Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA

Maternal loss of imprinting (LOI) at the H19/IGF2 locus results in biallelic IGF2 and reduced H19 expression and is associated with Beckwith-Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of Igf2 and H19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased Igf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These Igf2-dependent phenotypes are transient: cardiac size returns to normal once Igf2 expression is suppressed postnatally. However, reduced H19 expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, H19 expression is primarily in endothelial cells (ECs) and regulates EC differentiation both, in vivo and in vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend on H19 lncRNA interactions with Mirlet7 microRNAs.

Early maternal loss leads to short- but not long-term effects on diurnal cortisol slopes in wild chimpanzees

The biological embedding model (BEM) suggests that fitness costs of maternal loss arise when early-life experience embeds long-term alterations to hypothalamic-pituitary-adrenal (HPA) axis activity. Alternatively, the adaptive calibration model (ACM) regards physiological changes during ontogeny as short-term adaptations. Both models have been tested in humans but rarely in wild, long-lived animals. We assessed whether, as in humans, maternal loss had short- and long-term impacts on orphan wild chimpanzee urinary cortisol levels and diurnal urinary cortisol slopes, both indicative of HPA axis functioning. Immature chimpanzees recently orphaned and/or orphaned early in life had diurnal cortisol slopes reflecting heightened activation of the HPA axis. However, these effects appeared short-term, with no consistent differences between orphan and non-orphan cortisol profiles in mature males, suggesting stronger support for the ACM than the BEM in wild chimpanzees. Compensatory mechanisms, such as adoption, may buffer against certain physiological effects of maternal loss in this species.

“A Living Mosaic of Human Beings”: The Life Writing of Virginia Woolf and Zitkala-Ša

This essay examines life writing by English author Virginia Woolf (1882-1941) and Yankton Dakota writer Zitkala-Ša (1876-1938), specifically Woolf’s memoir, “A Sketch of the Past,” written in 1939-40 and first published in Moments of Being in 1976, and Zitkala-Ša’s autobiographical essays, published in the Atlantic Monthly in 1900. This comparative study explores how both women establish selfhood amid competing pressures vying for their minds and bodies; how mothers and maternal loss shape their autobiographies; how physical and psychological place and displacement influence their life writing; and how matters of audience affect their literary self-portraits. Reading Woolf and Zitkala-Ša together yields fresh insights into the intersections of race, class, gender, and feminism in women’s writing.

Social groups buffer maternal loss in mountain gorillas

Mothers are crucial for mammals’ survival before nutritional independence, but many social mammals reside with their mothers long after. In these species the social adversity caused by maternal loss later in life can dramatically reduce fitness. However, in some human populations these negative consequences can be overcome by care from other group members. We investigated the consequences of maternal loss in mountain gorillas and found no discernible fitness costs to maternal loss through survival, age at first birth, or survival of first offspring through infancy. Social network analysis revealed that relationships with other group members, particularly dominant males and those close in age, strengthened following maternal loss. In contrast to most social mammals, where maternal loss causes considerable social adversity, in mountain gorillas, as in certain human populations, this may be buffered by relationships within cohesive social groups, breaking the link between maternal loss, increased social adversity, and decreased fitness.

Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA

Maternal loss of imprinting (LOI) at the H19/IGF2 locus results in biallelic IGF2 and reduced H19 expression and is associated with Beckwith Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of Igf2 and H19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased Igf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These Igf2-dependent phenotypes are transient: cardiac size returns to normal once Igf2 expression is suppressed postnatally. However, reduced H19 expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, H19 expression is concentrated predominantly in endothelial cells (ECs) and regulates EC differentiation both, in vivo and in vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend on H19 lncRNA interactions with let7 microRNA.

Maternal death and offspring fitness in multiple wild primates

Primate offspring often depend on their mothers well beyond the age of weaning, and offspring that experience maternal death in early life can suffer substantial reductions in fitness across the life span. Here, we leverage data from eight wild primate populations (seven species) to examine two underappreciated pathways linking early maternal death and offspring fitness that are distinct from direct effects of orphaning on offspring survival. First, we show that, for five of the seven species, offspring face reduced survival during the years immediately preceding maternal death, while the mother is still alive. Second, we identify an intergenerational effect of early maternal loss in three species (muriquis, baboons, and blue monkeys), such that early maternal death experienced in one generation leads to reduced offspring survival in the next. Our results have important implications for the evolution of slow life histories in primates, as they suggest that maternal condition and survival are more important for offspring fitness than previously realized.

Cytomegalovirus-Specific T Cell Epitope Recognition in Congenital Cytomegalovirus Mother-Infant Pairs

Background: Congenital cytomegalovirus (cCMV) infection is the most common infection acquired before birth and from which about 20% of infants develop permanent neurodevelopmental effects regardless of presence or absence of symptoms at birth. Viral escape from host immune control may be a mechanism of CMV transmission and infant disease severity. We sought to identify and compare CMV epitopes recognized by mother-infant pairs. We also hypothesized that if immune escape were occurring, then one pattern of longitudinal CD8 T cell responses restricted by shared HLA alleles would be maternal loss (by viral escape) and infant gain (by viral reversion to wildtype) of CMV epitope recognition.Methods: The study population consisted of 6 women with primary CMV infection during pregnancy and their infants with cCMV infection. CMV UL83 and UL123 peptides with known or predicted restriction by maternal MHC class I alleles were identified, and a subset was selected for testing based on several criteria. Maternal or infant cells were stimulated with CMV peptides in the IFN-γ ELISpot assay.Results: Overall, 14 of 25 (56%; 8 UL83 and 6 UL123) peptides recognized by mother-infant pairs were not previously reported as CD8 T cell epitopes. Of three pairs with longitudinal samples, one showed maternal loss and infant gain of responses to a CMV epitope restricted by a shared HLA allele.Conclusions: CD8 T cell responses to multiple novel CMV epitopes were identified, particularly in infants. Moreover, the hypothesized pattern of CMV immune escape was observed in one mother-infant pair. These findings emphasize that knowledge of paired CMV epitope recognition allows exploration of viral immune escape that may operate within the maternal-fetal system. Our work provides rationale for future studies of this potential mechanism of CMV transmission during pregnancy or clinical outcomes of infants with cCMV infection.

Early maternal loss affects diurnal cortisol slopes in immature but not mature wild chimpanzees

In mammals, early life adversity negatively affects survival and reproductive success. A key causal mechanism is proposed by the biological embedding model which posits that adversity experienced early in life has deleterious consequences on individual physiology across the lifespan. In particular, early life adversity is expected to be a severe stressor leading to long-term alteration of the hypothalamic pituitary adrenal (HPA) axis activity. Here we tested this idea by assessing whether, as in humans, maternal loss had short and long-term impacts on orphan chimpanzee urinary cortisol levels and diurnal urinary cortisol slopes, as an indicator of the HPA axis functioning. We used 18 years of data on 50 immature and 28 mature male wild chimpanzees belonging to four communities in Taï National Park, Ivory Coast. Immature orphans who experienced early maternal loss had diurnal cortisol slopes characterised by higher early morning and late afternoon cortisol levels indicative of high activation of the HPA axis. Recently orphaned immatures had higher cortisol levels than other immatures, possibly reflecting social and nutritional stress. However, unlike in humans, we did not find significantly different cortisol profiles in orphan and non-orphan adult male chimpanzees. Our study highlights that long-term alteration of stress physiology related to early life adversity may not be viable in some wild animal populations and/or that chimpanzees, as humans, may have access to mechanisms that buffer this physiological stress, such as adoption. Our results suggest that biological embedding of altered HPA axis function is unlikely to be a mechanism contributing to the demonstrated long-term fitness consequences of maternal loss, such as reduced reproductive success, in wild long-lived mammals.

Strange Intimacies

This paper sits with the understudied subgenre of the contemporary black maternal memoir in the Black Lives Matter era. We read Sybrina Fulton and Tracy Martin’s Rest in Power: The Enduring Life of Trayvon Martin and Lezley McSpadden’s Tell the Truth and Shame the Devil: The Life, Legacy, and Love of My Son Michael Brown not only as performances of grief and of the birth of political subjectivity—even as they emphatically stage how respectable black maternal political subjectivity is born through loss. These black maternal memoirs also offer what we call strange intimacies, which strain the predictable scripts of the maternal memoir. We read the embeddedness of strange intimacies in these memoirs as a way of refusing the gendered logics of the reception of the black maternal, and as performances of intimacy that refuse and undo normative conceptions of familial intimacy and black maternal loss.