Evolutionary and biomedical implications of sex differences in the primate brain transcriptome.

Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest multi-brain-region bulk transcriptional datasets for the rhesus macaque and characterized sex-biased gene expression patterns to investigate the translatability of this species for sex-biased neurological conditions. We identify patterns similar to those in humans, which are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and support the rhesus macaque model for the translational study of these conditions.

Socioecological drivers of injuries in female and male rhesus macaques (Macaca mulatta).

Competition over access to resources, such as food and mates, is believed to be one of the major costs associated with group living. Two socioecological factors suggested to predict the intensity of competition are group size and the relative abundance of sexually active individuals. However, empirical evidence linking these factors to injuries and survival costs is scarce. Here, we leveraged 10 years of data from free-ranging rhesus macaques where injuries inflicted by conspecifics are associated with a high mortality risk. We tested if group size and adult sex ratio predicted the occurrence of injuries and used data on physical aggression to contextualise these results. We found that males were less likely to be injured when living in larger groups, potentially due to advantages in intergroup encounters. Females, instead, had higher injury risk when living in larger groups but this was not explained by within-group aggression among females. Further, male-biased sex ratios predicted a weak increase in injury risk in females and were positively related to male-female aggression, indicating that male coercion during mating competition may be a cause of injuries in females. Overall, our results provide insights into sex differences in the fitness-related costs of competition and empirical evidence for long-standing predictions on the evolution of group living.

Social ageing can protect against infectious disease in a group-living primate.

The benefits of social living are well established, but sociality also comes with costs, including infectious disease risk. This cost-benefit ratio of sociality is expected to change across individuals' lifespans, which may drive changes in social behaviour with age. To explore this idea, we combine data from a group-living primate for which social ageing has been described with epidemiological models to show that having lower social connectedness when older can protect against the costs of a hypothetical, directly transmitted endemic pathogen. Assuming no age differences in epidemiological characteristics (susceptibility to, severity, and duration of infection), older individuals suffered lower infection costs, which was explained largely because they were less connected in their social networks than younger individuals. This benefit of 'social ageing' depended on epidemiological characteristics and was greatest when infection severity increased with age. When infection duration increased with age, social ageing was beneficial only when pathogen transmissibility was low. Older individuals benefited most from having a lower frequency of interactions (strength) and network embeddedness (closeness) and benefited less from having fewer social partners (degree). Our study provides a first examination of the epidemiology of social ageing, demonstrating the potential for pathogens to influence evolutionary dynamics of social ageing in natural populations.

An exploratory analysis of PM 2.5 /PM 10 ratio during 2016-2018 in Metropolitan Lima.

Aerosols (PM 2.5 and PM 10 ) represent one of the most critical pollutants due to their negative effects on human health. This research analyzed the relationship of PM and its PM 2.5 /PM 10 ratios with climatic variables in the austral spring (2016-2018) in Metropolitan Lima. Overall, there was an average PM 2.5 /PM 10 ratio of 0.33 with fluctuations from 0.30 to 0.35. However, there have also been high point values that reached ratios greater than one. This situation indicates a moderate condition of contamination by particulate matter with a predominance of coarse aerosols in spring, with an increasing trend over the years. The locations Ate and Villa Maria del Triunfo, especially Ate, presented poor quality conditions. Thursdays showed outstanding pollution peaks by PM 10 , and a decrease is visible on Sundays. On the other hand, the PM 2.5 showed a similar pattern every day, including Sundays. The maximum peaks occurred in the morning and night hours. The increase in anthropogenic emissions associated with the formation of secondary aerosols has been evident, being the case of the location Campo de Marte, the one that had a significant increase in ratios PM 2.5 /PM 10 , which confirms a greater intensity of secondary formations of carbonaceous particles from industrial oil sources, vehicle exhaust, as well as aerosols from metal smelting and biomass burning. There were negative correlations of the ratios with PM 10 , temperature, wind speed, and direction, and positive correlations with PM 2.5 and relative humidity. Contour lines were successfully developed that demonstrated the interaction of climate with PM 2.5 /PM 10 ratios. This will deepen the exploration of emission sources and modeling, which allows for optimizing air quality indices to control emissions and adequately manage air quality in Metropolitan Lima.

STAT3 protects hematopoietic stem cells by preventing activation of a deleterious autocrine type-I interferon response.

Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, and interferon (IFN) pathways in Stat3-deficient HSPCs. Stat3-deficient LSKs accumulated γH2AX and showed increased expression of DNA sensors and type-I IFN (IFN-I), while treatment with A151-ODN inhibited expression of IFN-I and IFN-responsive genes. Further, the blockade of IFN-I receptor signaling suppressed aberrant cell cycling, STAT1 activation, and nuclear p53 accumulation. Collectively, our results show that STAT3 inhibits a deleterious autocrine IFN response in HSCs to maintain long-term HSC function. These data signify the importance of ensuring therapeutic STAT3 inhibitors are targeted specifically to diseased cells to avoid off-target loss of healthy HSPCs.

Surfactant-tail control of CsPbBr3 nanocrystal morphology.

CsPbBr3 nanocrystals (NCs) are promising optoelectronic and catalytic materials. Manipulating their morphology can improve their properties and stability. In this work, an alkene-derived zwitterionic ligand was used to control the morphology of CsPbBr3 NCs to yield the highly unusual rhombicuboctahedron morphology, showcasing the first example of a surfactant-tail controlled growth.

Neoantigen Cancer Vaccines and Different Immune Checkpoint Therapies Each Utilize Both Converging and Distinct Mechanisms that in Combination Enable Synergistic Therapeutic Efficacy.

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to eliminate cancer by expanding and/or sustaining T cells with anti-tumor capabilities. However, whether cancer vaccines and ICT enhance anti-tumor immunity by distinct or overlapping mechanisms remains unclear. Here, we compared effective therapeutic tumor-specific mutant neoantigen (NeoAg) cancer vaccines with anti-CTLA-4 and/or anti-PD-1 ICT in preclinical models. Both NeoAg vaccines and ICT induce expansion of intratumoral NeoAg-specific CD8 T cells, though the degree of expansion and acquisition of effector activity was much more substantial following NeoAg vaccination. Further, we found that NeoAg vaccines are particularly adept at inducing proliferating and stem-like NeoAg-specific CD8 T cells. Single cell T cell receptor (TCR) sequencing revealed that TCR clonotype expansion and diversity of NeoAg-specific CD8 T cells relates to their phenotype and functional state associated with specific immunotherapies employed. Effective NeoAg vaccines and ICT required both CD8 and CD4 T cells. While NeoAg vaccines and anti-PD-1 affected the CD4 T cell compartment, it was to less of an extent than observed with anti-CTLA-4, which notably induced ICOS+Bhlhe40+ Th1-like CD4 T cells and, when combined with anti-PD-1, a small subset of Th2-like CD4 T cells. Although effective NeoAg vaccines or ICT expanded intratumoral M1-like iNOS+ macrophages, NeoAg vaccines expanded rather than suppressed (as observed with ICT) M2-like CX3CR1+CD206+ macrophages, associated with the vaccine adjuvant. Further, combining NeoAg vaccination with ICT induced superior efficacy compared to either therapy in isolation, highlighting the utility of combining these modalities to eliminate cancer.

Epilepsy in cardiofaciocutaneous syndrome: Clinical burden and response to anti-seizure medication.

Treatment-resistant epilepsy is among the most serious complications of cardiofaciocutaneous syndrome (CFCS), a rare disorder caused by germline variants in the RAS-MAPK signaling pathway. This study analyzed the clinical characteristics of epilepsy and response to anti-seizure medications (ASMs) in a multinational CFCS cohort. A caregiver survey provided data regarding seizure history, use of ASMs and other treatment approaches, adverse effects, caregiver perception of treatment response, and neurological disease burden impact among individuals with CFCS. Results from 138 survey responses were quantitatively analyzed in conjunction with molecular genetic results and neurological records. The disease burden impact of CFCS was higher among individuals with epilepsy (n = 74/138), especially those with more severe seizure presentation. Oxcarbazepine, a sodium-channel blocker, had the best seizure control profile with relatively infrequent adverse effects. The most commonly prescribed ASM, levetiracetam, demonstrated comparatively poor seizure control. ASM efficacy was generally similar for individuals with BRAF and MAP2K1 gene variants. The high proportion of patients with CFCS who experienced poor seizure control despite use of multiple ASMs highlights a substantial unmet treatment need. Prospective study of ASM efficacy and clinical trials of therapies to attenuate RAS-MAPK signaling may improve avenues for clinical management.

Immune cell composition varies by age, sex and exposure to social adversity in free-ranging Rhesus Macaques.

Increasing age is associated with dysregulated immune function and increased inflammation-patterns that are also observed in individuals exposed to chronic social adversity. Yet we still know little about how social adversity impacts the immune system and how it might promote age-related diseases. Here, we investigated how immune cell diversity varied with age, sex and social adversity (operationalized as low social status) in free-ranging rhesus macaques. We found age-related signatures of immunosenescence, including lower proportions of CD20 + B cells, CD20 + /CD3 + ratio, and CD4 + /CD8 + T cell ratio - all signs of diminished antibody production. Age was associated with higher proportions of CD3 + /CD8 + Cytotoxic T cells, CD16 + /CD3- Natural Killer cells, CD3 + /CD4 + /CD25 + and CD3 + /CD8 + /CD25 + T cells, and CD14 + /CD16 + /HLA-DR + intermediate monocytes, and lower levels of CD14 + /CD16-/HLA-DR + classical monocytes, indicating greater amounts of inflammation and immune dysregulation. We also found a sex-dependent effect of exposure to social adversity (i.e., low social status). High-status males, relative to females, had higher CD20 + /CD3 + ratios and CD16 + /CD3 Natural Killer cell proportions, and lower proportions of CD8 + Cytotoxic T cells. Further, low-status females had higher proportions of cytotoxic T cells than high-status females, while the opposite was observed in males. High-status males had higher CD20 + /CD3 + ratios than low-status males. Together, our study identifies the strong age and sex-dependent effects of social adversity on immune cell proportions in a human-relevant primate model. Thus, these results provide novel insights into the combined effects of demography and social adversity on immunity and their potential contribution to age-related diseases in humans and other animals.

Early life adversity has sex-dependent effects on survival across the lifespan in rhesus macaques.

Exposure to adversity during early life is linked to lasting detrimental effects on evolutionary fitness across many taxa. However, due to the challenges of collecting longitudinal data, especially in species where one sex disperses, direct evidence from long-lived species remains relatively scarce. Here we test the effects of early life adversity on male and female longevity in a free-ranging population of rhesus macaques (Macaca mulatta) at Cayo Santiago, Puerto Rico. We leveraged six decades of data to quantify the relative importance of ten forms of early life adversity for 6,599 macaques (3,230 male, 3,369 female), with a smaller sample size (N=299) for one form of adversity (maternal social isolation) which required high-resolution behavioral data. We found that individuals who experienced more early life adversity died earlier than those who experienced less adversity. Mortality risk was highest during early life, defined as birth to four years old, suggesting acute survival effects of adversity, but heightened mortality risk was also present in macaques who survived to adulthood. Females and males were affected differently by some forms of adversity, and these differences might be driven by varying energetic demands, female philopatry, and male dispersal. By leveraging data on thousands of macaques collected over decades, our results show that the fitness consequences of early life adversity are not uniform across individuals but vary as a function of the type of adversity, timing, and social context, and thus contribute to our limited but growing understanding of the evolution of early life sensitivities in long-lived species.

Social responses to a hurricane drive greater epidemic risk.

The increasing frequency and intensity of extreme weather events due to climate change has the potential to alter ecosystem dynamics and wildlife health. Here we show that increasing social connections in response to a hurricane enhanced disease transmission risk for years after the event in a population of rhesus macaques. Our findings reveal that behavioural responses to natural disasters can elevate epidemic risk, thereby threatening wildlife health, population viability, and spillover to humans.

The Design and Validation of a Compassion Fatigue Scale in Peruvian Nurses.

The objective of this study was to design and validate the Compassion Fatigue Scale (EFat-Com) in Peruvian nurses. METHODS: A 13-item scale was designed using qualitative procedures and expert judgment. This version was administered to 201 nursing professionals using an electronic form along with two other measures: the Patient Health Questionnarie-2 and the Satisfaction with Life Scale. RESULTS: Exploratory factor analysis supported the existence of two factors with factor loadings > 0.54. Confirmatory factor analysis of the two-factor model yielded satisfactory fit indices after the elimination of two items. Regarding concurrent validity, a positive relationship was obtained between the EFat-Com and the measure of depression; however, no correlation was found with the measure of life satisfaction. The internal consistency was 0.807 for the total scale, 0.79 for Factor 1, and 0.83 for Factor 2. CONCLUSIONS: The EFat-Com showed adequate psychometric properties with respect to content-based validity evidence, internal structure, and reliability. Therefore, the instrument can be used in research and professional settings. However, it is essential to continue studying the validity evidence in other contexts.

A Network Analysis of Executive Functions in Children and Adolescents With and Without Attention-Deficit/Hyperactivity Disorder.

This study applied network analysis to executive function test performances to examine differences in network parameters between demographically matched children and adolescents with and without attention-deficit/hyperactivity disorder (ADHD) (n = 141 per group; M = 12.7 ± 2.9 years-old; 72.3% boys, 66.7% White, 65.2% ≥ 12 years maternal education). All participants completed the NIH Toolbox Cognition Battery, including the Flanker, measuring inhibition, Dimensional Change Card Sort, measuring shifting, and List Sorting test, measuring working memory. Children with and without ADHD had comparable mean test performances (d range: .05-0.11) but presented with differences in network parameters. Among participants with ADHD, shifting was less central, had a weaker relationship with inhibition, and did not mediate the relationship between inhibition and working memory. These network characteristics were consistent with the executive function network structure of younger ages in prior research and may reflect an immature executive function network among children and adolescents with ADHD, aligning with the delayed maturation hypothesis.

Heterogeneous heterogeneity by default: Testing categorical moderators in mixed-effects meta-analysis.

Categorical moderators are often included in mixed-effects meta-analysis to explain heterogeneity in effect sizes. An assumption in tests of categorical moderator effects is that of a constant between-study variance across all levels of the moderator. Although it rarely receives serious thought, there can be statistical ramifications to upholding this assumption. We propose that researchers should instead default to assuming unequal between-study variances when analysing categorical moderators. To achieve this, we suggest using a mixed-effects location-scale model (MELSM) to allow group-specific estimates for the between-study variance. In two extensive simulation studies, we show that in terms of Type I error and statistical power, little is lost by using the MELSM for moderator tests, but there can be serious costs when an equal variance mixed-effects model (MEM) is used. Most notably, in scenarios with balanced sample sizes or equal between-study variance, the Type I error and power rates are nearly identical between the MEM and the MELSM. On the other hand, with imbalanced sample sizes and unequal variances, the Type I error rate under the MEM can be grossly inflated or overly conservative, whereas the MELSM does comparatively well in controlling the Type I error across the majority of cases. A notable exception where the MELSM did not clearly outperform the MEM was in the case of few studies (e.g., 5). With respect to power, the MELSM had similar or higher power than the MEM in conditions where the latter produced non-inflated Type 1 error rates. Together, our results support the idea that assuming unequal between-study variances is preferred as a default strategy when testing categorical moderators.

STAT3 protects HSCs from intrinsic interferon signaling and loss of long-term blood-forming activity.

STAT3 function in hematopoietic stem and progenitor cells (HSPCs) has been difficult to discern as Stat3 deficiency in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. To address this, we established mixed bone marrow (BM) chimeric mice with CreER-mediated Stat3 deletion in 20% of the hematopoietic compartment. Stat3-deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM in contrast to Stat3-sufficient (CreER) controls. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells revealed altered transcriptional responses in Stat3-deficient hematopoietic stem cells (HSCs) and multipotent progenitors, including intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation, Stat3-deficient Lin-ckit+Sca1+ cells accumulated γH2AX over time. Following secondary BM transplantation, Stat3-deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs.

Ageing in a collective: the impact of ageing individuals on social network structure.

Ageing affects many phenotypic traits, but its consequences for social behaviour have only recently become apparent. Social networks emerge from associations between individuals. The changes in sociality that occur as individuals get older are thus likely to impact network structure, yet this remains unstudied. Here we use empirical data from free-ranging rhesus macaques and an agent-based model to test how age-based changes in social behaviour feed up to influence: (i) an individual's level of indirect connectedness in their network and (ii) overall patterns of network structure. Our empirical analyses revealed that female macaques became less indirectly connected as they aged for some, but not for all network measures examined. This suggests that indirect connectivity is affected by ageing, and that ageing animals can remain well integrated in some social contexts. Surprisingly, we did not find evidence for a relationship between age distribution and the structure of female macaque networks. We used an agent-based model to gain further understanding of the link between age-based differences in sociality and global network structure, and under which circumstances global effects may be detectable. Overall, our results suggest a potentially important and underappreciated role of age in the structure and function of animal collectives, which warrants further investigation. This article is part of a discussion meeting issue 'Collective behaviour through time'.

Spatio-temporal visualization and forecasting of [Formula: see text] in the Brazilian state of Minas Gerais.

Air pollution due to air contamination by gases, liquids, and solid particles in suspension, is a great environmental and public health concern nowadays. An important type of air pollution is particulate matter with a diameter of 10 microns or less ([Formula: see text]) because one of the determining factors that affect human health is the size of particles in the atmosphere due to the degree of permanence and penetration they have in the respiratory system. Therefore, it is extremely interesting to monitor and understand the behavior of [Formula: see text] concentrations so that they do not exceed the established critical levels. In this work, we will study the [Formula: see text] concentrations in all available monitoring stations in the Brazilian state of Minas Gerais. To better understand its behavior, we will provide a spatio-temporal visualization of the [Formula: see text] concentrations. Besides the descriptive and visualization analysis, we consider six standard and advanced time series models that will be used to fit and forecast [Formula: see text] concentrations, with application to three locations, one in Belo Horizonte, the Minas Gerais state capital, and the monitoring stations with the lowest and highest average [Formula: see text] concentration levels.

Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4-mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

Who is and is not "average"? Random effects selection with spike-and-slab priors.

Mixed-effects models are often employed to study individual differences in psychological science. Such analyses commonly entail testing whether between-subjects variability exists and including covariates to explain that variability. We argue that researchers have much to gain by explicitly focusing on the individual in individual differences research. To this end, we propose the spike-and-slab prior distribution for random effect selection in (generalized) mixed-effects models as a means to gain a more nuanced perspective of individual differences. The prior for each random effect is a two-component mixture consisting of a point-mass "spike" centered at zero and a diffuse "slab" capturing nonzero values. Effectively, such an approach allows researchers to answer questions about particular individuals; specifically, "Who is average?", in the sense of deviating from an average effect, such as the population-averaged slope. We begin with an illustrative example, where the spike-and-slab formulation is used to select random intercepts in logistic regression. This demonstrates the utility of the proposed methodology in a simple setting while also highlighting its flexibility in fitting different kinds of models. We then extend the approach to random slopes that capture experimental effects. In two cognitive tasks, we show that despite there being little variability in the slopes, there were many individual differences in performance. In two simulation studies, we assess the ability of the proposed method to correctly identify (non)average individuals without compromising the mixed-effects estimates. We conclude with future directions for the presented methodology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Multiregion transcriptomic profiling of the primate brain reveals signatures of aging and the social environment.

Aging is accompanied by a host of social and biological changes that correlate with behavior, cognitive health and susceptibility to neurodegenerative disease. To understand trajectories of brain aging in a primate, we generated a multiregion bulk (N = 527 samples) and single-nucleus (N = 24 samples) brain transcriptional dataset encompassing 15 brain regions and both sexes in a unique population of free-ranging, behaviorally phenotyped rhesus macaques. We demonstrate that age-related changes in the level and variance of gene expression occur in genes associated with neural functions and neurological diseases, including Alzheimer's disease. Further, we show that higher social status in females is associated with younger relative transcriptional ages, providing a link between the social environment and aging in the brain. Our findings lend insight into biological mechanisms underlying brain aging in a nonhuman primate model of human behavior, cognition and health.