Insights into the skin microbiome of sickle cell disease leg ulcers.

Leg ulcers are estimated to occur in 1%-10% of North American patients with sickle cell disease (SCD). Their pathophysiology remains poorly defined, but as with other chronic wounds, it is hypothesised that the microbial milieu, or microbiome, contributes to their healing and clinical outcomes. This study utilises 16S ribosomal RNA (rRNA) gene sequencing to describe, for the first time, the microbiome of the SCD leg ulcer and its association with clinical factors. In a cross-sectional analysis of 42 ulcers, we recovered microbial profiles similar to other chronic wounds in the predominance of anaerobic bacteria and opportunistic pathogens including Staphylococcus, Corynebacterium, and Finegoldia. Ulcers separated into two clusters: one defined by predominance of Staphylococcus and smaller surface area, and the other displaying a greater diversity of taxa and larger surface area. We also find that the relative abundance of Porphyromonas is negatively associated with haemoglobin levels, a key clinical severity indicator for SCD, and that Finegoldia relative abundance is negatively associated with CD19+ B cell count. Finally, ratios of Corynebacterium:Lactobacillus and Staphylococcus:Lactobacillus are elevated in the intact skin of individuals with a history of SCD leg ulcers, while the ratio of Lactobacillus:Bacillus is elevated in that of individuals without a history of ulcers. Investigations of the skin microbiome in relation to SCD ulcer pathophysiology can inform clinical guidelines for this poorly understood chronic wound, as well as enhance broader understanding about the role of the skin microbiome in delayed wound healing.

Genetic risk for Alzheimer's dementia predicts motor deficits through multi-omic systems in older adults.

Alzheimer's disease manifests with both cognitive and motor deficits. However, the degree to which genetic risk of Alzheimer's dementia contributes to late-life motor impairment, and the specific molecular systems underlying these associations, are uncertain. Here, we adopted an integrative multi-omic approach to assess genetic influence on motor impairment in older adults and identified key molecular pathways that may mediate this risk. We built a polygenic risk score for clinical diagnosis of Alzheimer's dementia (AD-PRS) and examined its relationship to several motor phenotypes in 1885 older individuals from two longitudinal aging cohorts. We found that AD-PRS was associated with a previously validated composite motor scores and their components. The major genetic risk factor for sporadic Alzheimer's dementia, the APOE/TOMM40 locus, was not a major driver of these associations. To identify specific molecular features that potentially medicate the genetic risk into motor dysfunction, we examined brain multi-omics, including transcriptome, DNA methylation, histone acetylation (H3K9AC), and targeted proteomics, as well as diverse neuropathologies. We found that a small number of factors account for the majority of the influence of AD-PRS on motor function, which comprises paired helical filament tau-tangle density, H3K9AC in specific chromosomal regions encoding genes involved in neuromuscular process. These multi-omic factors have the potential to elucidate key molecular mechanisms developing motor impairment in the context of Alzheimer's dementia.

Cognition may link cortical IGFBP5 levels with motor function in older adults.

Alzheimer's disease and related disorders (ADRD) may manifest cognitive and non-cognitive phenotypes including motor impairment, suggesting a shared underlying biology. We tested the hypothesis that five cortical proteins identified from a gene network that drives AD and cognitive phenotypes are also related to motor function in the same individuals. We examined 1208 brains of older adults with motor and cognitive assessments prior to death. Cortical proteins were quantified with SRM proteomics and we collected indices of AD and other related pathologies. A higher level of IGFBP5 was associated with poorer motor function proximate to death but AK4, HSPB2, ITPK1 and PLXNB1 were unrelated to motor function. The association of IGFBP5 with motor function was unrelated to the presence of indices of brain pathologies. In contrast, the addition of a term for cognition attenuated the association of IGFBP5 with motor function by about 90% and they were no longer related. These data lend support for the idea that unidentified cortical proteins like IGFBP5, which may not manifest a known pathologic footprint, may contribute to motor and cognitive function in older adults.

Gene expression and DNA methylation are extensively coordinated with MRI-based brain microstructural characteristics.

Cognitive function relies on both molecular levels and cellular structures. However, systematic relationships between these two components of cognitive function, and their joint contribution to disease, are largely unknown. We utilize postmortem neuroimaging in tandem with gene expression and DNA methylation, from 222 deeply-phenotyped persons in a longitudinal aging cohort. Expression of hundreds of genes and methylation at thousands of loci are related to the microstructure of extensive regions of this same set of brains, as assessed by MRI. The genes linked to brain microstructure perform functions related to cell motility, transcriptional regulation and nuclear processes, and are selectively associated with Alzheimer's phenotypes. Similar methodology can be applied to other diseases to identify their joint molecular and structural basis, or to infer molecular levels in the brain on the basis of neuroimaging for precision medicine applications.

Leveraging the Learning Health Care Model to Improve Equity in the Age of Genomic Medicine.

To fully achieve the goals of a genomics-enabled learning health care system, purposeful efforts to understand and reduce health disparities and improve equity of care are essential. This paper highlights three major challenges facing genomics-enabled learning health care systems, as they pertain to ancestrally diverse populations: inequality in the utility of genomic medicine; lack of access to pharmacogenomics in clinical care; and inadequate incorporation of social and environmental data into the electronic health care record (EHR). We advance a framework that can not only be used to directly improve care for all within the learning health system, but can also be used to focus on the needs to address racial and ethnic health disparities and improve health equity.

Implications of the 21st Century Cures Act for the Behavioral and Social Sciences at the National Institutes of Health.

The 21st Century Cures Act provides funding for key initiatives relevant to the behavioral and social sciences and includes administrative provisions that facilitate health research and increase the privacy protections of research participants. At about the same time as the passage of the Act, the National Institutes of Health Office of Behavioral and Social Sciences Research released its Strategic Plan 2017-2021, which addresses three scientific priorities: (a) improve the synergy of basic and applied behavioral and social sciences research; (b) enhance and promote the research infrastructure, methods, and measures needed to support a more cumulative and integrated approach to behavioral and social sciences; and (c) facilitate the adoption of behavioral and social sciences research findings in health research and in practice. This commentary describes the implications of the Cures Act on these scientific priorities and on the behavioral and social sciences more broadly.

Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub.

The architecture of dendritic arbors contributes to neuronal connectivity in the brain. Conversely, abnormalities in dendrites have been reported in multiple mental disorders and are thought to contribute to pathogenesis. Rare copy number variations (CNVs) are genetic alterations that are associated with a wide range of mental disorders and are highly penetrant. The 16p11.2 microduplication is one of the CNVs most strongly associated with schizophrenia and autism, spanning multiple genes possibly involved in synaptic neurotransmission. However, disease-relevant cellular phenotypes of 16p11.2 microduplication and the driver gene(s) remain to be identified. We found increased dendritic arborization in isolated cortical pyramidal neurons from a mouse model of 16p11.2 duplication (dp/+). Network analysis identified MAPK3, which encodes ERK1 MAP kinase, as the most topologically important hub in protein-protein interaction networks within the 16p11.2 region and broader gene networks of schizophrenia-associated CNVs. Pharmacological targeting of ERK reversed dendritic alterations associated with dp/+ neurons, outlining a strategy for the analysis and reversal of cellular phenotypes in CNV-related psychiatric disorders.

A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness.

Dendritic spine pathology is a key feature of several neuropsychiatric disorders. The Rac1 guanine nucleotide exchange factor kalirin-7 is critical for spine morphogenesis on cortical pyramidal neurons. Here we identify a rare coding variant in the KALRN gene region that encodes the catalytic domain, in a schizophrenia patient and his sibling with major depressive disorder. The D1338N substitution significantly diminished the protein's ability to catalyse the activation of Rac1. Contrary to wild-type kalirin-7, kalirin-7-D1338N failed to increase spine size and density. Both subjects carrying the polymorphism displayed reduced cortical volume in the superior temporal sulcus (STS), a region implicated in schizophrenia. Consistent with this, mice with reduced kalirin expression showed reduced neuropil volume in the rodent homologue of the STS. These data suggest that single amino acid changes in proteins involved in dendritic spine function can have significant effects on the structure and function of the cerebral cortex.

Cultural Neuroscience: Progress and Promise.

The nature and origin of human diversity has been a source of intellectual curiosity since the beginning of human history. Contemporary advances in cultural and biological sciences provide unique opportunities for the emerging field of cultural neuroscience. Research in cultural neuroscience examines how cultural and genetic diversity shape the human mind, brain and behavior across multiple time scales: situation, ontogeny and phylogeny. Recent progress in cultural neuroscience provides novel theoretical frameworks for understanding the complex interaction of environmental, cultural and genetic factors in the production of adaptive human behavior. Here, we provide a brief history of cultural neuroscience, theoretical and methodological advances, as well as empirical evidence of the promise of and progress in the field. Implications of this research for population health disparities and public policy are discussed.

Population disparities in mental health: insights from cultural neuroscience.

By 2050, nearly 1 in 5 Americans (19%) will be an immigrant, including Hispanics, Blacks, and Asians, compared to the 1 in 8 (12%) in 2005. They will vary in the extent to which they are at risk for mental health disorders. Given this increase in cultural diversity within the United States and costly population health disparities across cultural groups, it is essential to develop a more comprehensive understanding of how culture affects basic psychological and biological mechanisms. We examine these basic mechanisms that underlie population disparities in mental health through cultural neuroscience. We discuss the challenges to and opportunities for cultural neuroscience research to determine sociocultural and biological factors that confer risk for and resilience to mental health disorders across the globe.

The role of culture-gene coevolution in morality judgment: examining the interplay between tightness-looseness and allelic variation of the serotonin transporter gene.

This research provides novel insights into the evolutionary basis of cultural norm development and maintenance. We yield evidence for a unique culture-gene coevolutionary model between ecological threat, allelic frequency of the serotonin transporter polymorphism (5-HTTLPR), cultural tightness-looseness-the strength of norms and tolerance for deviance from norms-and moral justifiability. As hypothesized, the results across 21 nations show that: (a) propensity for ecological threat correlates with short (S) allele frequency in the 5-HTTLPR, (b) allelic frequency in the 5-HTTLPR and vulnerability to ecological threat both correlate with cultural tightness-looseness, (c) susceptibility to ecological threat predicts tightness-looseness via the mediation of S allele carriers, and (d) frequency of S allele carriers predicts justifiability of morally relevant behavior via tightness-looseness. This research highlights the importance of studying the interplay between environmental, genetic, and cultural factors underlying contemporary differences in social behavior and presents an empirical framework for future research.

Culture-gene coevolution of individualism-collectivism and the serotonin transporter gene.

Culture-gene coevolutionary theory posits that cultural values have evolved, are adaptive and influence the social and physical environments under which genetic selection operates. Here, we examined the association between cultural values of individualism-collectivism and allelic frequency of the serotonin transporter functional polymorphism (5-HTTLPR) as well as the role this culture-gene association may play in explaining global variability in prevalence of pathogens and affective disorders. We found evidence that collectivistic cultures were significantly more likely to comprise individuals carrying the short (S) allele of the 5-HTTLPR across 29 nations. Results further show that historical pathogen prevalence predicts cultural variability in individualism-collectivism owing to genetic selection of the S allele. Additionally, cultural values and frequency of S allele carriers negatively predict global prevalence of anxiety and mood disorder. Finally, mediation analyses further indicate that increased frequency of S allele carriers predicted decreased anxiety and mood disorder prevalence owing to increased collectivistic cultural values. Taken together, our findings suggest culture-gene coevolution between allelic frequency of 5-HTTLPR and cultural values of individualism-collectivism and support the notion that cultural values buffer genetically susceptible populations from increased prevalence of affective disorders. Implications of the current findings for understanding culture-gene coevolution of human brain and behaviour as well as how this coevolutionary process may contribute to global variation in pathogen prevalence and epidemiology of affective disorders, such as anxiety and depression, are discussed.