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The house mouse ( Mus musculus ) is an exceptional model system, combining genetic tractability with close evolutionary affinity to humans 1 , 2 . Mouse gestation lasts only 3 weeks, during which the genome orchestrates the astonishing transformation of a single-cell zygote into a free-living pup composed of more than 500 million cells. Here, to establish a global framework for exploring mammalian development, we applied optimized single-cell combinatorial indexing 3 to profile the transcriptional states of 12.4 million nuclei from 83 embryos, precisely staged at 2- to 6-hour intervals spanning late gastrulation (embryonic day 8) to birth (postnatal day 0). From these data, we annotate hundreds of cell types and explore the ontogenesis of the posterior embryo during somitogenesis and of kidney, mesenchyme, retina and early neurons. We leverage the temporal resolution and sampling depth of these whole-embryo snapshots, together with published data 4 – 8 from earlier timepoints, to construct a rooted tree of cell-type relationships that spans the entirety of prenatal development, from zygote to birth. Throughout this tree, we systematically nominate genes encoding transcription factors and other proteins as candidate drivers of the in vivo differentiation of hundreds of cell types. Remarkably, the most marked temporal shifts in cell states are observed within one hour of birth and presumably underlie the massive physiological adaptations that must accompany the successful transition of a mammalian fetus to life outside the womb. Single-cell transcriptome profiling of mouse embryos and newborn pups is combined with previously published data to construct a tree of cell-type relationships tracing development from zygote to birth.

Alterations in enteric microbiota are associated with several highly prevalent immune-mediated and metabolic diseases 1 – 3 , and experiments involving faecal transplants have indicated that such alterations have a causal role in at least some such conditions 4 – 6 . The postnatal period is particularly critical for the development of microbiota composition, host–microbe interactions and immune homeostasis 7 – 9 . However, the underlying molecular mechanisms of this neonatal priming period have not been defined. Here we report the identification of a host-mediated regulatory circuit of bacterial colonization that acts solely during the early neonatal period but influences life-long microbiota composition. We demonstrate age-dependent expression of the flagellin receptor Toll-like receptor 5 (TLR5) in the gut epithelium of neonate mice. Using competitive colonization experiments, we demonstrate that epithelial TLR5-mediated REG3γ production is critical for the counter-selection of colonizing flagellated bacteria. Comparative microbiota transfer experiments in neonate and adult wild-type and Tlr5 -deficient germ-free mice reveal that neonatal TLR5 expression strongly influences the composition of the microbiota throughout life. Thus, the beneficial microbiota in the adult host is shaped during early infancy. This might explain why environmental factors that disturb the establishment of the microbiota during early life can affect immune homeostasis and health in adulthood. Age-dependent epithelial expression of the innate immune receptor TLR5 in the gut of newborn mice selects against the presence of flagellated bacteria and influences microbiota composition throughout life.

Colostrum is the milk produced during the first few days after birth and contains high levels of immunoglobulins, antimicrobial peptides, and growth factors. Colostrum is important for supporting the growth, development, and immunologic defence of neonates. Colostrum is naturally packaged in a combination that helps prevent its destruction and maintain bioactivity until it reaches more distal gut regions and enables synergistic responses between protective and reparative agents present within it. Bovine colostrum been used for hundreds of years as a traditional or complementary therapy for a wide variety of ailments and in veterinary practice. Partly due to concerns about the side effects of standard Western medicines, there is interest in the use of natural-based products of which colostrum is a prime example. Numerous preclinical and clinical studies have demonstrated therapeutic benefits of bovine colostrum for a wide range of indications, including maintenance of wellbeing, treatment of medical conditions and for animal husbandry. Articles within this Special Issue of Nutrients cover the effects and use bovine colostrum and in this introductory article, we describe the main constituents, quality control and an overview of the use of bovine colostrum in health and disease.

Precise spatiotemporal control of gene expression in the developing brain is critical for neural circuit formation, and comprehensive expression mapping in the developing primate brain is crucial to understand brain function in health and disease. Here, we developed an unbiased, automated, large-scale, cellular-resolution in situ hybridization (ISH)–based gene expression profiling system (GePS) and companion analysis to reveal gene expression patterns in the neonatal New World marmoset cortex, thalamus, and striatum that are distinct from those in mice. Gene-ontology analysis of marmoset-specific genes revealed associations with catalytic activity in the visual cortex and neuropsychiatric disorders in the thalamus. Cortically expressed genes with clear area boundaries were used in a three-dimensional cortical surface mapping algorithm to delineate higher-order cortical areas not evident in two-dimensional ISH data. GePS provides a powerful platform to elucidate the molecular mechanisms underlying primate neurobiology and developmental psychiatric and neurological disorders.

The immune system matures during the neonatal period and is influenced by environmental factors. Benjamin J. Marsland and his colleagues show that the lung is colonized by microbes early in life. Formation of the lung microbiota is associated with the induction of regulatory T cells and the development of tolerance to allergens. Absence of microbial colonization leads to allergic airway disease later in life, suggesting that the lung microbiota promotes immune tolerance. Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . The neonatal immune system matures during this period 9 , although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4 + Foxp3 + CD25 + Helios + regulatory T (T reg ) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios − T reg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization 10 or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of T reg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.

The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. To uncover the molecular mechanisms underlying neonatal heart regeneration, we compared the transcriptomes and epigenomes of regenerative and nonregenerative mouse hearts over a 7-d time period following myocardial infarction injury. By integrating gene expression profiles with histone marks associated with active or repressed chromatin, we identified transcriptional programs underlying neonatal heart regeneration, and the blockade to regeneration in later life. Our results reveal a unique immune response in regenerative hearts and a retained embryonic cardiogenic gene program that is active during neonatal heart regeneration. Among the unique immune factors and embryonic genes associated with cardiac regeneration, we identified Ccl24, which encodes a cytokine, and Igf2bp3, which encodes an RNA-binding protein, as previously unrecognized regulators of cardiomyocyte proliferation. Our data provide insights into the molecular basis of neonatal heart regeneration and identify genes that can be modulated to promote heart regeneration.

Abstract Background Group B streptococcus (GBS) causes serious diseases in newborn infants, often resulting in lifelong neurologic impairments or death. Prophylactic vaccination of pregnant women prior to delivery could provide comprehensive protection, as early onset and late-onset disease and maternal complications potentially could be addressed. Methods Capsular polysaccharide conjugate vaccine GBS6 was designed using surveillance data yielded by whole-genome sequencing of a global collection of recently recovered GBS isolates responsible for invasive neonatal GBS disease. Capsular polysaccharides were isolated, oxidized using sodium periodate, and conjugated to CRM197 by reductive amination in dimethyl sulfoxide. Immune responses in mice and rhesus macaques were measured in a multiplex Luminex immunoglobulin G (IgG) assay and opsonophagocytic activity assays. Results The optimized conjugates were immunogenic, alone and in combination, in mice and rhesus macaques, inducing IgG antibodies that mediated opsonophagocytic killing. Active immunization of murine dams with GBS6 prior to mating resulted in serotype-specific protection of pups from a lethal challenge with GBS. Protection following passive administration of serotype-specific IgG monoclonal antibodies to dams demonstrated conclusively that anticapsular polysaccharide IgG alone is sufficient for protection. Conclusions The findings support the ongoing clinical evaluation of maternal GBS6 vaccination as a potential alternative method to prevent GBS disease in infants. Six-valent capsular polysaccharide conjugate vaccine GBS6 for the prevention of neonatal Group B Streptococcal (GBS) infections was evaluated in preclinical models. Vaccination with GBS6 or administration of serotype-specific IgG to pregnant dams protected pups against lethal challenges with GBS.

Mice expressing a constitutively active form of RagA are unable to inhibit mTORC1 after birth and to trigger autophagy, and succumb perinatally. Rag GTPases as nutrient sensors for mTORC1 The mTOR complex 1 (mTORC1) pathway is a major regulator of growth in eukaryotes and a drug target for common diseases including cancer and neurodegeneration. It is known that mTORC1 senses amino acids through the Rag family of GTPases, but their physiological importance is unknown. David M. Sabatini and colleagues show that following birth, which stops the maternal nutrient supply, mTORC1 is inhibited in mice in a Rag-dependent fashion. This inhibition triggers autophagy, which promotes the release of amino acids needed to sustain plasma glucose levels via gluconeogenesis between birth and suckling. Thus the Rag pathway acts as a general nutrient sensor, and through its regulation of mTORC1, helps maintain nutrient homeostasis and survival in neonates. The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates organismal growth in response to many environmental cues, including nutrients and growth factors 1 . Cell-based studies showed that mTORC1 senses amino acids through the RagA–D family of GTPases 2 , 3 (also known as RRAGA, B, C and D), but their importance in mammalian physiology is unknown. Here we generate knock-in mice that express a constitutively active form of RagA (RagA GTP ) from its endogenous promoter. RagA GTP/GTP mice develop normally, but fail to survive postnatal day 1. When delivered by Caesarean section, fasted RagA GTP/GTP neonates die almost twice as rapidly as wild-type littermates. Within an hour of birth, wild-type neonates strongly inhibit mTORC1, which coincides with profound hypoglycaemia and a decrease in plasma amino-acid concentrations. In contrast, mTORC1 inhibition does not occur in RagA GTP/GTP neonates, despite identical reductions in blood nutrient amounts. With prolonged fasting, wild-type neonates recover their plasma glucose concentrations, but RagA GTP/GTP mice remain hypoglycaemic until death, despite using glycogen at a faster rate. The glucose homeostasis defect correlates with the inability of fasted RagA GTP/GTP neonates to trigger autophagy and produce amino acids for de novo glucose production. Because profound hypoglycaemia does not inhibit mTORC1 in RagA GTP/GTP neonates, we considered the possibility that the Rag pathway signals glucose as well as amino-acid sufficiency to mTORC1. Indeed, mTORC1 is resistant to glucose deprivation in RagA GTP/GTP fibroblasts, and glucose, like amino acids, controls its recruitment to the lysosomal surface, the site of mTORC1 activation. Thus, the Rag GTPases signal glucose and amino-acid concentrations to mTORC1, and have an unexpectedly key role in neonates in autophagy induction and thus nutrient homeostasis and viability.

Predicted increases in global average temperature are physiologically trivial for most endotherms. However, heat waves will also increase in both frequency and severity, and these will be physiologically more important. Lactating small mammals are hypothesized to be limited by heat dissipation capacity, suggesting high temperatures may adversely impact lactation performance. We measured reproductive performance of mice and striped hamsters (Cricetulus barabensis), including milk energy output (MEO), at temperatures between 21 and 36 °C. In both species, there was a decline in MEO between 21 and 33 °C. In mice, milk production at 33 °C was only 18% of that at 21 °C. This led to reductions in pup growth by 20% but limited pup mortality (0.8%), because of a threefold increase in growth efficiency. In contrast, in hamsters, MEO at 33 °C was reduced to 78.1% of that at 21 °C, yet this led to significant pup mortality (possibly infanticide) and reduced pup growth by 12.7%. Hamster females were more able to sustain milk production as ambient temperature increased, but they and their pups were less capable of adjusting to the lower supply. In both species, exposure to 36 °C resulted in rapid catastrophic lactation failure and maternal mortality. Upper lethal temperature was lowered by 3 to 6 °C in late lactation, making it a critically sensitive window to high ambient temperatures. Our data suggest future heat wave events will impact breeding success of small rodents, but this is based on animals with a long history in captivity. More work should be performed on wild rodents to confirm these impacts.

The innovations developed by scientists working on animal welfare are often not adopted in practice. In this paper, we argue that one important reason for this failure is that the solutions proposed do not adequately address the societal concerns that motivated the original research. Some solutions also fail because they do not adequately address perceived constraints within the industry. Using examples from our own recent work, we show how research methods from the social sciences can address both of these limitations. For example, those who persist in tail-docking cattle (despite an abundance of evidence showing that the practice has no benefits) often justify their position by citing concern for cow cleanliness. This result informs the nature of new extension efforts directed at farmers that continue to tail dock, suggesting that these efforts will be more effective if they focus on providing producers with methods (of proven efficacy) for keeping cows clean. Work on pain mitigation for dehorning shows that some participants reluctant to provide pain relief believe that the pain from this procedure is short lasting and has little impact on the calf. This result informs the direction of new biological research efforts to understand both the magnitude and duration of any suffering that result from this type of procedure. These, and other examples, illustrate how social science methodologies can document the shared and divergent values of different stakeholders (to ensure that proposed solutions align with mainstream values), beliefs regarding the available evidence (to help target new scientific research that meets the perceived gaps), and barriers in implementing changes (to ease adoption of ideas by addressing these barriers).