tend on average to be better educated and to have somewhat higher incomes than nonusers, and these factors may contribute to their health-consciousness. Dietary supplement use also tends to be more prevalent among women than among men, and the prevalence of use increases with age in both men and women. Numerous surveys document that users of dietary supplements are significantly more likely than nonusers to have somewhat better dietary patterns, exercise regularly, maintain a healthy weight, and avoid tobacco products. While supplement users tend to have better diets than nonusers, the differences are relatively small, their diets have some substantial nutrient shortfalls, and their supplement use has been shown to improve the adequacy of nutrient intakes. Overall, the evidence suggests that users of dietary supplements are seeking wellness and are consciously adopting a variety of lifestyle habits that they consider to contribute to healthy living.

Standard of care, professional obligations, and distributive justice.

The problem of standard-of-care in clinical research concerns the level of care that investigators ought to provide to research subjects in the control arm of their clinical trials. Commentators differ sharply on whether subjects in trials conducted in lower income countries should be provided with the same level of care as subjects in trials conducted in higher income countries. I consider an argument that commentators have employed on both sides of this debate: professional role arguments. These arguments claim to justify a conclusion to the standard-of-care problem solely by appeal to the professional obligations that investigators possess. I argue that prominent versions of professional role arguments cannot justify a solution to the problem of standard-of-care that is both determinate and reasonable simply by appeal to the professional obligations of investigators. Instead, to do so, one must also (1) determine the level of care or types of treatment that individuals are entitled to as a matter of distributive justice, and (2) identify which agents possess the duties that correspond to these entitlements. The level of care that investigators owe to subjects in the control arm of their clinical trials is thus in part dependent on the level of care that these subjects are entitled to as a matter of distributive justice, and whether it is the investigators who possess the corresponding distributive obligation to provide them with the care that they are entitled to.

Nutravigilance: principles and practices to enhance adverse event reporting in the dietary supplement and natural products industry.

Nutravigilance is defined as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects related to the use of a food, dietary supplement, or medical food". The nutravigilance approach is derived from well-defined principles of pharmacovigilance in the drug and biologics industries, which have been developed and refined over a number of years through expert recommendations. While the primary purpose of nutravigilance is to protect customer/patient safety, it also serves to reduce product liability risks for manufacturers and marketing agents of such products. Compliance with the current FDA adverse event reporting requirements is suboptimal, and FDA oversight and enforcement activities have recently increased. In order to better protect customer and product safety, dietary supplement manufacturers must significantly change their current approach, and demonstrate a proactive, systematic, risk-based, scientific approach to product safety, similar to one utilized successfully in the pharmaceutical industry. While this article focuses on FDA regulations, the principles are widely relevant to the supplement industry in the rest of the world.