Genomic architecture of autism from comprehensive whole-genome sequence annotation.

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

Specimen collection is essential for modern science.

Natural history museums are vital repositories of specimens, samples and data that inform about the natural world; this Formal Comment revisits a Perspective that advocated for the adoption of compassionate collection practices, querying whether it will ever be possible to completely do away with whole animal specimen collection.

Whole genome sequencing reveals stepping-stone dispersal buffered against founder effects in a range expanding seabird.

Many species are shifting their ranges in response to climate-driven environmental changes, particularly in high-latitude regions. However, the patterns of dispersal and colonization during range shifting events are not always clear. Understanding how populations are connected through space and time can reveal how species navigate a changing environment. Here, we present a fine-scale population genomics study of gentoo penguins (Pygoscelis papua), a presumed site-faithful colonial nesting species that has increased in population size and expanded its range south along the Western Antarctic Peninsula. Using whole genome sequencing, we analysed 129 gentoo penguin individuals across 12 colonies located at or near the southern range edge. Through a detailed examination of fine-scale population structure, admixture, and population divergence, we inferred that gentoo penguins historically dispersed rapidly in a stepping-stone pattern from the South Shetland Islands leading to the colonization of Anvers Island, and then the adjacent mainland Western Antarctica Peninsula. Recent southward expansion along the Western Antarctic Peninsula also followed a stepping-stone dispersal pattern coupled with limited post-divergence gene flow from colonies on Anvers Island. Genetic diversity appeared to be maintained across colonies during the historical dispersal process, and range-edge populations are still growing. This suggests large numbers of migrants may provide a buffer against founder effects at the beginning of colonization events to maintain genetic diversity similar to that of the source populations before migration ceases post-divergence. These results coupled with a continued increase in effective population size since approximately 500-800 years ago distinguish gentoo penguins as a robust species that is highly adaptable and resilient to changing climate.

Increasing the impact of vertebrate scientific collections through 3D imaging: The openVertebrate (oVert) Thematic Collections Network.

The impact of preserved museum specimens is transforming and increasing by three-dimensional (3D) imaging that creates high-fidelity online digital specimens. Through examples from the openVertebrate (oVert) Thematic Collections Network, we describe how we created a digitization community dedicated to the shared vision of making 3D data of specimens available and the impact of these data on a broad audience of scientists, students, teachers, artists, and more. High-fidelity digital 3D models allow people from multiple communities to simultaneously access and use scientific specimens. Based on our multiyear, multi-institution project, we identify significant technological and social hurdles that remain for fully realizing the potential impact of digital 3D specimens.

Marine sulfated glycans inhibit the interaction of heparin with S-protein of SARS-CoV-2 Omicron XBB variant.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide COVID-19 pandemic, leading to 6.8 million deaths. Numerous variants have emerged since its outbreak, resulting in its significantly enhanced ability to spread among humans. As with many other viruses, SARS­CoV­2 utilizes heparan sulfate (HS) glycosaminoglycan (GAG) on the surface of host cells to facilitate viral attachment and initiate cellular entry through the ACE2 receptor. Therefore, interfering with virion-HS interactions represents a promising target to develop broad-spectrum antiviral therapeutics. Sulfated glycans derived from marine organisms have been proven to be exceptional reservoirs of naturally existing HS mimetics, which exhibit remarkable therapeutic properties encompassing antiviral/microbial, antitumor, anticoagulant, and anti-inflammatory activities. In the current study, the interactions between the receptor-binding domain (RBD) of S-protein of SARS-CoV-2 (both WT and XBB.1.5 variants) and heparin were applied to assess the inhibitory activity of 10 marine-sourced glycans including three sulfated fucans, three fucosylated chondroitin sulfates and two fucoidans derived from sea cucumbers, sea urchin and seaweed Saccharina japonica, respectively. The inhibitory activity of these marine derived sulfated glycans on the interactions between RBD of S-protein and heparin was evaluated using Surface Plasmon Resonance (SPR). The RBDs of S-proteins from both Omicrion XBB.1.5 and wild-type (WT) were found to bind to heparin, which is a highly sulfated form of HS. All the tested marine-sourced sulfated glycans exhibited strong inhibition of WT and XBB.1.5 S-protein binding to heparin. We believe the study on the molecular interactions between S-proteins and host cell glycosaminoglycans provides valuable insight for the development of marine-sourced, glycan-based inhibitors as potential anti-SARS-CoV-2 agents.

Kindergarten conduct problems are associated with monetized outcomes in adolescence and adulthood.

BACKGROUND: Across several sites in the United States, we examined whether kindergarten conduct problems among mostly population-representative samples of children were associated with increased criminal and related (criminal + lost offender productivity + victim; described as criminal + victim hereafter) costs across adolescence and adulthood, as well as government and medical services costs in adulthood. METHODS: Participants (N = 1,339) were from two multisite longitudinal studies: Fast Track (n = 754) and the Child Development Project (n = 585). Parents and teachers reported on kindergarten conduct problems, administrative and national database records yielded indexes of criminal offending, and participants self-reported their government and medical service use. Outcomes were assigned costs, and significant associations were adjusted for inflation to determine USD 2020 costs. RESULTS: A 1SD increase in kindergarten conduct problems was associated with a $21,934 increase in adolescent criminal + victim costs, a $63,998 increase in adult criminal + victim costs, a $12,753 increase in medical services costs, and a $146,279 increase in total costs. In the male sample, a 1SD increase in kindergarten conduct problems was associated with a $28,530 increase in adolescent criminal + victim costs, a $58,872 increase in adult criminal + victim costs, and a $144,140 increase in total costs. In the female sample, a 1SD increase in kindergarten conduct problems was associated with a $15,481 increase in adolescent criminal + victim costs, a $62,916 increase in adult criminal + victim costs, a $24,105 increase in medical services costs, and a $144,823 increase in total costs. CONCLUSIONS: This investigation provides evidence of the long-term costs associated with early-starting conduct problems, which is important information that can be used by policymakers to support research and programs investing in a strong start for children.

Contrasting drivers of diversity in hosts and parasites across the tropical Andes.

Geographic turnover in community composition is created and maintained by eco-evolutionary forces that limit the ranges of species. One such force may be antagonistic interactions among hosts and parasites, but its general importance is unknown. Understanding the processes that underpin turnover requires distinguishing the contributions of key abiotic and biotic drivers over a range of spatial and temporal scales. Here, we address these challenges using flexible, nonlinear models to identify the factors that underlie richness (alpha diversity) and turnover (beta diversity) patterns of interacting host and parasite communities in a global biodiversity hot spot. We sampled 18 communities in the Peruvian Andes, encompassing ∼1,350 bird species and ∼400 hemosporidian parasite lineages, and spanning broad ranges of elevation, climate, primary productivity, and species richness. Turnover in both parasite and host communities was most strongly predicted by variation in precipitation, but secondary predictors differed between parasites and hosts, and between contemporary and phylogenetic timescales. Host communities shaped parasite diversity patterns, but there was little evidence for reciprocal effects. The results for parasite communities contradicted the prevailing view that biotic interactions filter communities at local scales while environmental filtering and dispersal barriers shape regional communities. Rather, subtle differences in precipitation had strong, fine-scale effects on parasite turnover while host-community effects only manifested at broad scales. We used these models to map bird and parasite turnover onto the ecological gradients of the Andean landscape, illustrating beta-diversity hot spots and their mechanistic underpinnings.

The degree of polymerization and sulfation patterns in heparan sulfate are critical determinants of cytomegalovirus entry into host cells.

Several enveloped viruses, including herpesviruses attach to host cells by initially interacting with cell surface heparan sulfate (HS) proteoglycans followed by specific coreceptor engagement which culminates in virus-host membrane fusion and virus entry. Interfering with HS-herpesvirus interactions has long been known to result in significant reduction in virus infectivity indicating that HS play important roles in initiating virus entry. In this study, we provide a series of evidence to prove that specific sulfations as well as the degree of polymerization (dp) of HS govern human cytomegalovirus (CMV) binding and infection. First, purified CMV extracellular virions preferentially bind to sulfated longer chain HS on a glycoarray compared to a variety of unsulfated glycosaminoglycans including unsulfated shorter chain HS. Second, the fraction of glycosaminoglycans (GAG) displaying higher dp and sulfation has a larger impact on CMV titers compared to other fractions. Third, cell lines deficient in specific glucosaminyl sulfotransferases produce significantly reduced CMV titers compared to wild-type cells and virus entry is compromised in these mutant cells. Finally, purified glycoprotein B shows strong binding to heparin, and desulfated heparin analogs compete poorly with heparin for gB binding. Taken together, these results highlight the significance of HS chain length and sulfation patterns in CMV attachment and infectivity.

Leveraging natural history biorepositories as a global, decentralized, pathogen surveillance network.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic reveals a major gap in global biosecurity infrastructure: a lack of publicly available biological samples representative across space, time, and taxonomic diversity. The shortfall, in this case for vertebrates, prevents accurate and rapid identification and monitoring of emerging pathogens and their reservoir host(s) and precludes extended investigation of ecological, evolutionary, and environmental associations that lead to human infection or spillover. Natural history museum biorepositories form the backbone of a critically needed, decentralized, global network for zoonotic pathogen surveillance, yet this infrastructure remains marginally developed, underutilized, underfunded, and disconnected from public health initiatives. Proactive detection and mitigation for emerging infectious diseases (EIDs) requires expanded biodiversity infrastructure and training (particularly in biodiverse and lower income countries) and new communication pipelines that connect biorepositories and biomedical communities. To this end, we highlight a novel adaptation of Project ECHO's virtual community of practice model: Museums and Emerging Pathogens in the Americas (MEPA). MEPA is a virtual network aimed at fostering communication, coordination, and collaborative problem-solving among pathogen researchers, public health officials, and biorepositories in the Americas. MEPA now acts as a model of effective international, interdisciplinary collaboration that can and should be replicated in other biodiversity hotspots. We encourage deposition of wildlife specimens and associated data with public biorepositories, regardless of original collection purpose, and urge biorepositories to embrace new specimen sources, types, and uses to maximize strategic growth and utility for EID research. Taxonomically, geographically, and temporally deep biorepository archives serve as the foundation of a proactive and increasingly predictive approach to zoonotic spillover, risk assessment, and threat mitigation.

Climate change affects bird nesting phenology: Comparing contemporary field and historical museum nesting records.

Global climate change impacts species and ecosystems in potentially harmful ways. For migratory bird species, earlier spring warm-up could lead to a mismatch between nesting activities and food availability. CO2 provides a useful proxy for temperature and an environmental indicator of climate change when temperature data are not available for an entire time series. Our objectives were to (a) examine nesting phenology over time; (b) determine how nesting phenology relates to changes in atmospheric CO2 concentration; and (c) demonstrate the usefulness of historical museum collections combined with modern observations for trend analyses. We assessed changes in nesting dates of 72 bird species in the Upper Midwest of the United States by comparing contemporary lay dates with those obtained from archived, historical museum nest records over a 143-year period (1872-2015). Species-specific changes in lay date per one unit change in the CO2 residual ranged from -0.75 (95% CI: -1.57 to -0.10) to 0.45 (95% CI: -0.29 to 1.43). Overall, lay dates advanced ~10 days over the 143-year period. Resident, short-distance migrants and long-distance migrants lay dates advanced by ~15, 18 and 16 days on average respectively. Twenty-four species (33.3%) significantly advanced, one (1.4%) significantly delayed and we failed to detect an advance or delay in lay date for 47 species (65.3%). Overall mean advance in first lay date (for the species that have significantly advanced laying date) was 25.1 days (min: 10.7, max: 49.9). Our study highlights the scientific importance of both data gathering and archiving through time to understand phenological change. The detailed archived information reported by egg collectors provide the early data of our study. As with studies of egg-shell thinning and pesticide exposure, our use of these data illustrates another scientific utility of egg collections that these pioneer naturalists never imagined. As museums archive historical data, these locations are also ideal candidates to store contemporary field data as it is collected. Together, such information will provide the ability to track, understand and perhaps predict responses to human-driven environmental change.

Predictors of problematic adult alcohol, cannabis, and other substance use: A longitudinal study of two samples.

This study examined whether a key set of adolescent and early adulthood risk factors predicts problematic alcohol, cannabis, and other substance use in established adulthood. Two independent samples from the Child Development Project (CDP; n = 585; 48% girls; 81% White, 17% Black, 2% other race/ethnicity) and Fast Track (FT; n = 463; 45% girls; 52% White, 43% Black, 5% other race/ethnicity) were recruited in childhood and followed through age 34 (CDP) or 32 (FT). Predictors of substance use were assessed in adolescence based on adolescent and parent reports and in early adulthood based on adult self-reports. Adults reported their own problematic substance use in established adulthood. In both samples, more risk factors from adolescence and early adulthood predicted problematic alcohol use in established adulthood (compared to problematic cannabis use and other substance use). Externalizing behaviors and prior substance use in early adulthood were consistent predictors of problematic alcohol and cannabis misuse in established adulthood across samples; other predictors were specific to the sample and type of substance misuse. Prevention efforts might benefit from tailoring to address risk factors for specific substances, but prioritizing prevention of externalizing behaviors holds promise for preventing both alcohol and cannabis misuse in established adulthood.

Children's Sleep and Externalizing Problems: A Day-to-day Multilevel Modeling Approach.

BACKGROUND: Sleep problems and externalizing problems tend to be positively associated, but the direction of this association is unclear. METHOD: Day-to-day associations between sleep and behavior were examined in children (N = 22) ages 3-8 with clinical levels of externalizing problems. These children were enrolled in Parent Management Training and behavioral sleep intervention. During assessments before and after treatment, children wore actigraphs for seven days and parents concurrently completed sleep diaries and daily tallies of noncompliance, aggression, and tantrums. Multilevel modeling was used to account for the nested structure of the data, at the day-to-day level (level 1), within assessment points (level 2), and within children (level 3). RESULTS: Late sleep timing and fragmentation were predictive of next-day noncompliance and tantrums, respectively. There were fewer associations for a given day's behavior predicting that night's sleep, although children who showed more aggression and noncompliance at baseline tended to have later bedtimes and sleep onset times compared to other children.

Predictive Validity of Adolescent Callous-Unemotional Traits and Conduct Problems with Respect to Adult Outcomes: High- and Low-Risk Samples.

Current understanding of the predictive validity of callous-unemotional (CU) traits is limited by (a) the focus on externalizing psychopathology and antisocial behaviors, (b) a lack of long-term prospective longitudinal data, (c) samples comprised of high-risk or low-risk individuals. We tested whether adolescent CU traits and conduct problems were associated with theoretically relevant adult outcomes 12-18 years later. Participants were drawn from two studies: higher-risk Fast Track (FT; n = 754) and lower-risk Child Development Project (CDP; n = 585). FT: conduct problems positively predicted externalizing and internalizing psychopathology and partner violence, and negatively predicted health, wellbeing, and education. Three conduct problems × CU traits interaction effects were also found. CDP: CU traits positively predicted depression and negatively predicted health and education; conduct problems positively predicted externalizing and internalizing psychopathology and substance use, and negatively predicted wellbeing. CU traits did not provide incremental predictive validity for multiple adult outcomes relative to conduct problems.

Digital Extended Specimens: Enabling an Extensible Network of Biodiversity Data Records as Integrated Digital Objects on the Internet.

The early twenty-first century has witnessed massive expansions in availability and accessibility of digital data in virtually all domains of the biodiversity sciences. Led by an array of asynchronous digitization activities spanning ecological, environmental, climatological, and biological collections data, these initiatives have resulted in a plethora of mostly disconnected and siloed data, leaving to researchers the tedious and time-consuming manual task of finding and connecting them in usable ways, integrating them into coherent data sets, and making them interoperable. The focus to date has been on elevating analog and physical records to digital replicas in local databases prior to elevating them to ever-growing aggregations of essentially disconnected discipline-specific information. In the present article, we propose a new interconnected network of digital objects on the Internet-the Digital Extended Specimen (DES) network-that transcends existing aggregator technology, augments the DES with third-party data through machine algorithms, and provides a platform for more efficient research and robust interdisciplinary discovery.

Developmental connections between socioeconomic status, self-regulation, and adult externalizing problems.

Children from low socioeconomic status (SES) backgrounds are at particularly heightened risk for developing later externalizing problems. A large body of research has suggested an important role for self-regulation in this developmental linkage. Self-regulation has been conceptualized as a mediator as well as a moderator of these connections. Using data from the Child Development Project (CDP, N = 585), we probe these contrasting (mediating/moderating) conceptualizations, using both Frequentist and Bayesian statistical approaches, in the linkage between early SES and later externalizing problems in a multi-decade longitudinal study. Connecting early SES, physiology (i.e., heart rate reactivity) and inhibitory control (a Stroop task) in adolescence, and externalizing symptomatology in early adulthood, we found the relation between SES and externalizing problems was moderated by multiple facets of self-regulation. Participants from lower early SES backgrounds, who also had high heart rate reactivity and lower inhibitory control, had elevated levels of externalizing problems in adulthood relative to those with low heart rate reactivity and better inhibitory control. Such patterns persisted after controlling for externalizing problems earlier in life. The present results may aid in understanding the combinations of factors that contribute to the development of externalizing psychopathology in economically marginalized youth.

A defensive mindset: A pattern of social information processing that develops early and predicts life course outcomes.

The hypothesis was tested that some children develop a defensive mindset that subsumes individual social information processing (SIP) steps, grows from early experiences, and guides long-term outcomes. In Study 1 (Fast Track [FT]), 463 age-5 children (45% girls; 43% Black) were first assessed in 1991 and followed through age 32 (83% retention). In Study 2 (Child Development Project [CDP]), 585 age-5 children (48% girls, 17% Black) were first assessed in 1987 and followed through age 34 (78% retention). In both studies, measures were collected of early adverse experiences, defensive mindset and SIP, and adult outcomes. Across both studies, a robust latent construct of school-age defensive mindset was validated empirically (comparative fit index = .99 in each study) and found to mediate the impact of early child abuse (38% in FT and 29% in CDP of total effect) and peer social rejection (14% in FT and 7% in CDP of total effect) on adult incarceration.

Naïve CD4+ T Cell Activation in the Nasal-Associated Lymphoid Tissue following Intranasal Immunization with a Flagellin-Based Subunit Vaccine.

The nasal-associated lymphoid tissues (NALT) are generally accepted as an immune induction site, but the activation of naïve T-cells in that compartment has not been well-characterized. I wanted to determine if early events in naïve CD4+ T cell activation and the extent of antigen specific cell division are similar in NALT to that observed in other secondary lymphoid compartments. I performed antigen tracking experiments and analyzed the activation of naïve antigen-specific CD4+ T cells in the nasal-associated lymphoid tissues (NALT). I directly observed transepithelial transport of fluorescently labeled antigen from the lumen of the airway to the interior of the NALT two hours following immunization. One day following intranasal (i.n.) immunization with antigen and adjuvant, antigen-specific CD4+ T cells in the NALT associated as clusters, while antigen-specific CD4+ T cells in control mice immunized with adjuvant only remained dispersed. The antigen-specific CD4+ populations in the NALT and cranial deep cervical lymph nodes of immunized mice expanded significantly by day three following immunization. These findings are consistent with initial activation of naïve CD4+ T cells in the NALT and offer insight into adjuvant mechanism of flagellin in the upper respiratory compartment.

Repeated sampling of individuals reveals impact of tropical and temperate habitats on microbiota of a migratory bird.

Migratory animals experiencing substantial change in diet and habitat across the annual cycle may have corresponding shifts in host-associated microbial diversity. Using automated telemetry and radio tags to recapture birds, we examined gut microbiota structure in the same population and often same individual of Kirtland's Warblers (Setophaga kirtlandii) initially sampled on their wintering grounds in The Bahamas and subsequently resampled within their breeding territories in Michigan, USA. Initial sampling occurred in March and April and resampling occurred in May, June and early July. The composition of the most abundant phyla and classes of the warblers' microbiota is similar to that of other migratory birds. However, we detected notable variation in abundance and diversity of numerous bacterial taxa, including a decrease in microbial richness and significant differences in microbial communities when comparing the microbiota of birds first captured in The Bahamas to that of birds recaptured in Michigan. This is observed at the individual and population level. Furthermore, we found that 22 bacterial genera exhibit heightened abundance within specific sampling periods and are probably associated with diet and environmental change. Finally, we described a small, species-specific shared microbial profile that spans multiple time periods and environments within the migratory cycle. Our research highlights that the avian gut microbiota is dynamic over time, most significantly impacted by changing environments associated with migration. These results support the need for full annual cycle monitoring of migratory bird microbiota to improve understanding of seasonal host movement ecologies and response to recurrent physiological stressors.

Cumulative early childhood adversity and later antisocial behavior: The mediating role of passive avoidance.

Twenty-six percent of children experience a traumatic event by the age of 4. Negative events during childhood have deleterious correlates later in life, including antisocial behavior. However, the mechanisms that play into this relation are unclear. We explored deficits in neurocognitive functioning, specifically problems in passive avoidance, a construct with elements of inhibitory control and learning as a potential acquired mediator for the pathway between cumulative early childhood adversity from birth to age 7 and later antisocial behavior through age 18, using prospective longitudinal data from 585 participants. Path analyses showed that cumulative early childhood adversity predicted impaired passive avoidance during adolescence and increased antisocial behavior during late adolescence. Furthermore, poor neurocognition, namely, passive avoidance, predicted later antisocial behavior and significantly mediated the relation between cumulative early childhood adversity and later antisocial behavior. This research has implications for understanding the development of later antisocial behavior and points to a potential target for neurocognitive intervention within the pathway from cumulative early childhood adversity to later antisocial behavior.

The Family Context of Toddler Sleep: Routines, Sleep Environment, and Emotional Security Induction in the Hour before Bedtime.

Family processes during the pre-bedtime period likely have a crucial influence on toddler sleep, but relatively little previous research has focused on family process in this context. The current study examined several aspects of family process during the pre-bedtime period, including the use of bedtime routines, the qualities of the child's home sleep environment, and the promotion of child emotional security, in families of 30-month-old toddlers (N= 546; 265 female) who were part of a multi-site longitudinal study of toddler development. These characteristics were quantified using a combination of parent- and observer-reports and examined in association with child sleep using correlation and multiple regression. Child sleep was assessed using actigraphy to measure sleep duration, timing, variability, activity, and latency. Bedtime routines were examined using parents' daily records. Home sleep environment and emotional security induction were quantified based on observer ratings and in-home observation notes, respectively. All three measures of pre-bedtime context (i.e., bedtime routine inconsistency, poor quality sleep environments, and emotional security induction) were correlated with various aspects of child sleep (significant correlations:.11-.22). The most robust associations occurred between the pre-bedtime context measures and sleep timing (i.e., the timing of the child's sleep schedule) and variability (i.e., night to night variability in sleep timing and duration). Pre-bedtime variables, including bedtime routine consistency, home sleep environment quality, and positive emotional security induction, also mediated the association between family socioeconomic status and child sleep. Our findings underscore the value of considering family context when examining individual differences in child sleep.