The shingled girl: Catherine Janet Hill and her contributions to embryology.

Catherine J. Hill is best remembered for her dedication to cataloguing the comprehensive embryological collection of her father J. P. Hill. Yet, her own research, during the interwar years, is little known. She made a significant contribution to interpreting the autonomic innervation of the gut, work that was presented to The Royal Society and earned her a PhD. Working in her father's laboratory, she then set about solving the sequence of secretions from the tubal epithelium and uterine glands that contributed the two layers of egg albumen and three shell layers of the monotreme egg. She was also the first to understand twinning in the marmoset and how two embryos came to share a single extraembryonic coelom, work that often is credited to J. P. Hill. Here. I explain how that happened and explore the context in which she and other female scientists worked at the time.

I W Rowlands, Barbara J Weir and the biology of the hystricomorph rodents.

In brief: Current research on the genomics, ecology and reproductive biology of hystricomorph rodents relies on the pioneering studies of B J Weir and I W Rowlands. We show the enduring influence of a symposium on hystricomorph biology held 50 years ago. Abstract: The rodent suborder Hystricomorpha comprises seven families from Africa and Asia and ten from South America, where they have undergone an extensive radiation and occupy a variety of biomes. Although the guinea pig was a common laboratory rodent, little was known about reproductive biology in the other species until the ambitious research programme of Barbara Weir and her mentor I W Rowlands. Much of their work and of others then in the field was summarized at a symposium held 50 years ago at The Zoological Society of London. Currently, there is a resurgence of interest in the reproductive biology of the South American species. Compared to other rodents, unique features include a long gestation, a long oestrous cycle, a tendency to form accessory corpora lutea and a vaginal closure membrane. There is a distinctive placental structure, the subplacenta. Most give birth to precocial young. Individual species exhibit peculiarities such as polyovulation, systematic fetal loss and an active female prostate. Here, we highlight the achievements of Barbara Weir and show how her legacy has been sustained in the twenty-first century by South American scientists.

The Rb/E2F axis is a key regulator of the molecular signatures instructing the quiescent and activated adult neural stem cell state.

Long-term maintenance of the adult neurogenic niche depends on proper regulation of entry and exit from quiescence. Neural stem cell (NSC) transition from quiescence to activation is a complex process requiring precise cell-cycle control coordinated with transcriptional and morphological changes. How NSC fate transitions in coordination with the cell-cycle machinery remains poorly understood. Here we show that the Rb/E2F axis functions by linking the cell-cycle machinery to pivotal regulators of NSC fate. Deletion of Rb family proteins results in activation of NSCs, inducing a transcriptomic transition toward activation. Deletion of their target activator E2Fs1/3 results in intractable quiescence and cessation of neurogenesis. We show that the Rb/E2F axis mediates these fate transitions through regulation of factors essential for NSC function, including REST and ASCL1. Thus, the Rb/E2F axis is an important regulator of NSC fate, coordinating cell-cycle control with NSC activation and quiescence fate transitions.

Embryonic specializations for vertebrate placentation.

The vertebrate placenta, a close association of fetal and parental tissue for physiological exchange, has evolved independently in sharks, teleost fishes, coelacanths, amphibians, squamate reptiles and mammals. This transient organ forms during pregnancy and is an important contributor to embryonic development in both viviparous and oviparous, brooding species. Placentae may be involved in transport of respiratory gases, wastes, immune molecules, hormones and nutrients. Depending on the taxon, the embryonic portion of the placenta is comprised of either extraembryonic membranes (yolk sac or chorioallantois) or temporary embryonic tissues derived via hypertrophy of pericardium, gill epithelium, gut, tails or fins. These membranes and tissues have been recruited convergently into placentae in several lineages. Here, we highlight the diversity and common features of embryonic tissues involved in vertebrate placentation and suggest future studies that will provide new knowledge about the evolution of pregnancy. This article is part of the theme issue 'Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom'.

Fetoplacental oxygen homeostasis in pregnancies with maternal diabetes mellitus and obesity.

Despite improvements in clinical management, pregnancies complicated by pre-existing diabetes mellitus, gestational diabetes mellitus or obesity carry substantial risks for parent and offspring. Some of the endocrine and metabolic changes in parent and fetus in diabetes mellitus and obesity lead to fetal oxygen deficit, mostly due to insulin-induced accelerated fetal metabolism. The human fetus deals with reduced oxygenation through a wide range of adaptive responses that act at various levels in the placenta as well as the fetus. These responses ensure adequate oxygen delivery to the fetus, increase the oxygen transport capacity of fetal blood and redistribute oxygen-rich blood to vital organs such as the brain and heart. The liver has a central role in adapting to reduced oxygenation by increasing its oxygen extraction and stimulating erythropoietin synthesis to increase haematocrit. The type of adaptive response depends on the onset and duration of hypoxia and the severity of the metabolic disturbance. In pregnancies characterized by diabetes mellitus or obesity, these adaptive systems come under additional strain owing to the increased maternal supply of glucose and resultant fetal hyperinsulinaemia, both of which stimulate oxidative metabolism. In the rare situation that the adaptive responses are overwhelmed, stillbirth can ensue.

Evolution of Placental Hormones: Implications for Animal Models.

Human placenta secretes a variety of hormones, some of them in large amounts. Their effects on maternal physiology, including the immune system, are poorly understood. Not one of the protein hormones specific to human placenta occurs outside primates. Instead, laboratory and domesticated species have their own sets of placental hormones. There are nonetheless several examples of convergent evolution. Thus, horse and human have chorionic gonadotrophins with similar functions whilst pregnancy-specific glycoproteins have evolved in primates, rodents, horses, and some bats, perhaps to support invasive placentation. Placental lactogens occur in rodents and ruminants as well as primates though evolved through duplication of different genes and with functions that only partially overlap. There are also placental hormones, such as the pregnancy-associated glycoproteins of ruminants, that have no equivalent in human gestation. This review focusses on the evolution of placental hormones involved in recognition and maintenance of pregnancy, in maternal adaptations to pregnancy and lactation, and in facilitating immune tolerance of the fetal semiallograft. The contention is that knowledge gained from laboratory and domesticated mammals can translate to a better understanding of human placental endocrinology, but only if viewed in an evolutionary context.

Homochiral Mn3+ Spin-Crossover Complexes: A Structural and Spectroscopic Study.

Structural, magnetic, and spectroscopic data on a Mn3+ spin-crossover complex with Schiff base ligand 4-OMe-Sal2323, isolated in crystal lattices with five different counteranions, are reported. Complexes of [Mn(4-OMe-Sal2323)]X where X = ClO4- (1), BF4- (2), NO3- (3), Br- (4), and I- (5) crystallize isotypically in the chiral orthorhombic space group P21212 with a range of spin state preferences for the [Mn(4-OMe-Sal2323)]+ complex cation over the temperature range 5-300 K. Complexes 1 and 2 are high-spin, complex 4 undergoes a gradual and complete thermal spin crossover, while complexes 3 and 5 show stepped crossovers with different ratios of spin triplet and quintet forms in the intermediate temperature range. High-field electron paramagnetic resonance was used to measure the zero-field splitting parameters associated with the spin triplet and quintet states at temperatures below 10 K for complexes 4 and 2 with respective values: DS=1 = +23.38(1) cm-1, ES=1 = +2.79(1) cm-1, and DS=2 = +6.9(3) cm-1, with a distribution of E parameters for the S = 2 state. Solid-state circular dichroism (CD) spectra on high-spin complex 1 at room temperature reveal a 2:1 ratio of enantiomers in the chiral conglomerate, and solution CD measurements on the same sample in methanol show that it is stable toward racemization. Solid-state UV-vis absorption spectra on high-spin complex 1 and mixed S = 1/S = 2 sample 5 reveal different intensities at higher energies, in line with the different electronic composition. The statistical prevalence of homochiral crystallization of [Mn(4-OMe-Sal2323)]+ in five lattices with different achiral counterions suggests that the chirality may be directed by the 4-OMe-Sal2323 ligand.

The trophoblast giant cells of cricetid rodents.

Giant cells are a prominent feature of placentation in cricetid rodents. Once thought to be maternal in origin, they are now known to be trophoblast giant cells (TGCs). The large size of cricetid TGCs and their nuclei reflects a high degree of polyploidy. While some TGCs are found at fixed locations, others migrate throughout the placenta and deep into the uterus where they sometimes survive postpartum. Herein, we review the distribution of TGCs in the placenta of cricetids, including our own data from the New World subfamily Sigmodontinae, and attempt a comparison between the TGCs of cricetid and murid rodents. In both families, parietal TGCs are found in the parietal yolk sac and as a layer between the junctional zone and decidua. In cricetids alone, large numbers of TGCs, likely from the same lineage, accumulate at the edge of the placental disk. Common to murids and cricetids is a haemotrichorial placental barrier where the maternal-facing layer consists of cytotrophoblasts characterized as sinusoidal TGCs. The maternal channels of the labyrinth are supplied by trophoblast-lined canals. Whereas in the mouse these are lined largely by canal TGCs, in cricetids canal TGCs are interspersed with syncytiotrophoblast. Transformation of the uterine spiral arteries occurs in both murids and cricetids and spiral artery TGCs line segments of the arteries that have lost their endothelium and smooth muscle. Since polyploidization of TGCs can amplify selective genomic regions required for specific functions, we argue that the TGCs of cricetids deserve further study and suggest avenues for future research.

Unique Aspects of Human Placentation.

Human placentation differs from that of other mammals. A suite of characteristics is shared with haplorrhine primates, including early development of the embryonic membranes and placental hormones such as chorionic gonadotrophin and placental lactogen. A comparable architecture of the intervillous space is found only in Old World monkeys and apes. The routes of trophoblast invasion and the precise role of extravillous trophoblast in uterine artery transformation is similar in chimpanzee and gorilla. Extended parental care is shared with the great apes, and though human babies are rather helpless at birth, they are well developed (precocial) in other respects. Primates and rodents last shared a common ancestor in the Cretaceous period, and their placentation has evolved independently for some 80 million years. This is reflected in many aspects of their placentation. Some apparent resemblances such as interstitial implantation and placental lactogens are the result of convergent evolution. For rodent models such as the mouse, the differences are compounded by short gestations leading to the delivery of poorly developed (altricial) young.

PEGylation Increases the Strength of a Nearby NH-π Hydrogen Bond in the WW Domain.

Here we show that an NH-π interaction between a highly conserved Asn and a nearby Trp stabilizes the WW domain of the human protein Pin1. The strength of this NH-π interaction depends on the structure of the arene, with NH-π interactions involving Trp or naphthylalanine being substantially more stabilizing than those involving Tyr or Phe. Calculations suggest arene size and polarizability are key structural determinants of NH-π interaction strength. Methylation or PEGylation of the Asn side-chain amide nitrogen each strengthens the associated NH-π interaction, though likely for different reasons. We hypothesize that methylation introduces steric clashes that destabilize conformations in which the NH-π interaction is not possible, whereas PEGylation strengthens the NH-π interaction via localized desolvation of the protein surface.

Remote Ischemic Conditioning and Stroke Recovery.

Remote ischemic conditioning (RIC) is a noninvasive procedure whereby several periods of ischemia are induced in a limb. Although there is growing interest in using RIC to improve stroke recovery, preclinical RIC research has focused exclusively on neuroprotection, using male animals and the intraluminal suture stroke model, and delivered RIC at times not relevant to either brain repair or behavioral recovery. In alignment with the Stroke Recovery and Rehabilitation Roundtable, we address these shortcomings. First, a standardized session (5-minute inflation/deflation, 4 repetitions) of RIC was delivered using a cuff on the contralesional hindlimb in both male and female Sprague-Dawley rats. Using the endothelin-1 stroke model, RIC was delivered once either prestroke (18 hours before, pre-RIC) or poststroke (4 hours after, post-RIC), and infarct volume was assessed at 24 hours poststroke using magnetic resonance imaging. RIC was delivered at these times to mimic the day before a surgery where clots are possible or as a treatment similar to tissue plasminogen activator, respectively. Pre-RIC reduced infarct volume by 41% compared with 29% with post-RIC. RIC was neuroprotective in both sexes, but males had a 46% reduction of infarct volume compared with 23% in females. After confirming the acute efficacy of RIC, we applied it chronically for 4 weeks, beginning 5 days poststroke. This delayed RIC failed to enhance poststroke behavioral recovery. Based on these findings, the most promising application of RIC is during the hyperacute and early acute phases of stroke, a time when other interventions such as exercise may be contraindicated.

An Exercise Mimetic Approach to Reduce Poststroke Deconditioning and Enhance Stroke Recovery.

Evidence supports early rehabilitation after stroke to limit disability. However, stroke survivors are typically sedentary and experience significant cardiovascular and muscular deconditioning. Despite growing consensus that preclinical and clinical stroke recovery research should be aligned, there have been few attempts to incorporate cardiovascular and skeletal muscle deconditioning into animal models of stroke. Here, we demonstrate in rats that a hindlimb sensorimotor cortex stroke results in both cardiovascular and skeletal muscle deconditioning and impairments in gait akin to those observed in humans. To reduce poststroke behavioral, cardiovascular, and skeletal muscle perturbations, we then used a combinatorial intervention consisting of aerobic and resistance exercise in conjunction with administration of resveratrol (RESV), a drug with exercise mimetic properties. A combination of aerobic and resistance exercise mitigated decreases in cardiovascular fitness and attenuated skeletal muscle abnormalities. RESV, beginning 24 hours poststroke, reduced acute hindlimb impairments, improved recovery in hindlimb function, increased vascular density in the perilesional cortex, and attenuated skeletal muscle fiber changes. Early RESV treatment and aerobic and resistance exercise independently provided poststroke benefits, at a time when individuals are rapidly becoming deconditioned as a result of inactivity. Although no additive effects were observed in these experiments, this approach represents a promising strategy to reduce poststroke behavioral impairments and minimize deconditioning. As such, this treatment regime has potential for enabling patients to engage in more intensive rehabilitation at an earlier time following stroke when mechanisms of neuroplasticity are most prevalent.

T. Thomson Flynn and the monotreme egg from oocyte maturation to germ layer formation.

Knowledge of oocyte development and the early differentiation of the germ layers in monotremes stems largely from two articles by J. P. Hill and T. Thomson Flynn. The completeness of their account was due to the large series of echidna ovaries and eggs collected on Tasmania by Flynn, an Australian biologist of whom a brief account is given. A striking finding in the oocyte and early embryo of monotremes was the presence of a latebra connected to the yolk bed beneath the germinal disc as described in birds and several reptiles. A further resemblance was the presence early in vitellogenesis of a striate zone beneath the zona pellucida. Cleavage resulted first in a lens-shaped blastodisc encircled by cells called vitellocytes that later fused to form a germ-ring. The blastodisc gave rise to a blastoderm that eventually became unilaminar but comprised two cell types identified as ectoderm and primitive endoderm. Eventually these segregated into two layers and formed a blastula. This sequence resembled that in marsupials except there was no obvious distinction between future embryonic and extra-embryonic regions. As the blastoderm extended over the surface of the yolk, it was preceded by the germ-ring that eventually played a role in forming the yolk navel. This was a unique feature of monotreme development. It is shown that Flynn played an important role in analysis of the material as well as in its collection.

The role of mammalian foetal membranes in early embryogenesis: Lessons from marsupials.

Across mammals, early embryonic development is supported by uterine secretions taken up through the yolk sac and other foetal membranes (histotrophic nutrition). The marsupial conceptus is enclosed in a shell coat for the first two-thirds of gestation and nutrients pass to the embryo through the shell and the avascular bilaminar yolk sac. At around the time of shell rupture, part of the yolk sac is trilaminar and supplied with blood vessels. It attaches to the uterus and forms a choriovitelline placenta. Rapid growth of the embryo ensues, still supported by histotrophe as well as exchange of oxygen and nutrients between maternal and foetal blood vessels (haemotrophic nutrition). Few marsupials have a chorioallantoic placenta and the highly altricial newborn is delivered after a short gestation. Eutherian embryos pass through a similar sequence before there is a fully functional chorioallantoic placenta. In most orders, there is transient yolk sac placentation, but even before this, nutrients are transferred through an avascular yolk sac. Yolk sac placentation does not occur in rodents or catarrhine primates. Early embryonic development in the mouse is nonetheless dependent on histotrophic nutrition. In the first trimester of human pregnancy, uterine glands open to the intervillous space and secretion products are taken up by the trophoblast. Transfer of nutrients to the early human embryo also involves the yolk sac, which floats free in the exocoelom. Marsupials can therefore inform us about the role of foetal membranes and histotrophic nutrition in early embryogenesis, knowledge that can translate to eutherians.

Animal models of human pregnancy and placentation: alternatives to the mouse.

The mouse is often criticized as a model for pregnancy research as gestation is short, with much of organ development completed postnatally. There are also differences in the structure and physiology of the placenta between mouse and human. This review considers eight alternative models that recently have been proposed and two established ones that seem underutilized. A promising newcomer among rodents is the spiny mouse, which has a longer gestation than the mouse with organogenesis complete at birth. The guinea pig is also recommended both because it has well-developed neonates and because there is a wealth of information on pregnancy and placentation in the literature. Several smaller primates are considered. The mouse lemur has its advocates yet is less suited as a model for human pregnancy as its young are altricial, placentation very different from that of humans, and husbandry requirements not fully assessed. In contrast, the common marmoset, a New World monkey, has well-developed neonates and is kept at many primate centres. Marmoset placenta has some features that closely resemble human placentation, such as the interhaemal barrier, although it is uncertain if invasion of the uterine arteries occurs in this species. In conclusion, pregnancy research would benefit greatly from increased use of alternative models such as the spiny mouse and common marmoset.

Viviparity in the longest-living vertebrate, the Greenland shark (Somniosus microcephalus).

BACKGROUND: The Greenland shark is renowned for its great longevity, yet little is known about its reproduction. METHODS: We supplemented the sparse information on this species by extrapolation from observations on other members of the sleeper shark family and the order Squaliformes. RESULTS AND CONCLUSION: The Greenland shark is viviparous and a single observation suggests a litter size of about ten. The gestation period is unknown, but embryos reach a length of around 40 cm at birth. Nutrition is derived from the yolk sac with minimal histotrophy. The surface area of the uterus is increased by villi that presumably increase in length with advancing gestation. These villi are not likely to be secretory but play a key role in the oxygen supply to the embryo. We argue that the ability of the uterus to supply oxygen is a limiting factor for litter size, which is not likely to exceed the small number reported in this and other sleeper sharks.