Systematic enhancement of protein crystallization efficiency by bulk lysine-to-arginine (KR) substitution.

Structural genomics consortia established that protein crystallization is the primary obstacle to structure determination using x-ray crystallography. We previously demonstrated that crystallization propensity is systematically related to primary sequence, and we subsequently performed computational analyses showing that arginine is the most overrepresented amino acid in crystal-packing interfaces in the Protein Data Bank. Given the similar physicochemical characteristics of arginine and lysine, we hypothesized that multiple lysine-to-arginine (KR) substitutions should improve crystallization. To test this hypothesis, we developed software that ranks lysine sites in a target protein based on the redundancy-corrected KR substitution frequency in homologs. This software can be run interactively on the worldwide web at https://www.pxengineering.org/. We demonstrate that three unrelated single-domain proteins can tolerate 5-11 KR substitutions with at most minor destabilization, and, for two of these three proteins, the construct with the largest number of KR substitutions exhibits significantly enhanced crystallization propensity. This approach rapidly produced a 1.9 Å crystal structure of a human protein domain refractory to crystallization with its native sequence. Structures from Bulk KR-substituted domains show the engineered arginine residues frequently make hydrogen-bonds across crystal-packing interfaces. We thus demonstrate that Bulk KR substitution represents a rational and efficient method for probabilistic engineering of protein surface properties to improve crystallization.

Is the concept of personality capacious enough to incorporate virtues?

We will consider four answers to the question about whether the concept of personality is capacious enough to incorporate virtues. The simplest is that the concept of personality encompasses all individual variations in persons. It follows from this answer that virtues would, as individual differences, be incorporated into personality. Unfortunately, definitions of personality do not always invoke such capaciousness, and, in practice, most scholars limit their work to the Big Five or HEXACO models, which do not incorporate virtues. The second answer is that the concept of personality incorporates all trait or dimension level variations across persons, with some exceptions, such as intelligence, attachment style, and psychopathy. Following this definition, virtues, as traits, would be incorporated into such a broad definition of personality. Unfortunately, the boundaries for inclusion and exclusion into personality are fuzzy in this case, and there is no extant definition of personality that solves this problem. The third answer is that personality traits and virtue traits are similar, but distinct concepts. This article presents conceptual and empirical arguments for this similarity in seeing traits as a higher order concept that includes the species of personality and the species of virtue. The fourth answer is that personality and virtue are unrelated. This answer is dismissed because there are many studies that indicate that they are correlated, and few advocate such a clear differentiation. The conclusion is that, pending conceptual and empirical results indicating otherwise, the genus-species relationship seems most fitting where traits are a genus, and personality and virtue are each a species within that genus.

The ontogeny of selection on genetic diversity in harvester ants.

Selection may favour traits throughout an individual's lifetime or at a particular life stage. In many species of social insects, established colonies that are more genetically diverse outperform less diverse colonies with respect to a variety of traits that contribute to fitness, but whether selection favours high diversity in small colonies is unknown. We tested the hypothesis that selection favours genetically diverse colonies during the juvenile period using a multi-year field experiment with the harvester ant, Pogonomyrmex occidentalis. We used controlled matings to generate colonies that varied in genetic diversity and transplanted them into the field. We monitored their survival for seven (the 2015 cohort, n = 149) and six (the 2016 cohort, n = 157) years. Genetically more diverse colonies had greater survival, resulting in significant viability selection. However, in both cohorts survival was not influenced by genetic diversity until colonies were three years old. We suggest that changes in their internal organization enabled colonies to use the benefits of multiple genotypes, and discuss possible mechanisms that can generate this pattern.

The benefits of being big and diverse: early colony survival in harvester ants.

In sessile organisms such as plants and benthic invertebrates, founding propagules typically suffer extremely high rates of mortality due to both extrinsic and intrinsic factors. Many social insect species share similarities with these groups, but factors influencing early colony survival are relatively unstudied. We used a field experiment to measure the importance of environmental quality relative to intrinsic colony properties in the harvester ant, Pogonomyrmex occidentalis, by monitoring the survival of 584 experimental colonies. We measured survival of transplanted colonies over four months in each of three years (2014-2016) at a site in western Colorado. Colony survival was primarily determined by colony features. Multiple mating by the queen and larger colony size at the time of transplant increased survival, but queen size, maternal lineage and the composition of plant species in the vicinity of the colony did not. Food supplementation increased survival significantly when natural food was scarce, but was not consistently beneficial, in contrast to predictions. Our results emphasize the general importance of rapid growth and early attainment of large size in the survival of sessile species. However, attributes specific to ants that are a consequence of their sociality also strongly affected survival. Colonies with multiply-mated queens were more likely to survive over a wide range of circumstances, highlighting the importance of this trait even at the early stages of colony life.

Courage, Justice, and Practical Wisdom as Key Virtues in the Era of COVID-19.

Fowers et al. (2017) recently made a general argument for virtues as the characteristics necessary for individuals to flourish, given inherent human limitations. For example, people can flourish by developing the virtue of friendship as they navigate the inherent (healthy) human dependency on others. This general argument also illuminates a pathway to flourishing during the COVID-19 pandemic, the risks of which have induced powerful fears, exacerbated injustices, and rendered life and death decisions far more common. Contexts of risk and fear call for the virtue of courage. Courage has emerged more powerfully as a central virtue among medical personnel, first responders, and essential workers. Longstanding inequalities have been highlighted during the pandemic, calling for the virtue of justice. When important personal and public health decisions must be made, the central virtue of practical wisdom comes to the fore. Wise decisions and actions incorporate the recognition of relevant moral concerns and aims, as well as responding in fitting and practical ways to the specifics of the situation. Practicing courage, justice, and practical wisdom illuminates a path to flourishing, even in a pandemic.

TET-TDG Active DNA Demethylation at CpG and Non-CpG Sites.

In mammalian genomes, cytosine methylation occurs predominantly at CG (or CpG) dinucleotide contexts. As part of dynamic epigenetic regulation, 5-methylcytosine (mC) can be erased by active DNA demethylation, whereby ten-eleven translocation (TET) enzymes catalyze the stepwise oxidation of mC to 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), and 5-carboxycytosine (caC), thymine DNA glycosylase (TDG) excises fC or caC, and base excision repair yields unmodified cytosine. In certain cell types, mC is also enriched at some non-CG (or CH) dinucleotides, however hmC is not. To provide biochemical context for the distribution of modified cytosines observed in biological systems, we systematically analyzed the activity of human TET2 and TDG for substrates in CG and CH contexts. We find that while TET2 oxidizes mC more efficiently in CG versus CH sites, this context preference can be diminished for hmC oxidation. Remarkably, TDG excision of fC and caC is only modestly dependent on CG context, contrasting its strong context dependence for thymine excision. We show that collaborative TET-TDG oxidation-excision activity is only marginally reduced for CA versus CG contexts. Our findings demonstrate that the TET-TDG-mediated demethylation pathway is not limited to CG sites and suggest a rationale for the depletion of hmCH in genomes rich in mCH.

The Emerging Science of Virtue.

Numerous scholars have claimed that positive ethical traits such as virtues are important in human psychology and behavior. Psychologists have begun to test these claims. The scores of studies on virtue do not yet constitute a mature science of virtue because of unresolved theoretical and methods challenges. In this article, we addressed those challenges by clarifying how virtue research relates to prosocial behavior, positive psychology, and personality psychology and does not run afoul of the fact-value distinction. The STRIVE-4 (Scalar Traits that are Role sensitive, include Situation × Trait Interactions, and are related to important Values that help to constitute Eudaimonia) model of virtue is proposed to help resolve the theoretical and methods problems and encourage a mature science of virtue. The model depicts virtues as empirically verifiable, acquired scalar traits that are role sensitive, involve Situation × Trait interactions, and relate to important values that partly constitute eudaimonia (human flourishing). The model also holds that virtue traits have four major components: knowledge, behavior, emotion/motivation, and disposition. Heuristically, the STRIVE-4 model suggests 26 hypotheses, which are discussed in light of extant research to indicate which aspects of the model have been assessed and which have not. Research on virtues has included survey, intensive longitudinal, informant-based, experimental, and neuroscientific methods. This discussion illustrates how the STRIVE-4 framework can unify extant research and fruitfully guide future research.

Lifestyle behaviors, psychological distress, and well-being: A daily diary study.

RATIONALE: Many lifestyle behaviors such as diet, exercise, social interaction, and substance use are related to physical and mental health. Less understood are the day-to-day associations of these behaviors with both psychological distress, well-being, and with each other. OBJECTIVE: This study investigated how a number of common lifestyle behaviors were associated with psychological distress and well-being using a daily diary study with multilevel modeling. Associations among behaviors were analyzed with multilevel mediation and network models. METHODS: An online participant pool consisting of seventy-six adults (age range: 19-64; mean age: 40.29; 58% female) completed daily diary surveys over 14 days and reported their engagement in lifestyle behaviors, psychological distress, hedonic well-being, and eudaimonic well-being. RESULTS: Time spent in social interaction was the most consistent within-person correlate of psychological distress and well-being. The association between daily time in nature and well-being was mediated by social interaction and exercise. Network models found within-person associations among the lifestyle behaviors. CONCLUSION: The results indicate that social interaction may be an especially important lifestyle behavior to consider when promoting well-being. Future research should recognize that daily fluctuations in many lifestyle behaviors cluster together.

Comparative advantage and caste evolution.

Most of the theory for the evolution of caste specialization in social insects assumes that increased efficiency in worker labor leads to specialization and increased worker efficiency gives colonies with behavioral specialists an advantage. However, there are an increasing number of studies that show that the task specialists within social insect colonies do not have the highest efficiency. Indeed, some studies show that some groups of workers are uniformly better than all other groups at every task. In this note, I adapt the principle of comparative advantage from economics to show that, rather than maximizing the payoff, specialization is advantageous when minimizing opportunity costs. This leads to the prediction that caste specialization should be associated with reduced opportunity costs rather than increased task efficiency.

A shared understanding of purposeful caregiving: Reply to Hill, Wynn, and Carpenter (2020).

Replies to comments made by P. L. Hill, M. J. Wynn, and B. D. Carpenter (see record 2019-81943-006) on the original article by S. F. Lang and B. J. Fowers (see record 2018-24691-001). Hill, Wynn, and Carpenter's (2020) discussion of Alzheimer's caregiving being motivated by purposeful engagement is a welcome perspective. Their views are timely, given the growing literature on caregiving as a deeply meaningful and worthwhile activity. Hill et al., however, focus on caregivers' subjective perception of caregiving as purposeful, disregarding the source of this perspective. It is reasonable to see the shared relationship history between caregivers and their loved ones as a primary source of the purposefulness of caregiving. This reply offers an integration of caregivers' purposeful activity with shared identity. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Baseline Performance of Real-World Clinical Practice Within a Statewide Emergency Medicine Quality Network: The Michigan Emergency Department Improvement Collaborative (MEDIC).

STUDY OBJECTIVE: Large-scale quality and performance measurement across unaffiliated hospitals is an important strategy to drive practice change. The Michigan Emergency Department Improvement Collaborative (MEDIC), established in 2015, has baseline performance data to identify practice variation across 15 diverse emergency departments (EDs) on key emergency care quality indicators. METHODS: MEDIC is a unique physician-led partnership supported by a major third-party payer. Member sites contribute electronic health record data and trained abstractors add supplementary data for eligible cases. Quality measures include computed tomography (CT) appropriateness for minor head injury, using the Canadian CT Head Rule for adults and Pediatric Emergency Care Applied Network rules for children; chest radiograph use for children with asthma, bronchiolitis, and croup; and diagnostic yield of CTs for suspected pulmonary embolism. Baseline performance was established with statistical process control charts. RESULTS: From June 1, 2016, to October 31, 2017, the MEDIC registry contained 1,124,227 ED visits, 23.2% for children (<18 years). Overall baseline performance included the following: 40.9% of adult patients with minor head injury (N=11,857) had appropriate CTs (site range 24.3% to 58.6%), 10.3% of pediatric minor head injury cases (N=11,183) exhibited CT overuse (range 5.8% to 16.8%), 38.1% of pediatric patients with a respiratory condition (N=18,190) received a chest radiograph (range 9.0% to 62.1%), and 8.7% of pulmonary embolism CT results (N=16,205) were positive (range 7.5% to 14.3%). CONCLUSION: Performance varied greatly, with demonstrated opportunity for improvement. MEDIC provides a robust platform for emergency physician engagement across ED practice settings to improve care and is a model for other states.

Defining the Role of Nucleotide Flipping in Enzyme Specificity Using 19F NMR.

A broad range of proteins employ nucleotide flipping to recognize specific sites in nucleic acids, including DNA glycosylases, which remove modified nucleobases to initiate base excision repair. Deamination, a pervasive mode of damage, typically generates lesions that are recognized by glycosylases as being foreign to DNA. However, deamination of 5-methylcytosine (mC) generates thymine, a canonical DNA base, presenting a challenge for damage recognition. Nevertheless, repair of mC deamination is important because the resulting G·T mispairs cause C → T transition mutations, and mC is abundant in all three domains of life. Countering this threat are three types of glycosylases that excise thymine from G·T mispairs, including thymine DNA glycosylase (TDG). These enzymes must minimize excision of thymine that is not generated by mC deamination, in A·T pairs and in polymerase-generated G·T mispairs. TDG preferentially removes thymine from DNA contexts in which cytosine methylation is prevalent, including CG and one non-CG site. This remarkable context specificity could be attained through modulation of nucleotide flipping, a reversible step that precedes base excision. We tested this idea using fluorine NMR and DNA containing 2'-fluoro-substituted nucleotides. We find that dT nucleotide flipping depends on DNA context and is efficient only in contexts known to feature cytosine methylation. We also show that a conserved Ala residue limits thymine excision by hindering nucleotide flipping. A linear free energy correlation reveals that TDG attains context specificity for thymine excision through modulation of nucleotide flipping. Our results provide a framework for characterizing nucleotide flipping in nucleic acids using 19F NMR.

An expanded theory of Alzheimer's caregiving.

The ancient and cross-culturally prevalent pattern of caregiving suggests that long-term caregiving is species characteristic for humans. If so, then an evolutionary account of the adaptation(s) that underwrite this caregiving is necessary, particularly for the one-sided and long-term nature of Alzheimer's caregiving. Four standard evolutionary explanations are evaluated: kin selection theory, the grandmother hypothesis, direct reciprocity, and indirect reciprocity. Each is found inadequate to explain caregiving because of the lack of reproductive benefits. These evolutionary accounts also assume that relationships are only valuable to the degree that they provide benefits and that relationship partners are predominantly motivated by self-interest. Attachment provides another explanation, which evolved initially to ensure infant protection and nurturance, but was exapted for important adult relationships. Attachment relationships naturally include caregiving and engender long-term relational commitment. Yet attachment theory is ambiguous about whether relationships are maintained for the sake of security benefits or because they have inherent value. This ambiguity undermines the explanatory value of attachment theory for Alzheimer's caregiving. Therefore, a shared identity theory is offered that highlights the inherent value of the relationship and the loved one, transcending the predominant focus on beneficial individual outcomes. The theory emphasizes the frequent human motivation to benefit others because of their mutual commitment, shared identity, and shared goals. The conclusion is that fully understanding and supporting the arduous efforts of caregiving for loved ones with Alzheimer's requires psychologists to fully appreciate and support the deep and meaningful motivations that often inspire the humanity seen in caregiving. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Nucleosomes and the three glycosylases: High, medium, and low levels of excision by the uracil DNA glycosylase superfamily.

Human cells express the UDG superfamily of glycosylases, which excise uracil (U) from the genome. The three members of this structural superfamily are uracil DNA glycosylase (UNG/UDG), single-strand selective monofunctional uracil DNA glycosylase (SMUG1), and thymine DNA glycosylase (TDG). We previously reported that UDG is efficient at removing U from DNA packaged into nucleosome core particles (NCP) and is minimally affected by the histone proteins when acting on an outward-facing U in the dyad region. In an effort to determine whether this high activity is a general property of the UDG superfamily of glycosylases, we compare the activity of UDG, SMUG1, and TDG on a U:G wobble base pair using NCP assembled from Xenopus laevis histones and the Widom 601 positioning sequence. We found that while UDG is highly active, SMUG1 is severely inhibited on NCP and this inhibition is independent of sequence context. Here we also provide the first report of TDG activity on an NCP, and found that TDG has an intermediate level of activity in excision of U and is severely inhibited in its excision of T. These results are discussed in the context of cellular roles for each of these enzymes.

On properly characterizing moral agency.

Doris (2015b) develops a theory of moral agency to avoid a skeptical challenge arising from psychology studies indicating that (im)moral behavior is caused by trivial situational factors. His theory is flawed in attending only to situational influences on behavior and neglecting individual differences such as moral identity and virtue. A focus on individual differences in resilience to influence from trivial situational factors defangs the skeptical challenge and offers a better account of moral agency.

Offspring Size and Reproductive Allocation in Harvester Ants.

A fundamental decision that an organism must make is how to allocate resources to offspring, with respect to both size and number. The two major theoretical approaches to this problem, optimal offspring size and optimistic brood size models, make different predictions that may be reconciled by including how offspring fitness is related to size. We extended the reasoning of Trivers and Willard (1973) to derive a general model of how parents should allocate additional resources with respect to the number of males and females produced, and among individuals of each sex, based on the fitness payoffs of each. We then predicted how harvester ant colonies should invest additional resources and tested three hypotheses derived from our model, using data from 3 years of food supplementation bracketed by 6 years without food addition. All major results were predicted by our model: food supplementation increased the number of reproductives produced. Male, but not female, size increased with food addition; the greatest increases in male size occurred in colonies that made small females. We discuss how use of a fitness landscape improves quantitative predictions about allocation decisions. When parents can invest differentially in offspring of different types, the best strategy will depend on parental state as well as the effect of investment on offspring fitness.

Enhancing relationship quality measurement: The development of the Relationship Flourishing Scale.

Relationship quality is the most frequently assessed construct in the intimate relationships literature. Dozens of assessment instruments exist, but the vast majority conceptualize relationship quality in terms of satisfaction (or a similar construct), which focuses on the hedonic (pleasure or happiness) dimension of the relationship. Some scholars question whether the richness and depth of adult intimate relationships can be captured by satisfaction ratings and suggest focusing on a complementary eudaimonic (human flourishing) dimension of the relationship. This study evaluates the development of the Relationship Flourishing Scale, a 12-item measure of eudaimonic relationship quality that assesses meaning, personal growth, relational giving, and goal sharing. The study supports the construct validity of the Relationship Flourishing Scale, including its content, concurrent, convergent, discriminant, and incremental validity. Its incremental validity and independence suggest that it provides information about deeper and richer aspects of relationship quality than do current hedonic relationship quality measures. (PsycINFO Database Record

The inescapability of intersubjectivity in meaning.

Comments on the original article "Life is pretty meaningful," by S. J. Heintzelman and L. A. King (see record 2014-03265-001). The current authors welcome Heintzelman and King's discussion of meaning and agree that meaning is necessary for a good human life. The authors endorse a fully subjective understanding of meaning by focusing on personal experiences of purpose, significance, and life making sense. The current authors suggest, however, that (a) a subjective theory of meaning is only one approach to meaning, (b) the subjective theory creates serious difficulties, and (c) intersubjectivity is necessary to adequately understand meaning.