Opportunities and challenges of macrogenetic studies.

The rapidly emerging field of macrogenetics focuses on analysing publicly accessible genetic datasets from thousands of species to explore large-scale patterns and predictors of intraspecific genetic variation. Facilitated by advances in evolutionary biology, technology, data infrastructure, statistics and open science, macrogenetics addresses core evolutionary hypotheses (such as disentangling environmental and life-history effects on genetic variation) with a global focus. Yet, there are important, often overlooked, limitations to this approach and best practices need to be considered and adopted if macrogenetics is to continue its exciting trajectory and reach its full potential in fields such as biodiversity monitoring and conservation. Here, we review the history of this rapidly growing field, highlight knowledge gaps and future directions, and provide guidelines for further research.

RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells.

Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.

Male mastodon landscape use changed with maturation (late Pleistocene, North America).

Under harsh Pleistocene climates, migration and other forms of seasonally patterned landscape use were likely critical for reproductive success of mastodons (Mammut americanum) and other megafauna. However, little is known about how their geographic ranges and mobility fluctuated seasonally or changed with sexual maturity. We used a spatially explicit movement model that coupled strontium and oxygen isotopes from two serially sampled intervals (5+ adolescent years and 3+ adult years) in a male mastodon tusk to test for changes in landscape use associated with maturation and reproductive phenology. The mastodon's early adolescent home range was geographically restricted, with no evidence of seasonal preferences. Following inferred separation from the matriarchal herd (starting age 12 y), the adolescent male's mobility increased as landscape use expanded away from his natal home range (likely central Indiana). As an adult, the mastodon's monthly movements increased further. Landscape use also became seasonally structured, with some areas, including northeast Indiana, used only during the inferred mastodon mating season (spring/summer). The mastodon died in this area (>150 km from his core, nonsummer range) after sustaining a craniofacial injury consistent with a fatal blow from a competing male's tusk during a battle over access to mates. Northeast Indiana was likely a preferred mating area for this individual and may have been regionally significant for late Pleistocene mastodons. Similarities between mammutids and elephantids in herd structure, tusk dimorphism, tusk function, and the geographic component of male maturation indicate that these traits were likely inherited from a common ancestor.

Kinetic and Spectroscopic Investigation of the Y157F and C93G/Y157F Variants of Cysteine Dioxygenase: Dissecting the Roles of the Second-Sphere Residues C93 and Y157.

In mammals, l-cysteine (Cys) homeostasis is maintained by the mononuclear nonheme iron enzyme cysteine dioxygenase (CDO), which oxidizes Cys to cysteine sulfinic acid. CDO contains a rare post-translational modification, involving the formation of a thioether cross-link between a Cys residue at position 93 (Mus musculus CDO numbering) and a nearby tyrosine at position 157 (Cys-Tyr cross-link). As-isolated CDO contains both the cross-linked and non-cross-linked isoforms, and formation of the Cys-Tyr cross-link during repeated enzyme turnover increases CDO's catalytic efficiency by ∼10-fold. Interestingly, while the C93G CDO variant lacks the Cys-Tyr cross-link, it is similarly active as cross-linked wild-type (WT) CDO. Alternatively, the Y157F CDO variant, which also lacks the cross-link but maintains the free thiolate at position 93, exhibits a drastically reduced catalytic efficiency. These observations suggest that the untethered thiolate moiety of C93 is detrimental to CDO activity and/or that Y157 is essential for catalysis. To further assess the roles of residues C93 and Y157, we performed a spectroscopic and kinetic characterization of Y157F CDO and the newly designed C93G/Y157F CDO variant. Our results provide evidence that the non-cross-linked C93 thiolate stabilizes a water at the sixth coordination site of Cys-bound Y157F Fe(II)CDO. A water is also present, though more weakly coordinated, in Cys-bound C93G/Y157F Fe(II)CDO. The presence of a water molecule, which must be displaced by cosubstrate O2, likely makes a significant contribution to the ∼15-fold and ∼7-fold reduced catalytic efficiencies of the Y157F and C93G/Y157F CDO variants, respectively, relative to cross-linked WT CDO.

Folic acid supplementation in a mouse model of diabetes in pregnancy alters insulin sensitivity in female mice and beta cell mass in offspring.

Epidemiological studies have reported discrepant findings on the relationship between folic acid intake during pregnancy and risk for gestational diabetes mellitus (GDM). To begin to understand how folic acid impacts metabolic health during pregnancy, we determined the effects of excess folic acid supplementation (5× recommendation) on maternal and fetal offspring metabolic health. Using a mouse (female C57BL/6J) model of diet-induced diabetes in pregnancy (western diet) and control mice, we show that folic acid supplementation improved insulin sensitivity in the female mice fed the western diet and worsened insulin sensitivity in control mice. We found no unmetabolized folic acid in liver from supplemented mice suggesting the metabolic effects of folic acid supplementation are not due to unmetabolized folic acid. Male fetal (gestational day 18.5) offspring from folic acid supplemented dams (western and control) had greater beta cell mass and density than those from unsupplemented dams; this was not observed in female offspring. Differential sex-specific hepatic gene expression profiles were observed in the fetal offspring from supplemented dams but this differed between western and controls. Our findings suggest that folic acid supplementation affects insulin sensitivity in female mice, but is dependent on their metabolic phenotype and has sex-specific effects on offspring pancreas and liver.

Birth Prevalence of Sickle Cell Disease and County-Level Social Vulnerability - Sickle Cell Data Collection Program, 11 States, 2016-2020.

Sickle cell disease (SCD) remains a public health priority in the United States because of its association with complex health needs, reduced life expectancy, lifelong disabilities, and high cost of care. A cross-sectional analysis was conducted to calculate the crude and race-specific birth prevalence for SCD using state newborn screening program records during 2016-2020 from 11 Sickle Cell Data Collection program states. The percentage distribution of birth mother residence within Social Vulnerability Index quartiles was derived. Among 3,305 newborns with confirmed SCD (including 57% with homozygous hemoglobin S or sickle ß-null thalassemia across 11 states, 90% of whom were Black or African American [Black], and 4% of whom were Hispanic or Latino), the crude SCD birth prevalence was 4.83 per 10,000 (one in every 2,070) live births and 28.54 per 10,000 (one in every 350) non-Hispanic Black newborns. Approximately two thirds (67%) of mothers of newborns with SCD lived in counties with high or very high levels of social vulnerability; most mothers lived in counties with high or very high levels of vulnerability for racial and ethnic minority status (89%) and housing type and transportation (64%) themes. These findings can guide public health, health care systems, and community program planning and implementation that address social determinants of health for infants with SCD. Implementation of tailored interventions, including increasing access to transportation, improving housing, and advancing equity in high vulnerability areas, could facilitate care and improve health outcomes for children with SCD.

Exploring the structure of fearlessness using self-report measures.

OBJECTIVE: The present study examined the hierarchical structure of self-reported fearlessness and compared this structure to external criterion measures. BACKGROUND: Fearlessness is often discussed in relation to clinical and personality research. However, there is a paucity of research focusing on its empirical structure, in particular with self-report measures. METHOD: Using a preregistered analytical approach, we employed Goldberg's 2006 "bass-ackward" factor analysis on self-reported trait fear and fearlessness items to uncover the hierarchical structure of the construct. The final sample consisted of 619 participants and 562 informants. RESULTS: By assessing fit statistics and interpretability of the factors, we found a six-factor model fit the data best. The six-factor solution emerged as comprehensive and included components labeled Assertiveness, Low Anxiety, Sociability, Recklessness, Openness to Action, and Adventurousness. Criterion variables measuring boldness, fear, anxiety, psychopathy, basic personality traits, and impulsivity, were correlated with the factor scores at each factor level of the model. Conclusions The findings from this study elucidate how trait fearlessness unfolds at varying levels and how these factors relate to and diverge from various outcomes.

Momentary assessment of the relations between narcissistic traits, interpersonal behaviors, and aggression.

INTRODUCTION: This study explores the associations among narcissistic traits, interpersonal behaviors, and aggression using repeated, situation-based measurement. We examine narcissism's relations with aggression across three levels of its theorized hierarchy (level 1: narcissism; level 2: grandiose vs. vulnerable narcissism; level 3: antagonism, agentic extraversion, and narcissistic neuroticism). METHODS: Using an experience-sampling approach, the current study examined the effects of narcissism and its finer-grained components on daily affective experiences and aggressive behaviors in the context of interpersonal interactions. Data were collected from 477 undergraduate students who were instructed to complete four prompts a day for ten consecutive days. RESULTS: Narcissism at the global construct level positively predicted multiple indices of episodic aggression (i.e., aggressive temper, aggressive urge, verbal aggression). At the dual-dimension level, grandiose narcissism specifically predicted aggression, and then at the trifurcated level, interpersonal antagonism predicted aggression by itself and in interaction with event-level negative affect. Negative affect consistently exhibited both within- and between-person effects on aggression. CONCLUSION: In real-life social interactions, narcissism dimensions differentially affect the way individuals experience social interactions and process negative affect, and thus in both research and clinical practice, narcissism is best assessed as a heterogeneous, multidimensional construct.

The crucial role of genome-wide genetic variation in conservation.

The unprecedented rate of extinction calls for efficient use of genetics to help conserve biodiversity. Several recent genomic and simulation-based studies have argued that the field of conservation biology has placed too much focus on conserving genome-wide genetic variation, and that the field should instead focus on managing the subset of functional genetic variation that is thought to affect fitness. Here, we critically evaluate the feasibility and likely benefits of this approach in conservation. We find that population genetics theory and empirical results show that conserving genome-wide genetic variation is generally the best approach to prevent inbreeding depression and loss of adaptive potential from driving populations toward extinction. Focusing conservation efforts on presumably functional genetic variation will only be feasible occasionally, often misleading, and counterproductive when prioritized over genome-wide genetic variation. Given the increasing rate of habitat loss and other environmental changes, failure to recognize the detrimental effects of lost genome-wide genetic variation on long-term population viability will only worsen the biodiversity crisis.

Comparing Brief Measures of Narcissism-Internal Consistency, Validity, and Coverage.

Many measures, varying in breadth and length, have been constructed to measure narcissism. In recent years, super-short forms have become popular in research settings. Although brief measures hold some advantages, their brevity can come at psychometric costs. Participants recruited from Amazon's Mechanical Turk (N = 473) completed long and brief narcissism measures and criterion measures in a randomized order. Short forms were examined and compared to long forms in terms of their completion times and psychometric properties. Generally, the short forms demonstrated adequate internal consistency, variable convergence with each other, mostly moderate to strong convergence with long forms, and appropriate convergence with external criteria. These findings suggest that some short forms may be used when efficiency of survey administration is particularly important without significant psychometric cost. We discuss the advantages and disadvantages of the brief measures and make recommendations for which to use depending on the priorities of a given study.

Associations between food insecurity and child and parental physical, nutritional, psychosocial and economic well-being globally during the first 1000 days: A scoping review.

Food insecurity affects billions of individuals annually and contributes to myriad poor health outcomes. Experiences of food insecurity may be particularly harmful during the first 1000 days, but literature on the topic has not been synthesized. We therefore aimed to characterize all available studies examining associations between food insecurity and nutritional, psychosocial, physical and economic well-being among parents and children during this period. We implemented a standardized search strategy across 11 databases. Four researchers screened 10,257 articles, 120 of which met the inclusion criteria. Most studies were conducted in Sub-Saharan Africa (43.3%), followed by North America (20.8%). Studies were primarily quantitative (95.8%), cross-sectional (70.0%) and focused on women (pregnant or post-partum, 48.3%) or women and children (15.8%). Physical health outcomes were the most investigated (n = 87 studies), followed by nutritional (n = 69), psychosocial (n = 35) and economic well-being (n = 2). The most studied associations were between food insecurity and stunting (n = 15), maternal depression (n = 12), child dietary diversity (n = 7) and maternal body mass index (n = 6). The strength of evidence for the observed associations varied across populations as well as within and between examined outcomes. We recommend that future studies recruit more diverse study populations, consider temporality of relationships, use instruments that facilitate cross-site comparisons, measure individual-level food insecurity and outcomes most likely to be impacted by food insecurity, evaluate contextual factors that may modify the effects of food insecurity and employ analytic techniques that permit assessment of causal pathways.

Mapping nanocrystal orientations via scanning Laue diffraction microscopy for multi-peak Bragg coherent diffraction imaging.

The recent commissioning of a movable monochromator at the 34-ID-C endstation of the Advanced Photon Source has vastly simplified the collection of Bragg coherent diffraction imaging (BCDI) data from multiple Bragg peaks of sub-micrometre scale samples. Laue patterns arising from the scattering of a polychromatic beam by arbitrarily oriented nanocrystals permit their crystal orientations to be computed, which are then used for locating and collecting several non-co-linear Bragg reflections. The volumetric six-component strain tensor is then constructed by combining the projected displacement fields that are imaged using each of the measured reflections via iterative phase retrieval algorithms. Complications arise when the sample is heterogeneous in composition and/or when multiple grains of a given lattice structure are simultaneously illuminated by the polychromatic beam. Here, a workflow is established for orienting and mapping nanocrystals on a substrate of a different material using scanning Laue diffraction microscopy. The capabilities of the developed algorithms and procedures with both synthetic and experimental data are demonstrated. The robustness is verified by comparing experimental texture maps obtained with Laue diffraction microscopy at the beamline with maps obtained from electron back-scattering diffraction measurements on the same patch of gold nanocrystals. Such tools provide reliable indexing for both isolated and densely distributed nanocrystals, which are challenging to image in three dimensions with other techniques.

Body Composition Trajectories During the First 23 Months of Life Differ by HIV Exposure Among Infants in Western Kenya: A Prospective Study.

BACKGROUND: Infants who are HIV-exposed and uninfected have suboptimal growth patterns compared to those who are HIV-unexposed and uninfected. However, little is known about how these patterns persist beyond 1 year of life. OBJECTIVES: This study aimed to examine whether infant body composition and growth trajectories differed by HIV exposure during the first 2 years of life among Kenyan infants using advanced growth modeling. METHODS: Repeated infant body composition and growth measurements (mean: 6; range: 2-7) were obtained from 6 weeks to 23 months in the Pith Moromo cohort in Western Kenya (n = 295, 50% HIV-exposed and uninfected, 50% male). Body composition trajectory groups were fitted using latent class mixed modeling (LCMM) and associations between HIV exposure and growth trajectories were examined using logistic regression analysis. RESULTS: All infants exhibited poor growth. However, HIV-exposed infants generally grew suboptimally than unexposed infants. Across all body composition models except for the sum of skinfolds, HIV-exposed infants had a higher likelihood of belonging to the suboptimal growth groups identified by LCMM than the HIV-unexposed infants. Notably, HIV-exposed infants were 3.3 times more likely (95% CI: 1.5-7.4) to belong to the length-for-age z-score growth class that remained at a z-score of < -2, indicating stunted growth. HIV-exposed infants were also 2.6 times more likely (95% CI: 1.2-5.4) to belong to the weight-for-length-for-age z-score growth class that remained between 0 and -1, and were 4.2 times more likely (95% CI: 1.9-9.3) to belong to the weight-for-age z-score growth class that indicated poor weight gain besides stunted linear growth. CONCLUSIONS: In a cohort of Kenyan infants, HIV-exposed infants grew suboptimally compared to HIV-unexposed infants beyond 1 year of age. These growth patterns and longer-term effects should be further investigated to support the ongoing efforts to reduce early-life HIV exposure-related health disparities.

Impacts and mitigation of excess diesel-related NOx emissions in 11 major vehicle markets.

Vehicle emissions contribute to fine particulate matter (PM2.5) and tropospheric ozone air pollution, affecting human health, crop yields and climate worldwide. On-road diesel vehicles produce approximately 20 per cent of global anthropogenic emissions of nitrogen oxides (NOx), which are key PM2.5 and ozone precursors. Regulated NOx emission limits in leading markets have been progressively tightened, but current diesel vehicles emit far more NOx under real-world operating conditions than during laboratory certification testing. Here we show that across 11 markets, representing approximately 80 per cent of global diesel vehicle sales, nearly one-third of on-road heavy-duty diesel vehicle emissions and over half of on-road light-duty diesel vehicle emissions are in excess of certification limits. These excess emissions (totalling 4.6 million tons) are associated with about 38,000 PM2.5- and ozone-related premature deaths globally in 2015, including about 10 per cent of all ozone-related premature deaths in the 28 European Union member states. Heavy-duty vehicles are the dominant contributor to excess diesel NOx emissions and associated health impacts in almost all regions. Adopting and enforcing next-generation standards (more stringent than Euro 6/VI) could nearly eliminate real-world diesel-related NOx emissions in these markets, avoiding approximately 174,000 global PM2.5- and ozone-related premature deaths in 2040. Most of these benefits can be achieved by implementing Euro VI standards where they have not yet been adopted for heavy-duty vehicles.

The Questionable Practice of Partialing to Refine Scores on and Inferences About Measures of Psychological Constructs.

Partialing is a statistical approach researchers use with the goal of removing extraneous variance from a variable before examining its association with other variables. Controlling for confounds through analysis of covariance or multiple regression analysis and residualizing variables for use in subsequent analyses are common approaches to partialing in clinical research. Despite its intuitive appeal, partialing is fraught with undesirable consequences when predictors are correlated. After describing effects of partialing on variables, we review analytic approaches commonly used in clinical research to make inferences about the nature and effects of partialed variables. We then use two simulations to show how partialing can distort variables and their relations with other variables. Having concluded that, with rare exception, partialing is ill-advised, we offer recommendations for reducing or eliminating problematic uses of partialing. We conclude that the best alternative to partialing is to define and measure constructs so that it is not needed.

A comprehensive item-level examination of Conscientiousness' underlying structure across three large samples.

OBJECTIVE: The present study examined the hierarchical structure of Conscientiousness across three large samples using item-level analyses. BACKGROUND: Conscientiousness is among the strongest predictors of individual differences in major life outcomes. Yet decades of work understanding the optimal lower-order structure of Conscientiousness has not rectified the differences that remain among existing models and measures. To precisely measure its relations to major life outcomes, it is necessary to work toward a comprehensive, replicable conceptualization of the construct's structure. METHODS: The present pre-registered study used three samples (Ns = 446, 406, & 424) to explore the domain's latent structure with item-level "bass-ackward" factor analyses and evaluate the resulting structure's interpretability, parsimony, and replicability. Participants completed self-report measures of Conscientiousness and criteria in its nomological network (e.g., FFM traits, externalizing behavior, disinhibitory traits; informant reports were collected as well). RESULTS: The factor analyses identified five interpretable and replicable factors (i.e., deliberation, order, industriousness, self-discipline, and dependability) using predominant measures of general personality. An additional factor (i.e., traditionalism) was introduced in the six-factor solution when the item pool was expanded to include less widely used measures of general personality. CONCLUSION: The authors discuss the item composition of each factor, their relation to existing models and measures of the domain's structure, their association with relevant criteria, and the general implications of conceptualizing Conscientiousness using flexible, item-level factor analysis.

The structure of aggressive personality.

OBJECTIVE: We sought to factor analyze a broad array of aggression measures to identify a comprehensive, coherent factor structure for this construct. BACKGROUND: Measures and models of trait aggression have multiplied to the point of incoherence. METHOD: In Study 1, a diverse sample of 922 undergraduates completed a battery of items acquired from 42 self-report aggression questionnaires. In Study 2, we administered a curated item pool to another diverse sample of 1447 undergraduates, alongside criterion measures. RESULTS: We curated an initial item pool of 734 items down to 289 items that exhibited sufficient variability, were not redundant with other items, and possessed strong loadings onto a central 'trait aggression' factor. These remaining items were best characterized by a six-factor structure, which captured relational, angry, violent, retaliatory, intimate partner, and alcohol forms of aggression. We estimated their hierarchical structure, correlations with their original aggression scales, Five Factor Model trait dimensions, impulsivity facets, and found them to be robust to gender composition and the inclusion of alcohol-naive and intimate-partner-naive participants. CONCLUSIONS: This factor structure mostly supported widely-accepted models of aggressive personality that focus on its overt and relational forms and reactive functions, though proactive aggression only loosely emerged as a distinct entity. We retained the final items as the Comprehensive Aggression Scale (CAS).

Development of a measure of aggressive behavior expectancies in adults: The Aggression Expectancy Questionnaire.

According to sociocognitive theories, aggression is learned and elicited through a series of cognitive processes, such as expectancies, or the various consequences that an individual considers more or less likely following aggressive behavior. The current manuscript describes a measurement development project that ultimately yielded a 16-item measure of positive and negative aggression expectancies suitable for use in adult populations. Across two content generation surveys, two preliminary item refinement studies, and three full studies, we took an iterative approach and administered large item pools to several samples and refined item content through a combination of empirical (i.e., factor loadings, model fit) and conceptual (i.e., content breadth, non-redundancy) considerations. The Aggression Expectancy Questionnaire displays a four-factor structure, as well as evidence of convergent and divergent validity with self-reported aggression and relevant basic (e.g., antagonism, anger) and complex (e.g., psychopathy) personality variables. It is posited that this type of cognitive mechanism may serve as an intermediary link between distal characterological predictors of aggression and its proximal manifestation, which is in line with several prominent theories of personality and may ultimately hold clinical utility by providing a framework for aggression interventions.

Factor Structure of the FFM ATM: Antagonism, Emotional Stability, Impulsivity, and Agency.

The Dark Triad (DT) refers to three socially aversive personality constructs: psychopathy, narcissism, and Machiavellianism. In response to concerns with existing self-report questionnaires measuring these constructs, we created the Five Factor Model Antagonistic Triad Measure (FFM ATM), which uses 46 items to assess multidimensional, faceted versions of the three DT constructs. The current pre-registered study used two large samples (Ns = 600 and 1,247) to explore the structure of the FFM ATM using bass-ackward factor analyses. Participants completed the FFM ATM as well as measures of the five-factor model, aggression, antisocial behavior, and other criteria. A series of factor analyses identified four meaningful and replicable factors (i.e., Antagonism, Emotional Stability, Impulsivity, and Agency). The authors discuss the item composition of each of these factors, their relations to relevant criteria, and implications of conceptualizing the Antagonistic Triad as combinations of elemental traits (factors) as opposed to the multidimensional constructs of psychopathy, narcissism, and Machiavellianism.