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Even as a kid my existence as the son of Bunny and George Wilson seemed far-fetched to me. When I went over it in my head, none of it added up. The other kids on East 36th Street in Hamilton used to tell me stories of their mothers being pregnant and their newborn siblings coming home from the hospital. Nobody ever talked about Bunny's and my return from the hospital. In my mind my birth was like the nativity, only with gnarly dogs and dirty snow and a chipped picket fence and old blind people with short tempers and dim lights, ashtrays full of Export Plain cigarette butts and bottles of rum. Once, when I was about four, I asked Bunny, \"How come I don't look anything like you and George? How come you are old and the other moms are young?\" \"There are secrets I know about you that I'll take to my grave,\" she responded. And that pretty well finished that. Bunny built up a wall to protect her secrets, and as a result I built a wall to protect myself.

Key Points Retinoic acid (RA) was first implicated as a signalling molecule on the basis of its teratogenic effects on limb patterning. Studies in chick using treatment with RA or RA receptor antagonists suggested a two-signal model for limb proximodistal patterning in which a proximal RA signal opposes a distal fibroblast growth factor (FGF) signal. Genetic loss-of-function studies in mice confirmed a requirement for distal FGF but not proximal RA in limb proximodistal patterning, thus supporting a one-signal model in which distal FGFs alone control patterning. RA was found to promote forelimb initiation by repressing Fgf8 along the body axis before limb budding. RA–FGF8 antagonism has also been found to be essential for somitogenesis and neurogenesis during body axis extension. RA directly represses caudal Fgf8 through an upstream retinoic acid response element. Genetic loss of RA synthesis has identified several additional roles for RA signalling during organogenesis, including neuronal differentiation in the hindbrain and spinal cord, eye morphogenesis, differentiation of forebrain basal ganglia, heart development and spermatogenesis. The putative role of RA in these developmental processes has been backed up by the identification of target genes that both require RA for normal expression and have nearby functional retinoic acid response elements. Understanding the mechanism of RA-mediated activation and repression during development will benefit efforts to obtain differentiated cell types that are useful in regenerative medicine. Retinoic acid regulates transcription by interacting with nuclear retinoic acid receptors, which bind to retinoic acid response elements near target genes. Recent studies have refined our knowledge of retinoic acid function in the limb, which serves as a paradigm for understanding how it regulates other developmental processes, such as somitogenesis, neuronal differentiation and organogenesis. Retinoic acid (RA) signalling has a central role during vertebrate development. RA synthesized in specific locations regulates transcription by interacting with nuclear RA receptors (RARs) bound to RA response elements (RAREs) near target genes. RA was first implicated in signalling on the basis of its teratogenic effects on limb development. Genetic studies later revealed that endogenous RA promotes forelimb initiation by repressing fibroblast growth factor 8 ( Fgf8 ). Insights into RA function in the limb serve as a paradigm for understanding how RA regulates other developmental processes. In vivo studies have identified RAREs that control repression of Fgf8 during body axis extension or activation of homeobox (Hox) genes and other key regulators during neuronal differentiation and organogenesis.

Despite its inclusion in models of social and ecological determinants of health, work has not been explored in most health inequity research in the United States. Leaving work out of public health inequities research creates a blind spot in our understanding of how inequities are created and impedes our progress toward health equity. We first describe why work is vital to our understanding of observed societal-level health inequities. Next, we outline challenges to incorporating work in the study of health inequities, including (1) the complexity of work as a concept; (2) work’s overlap with socioeconomic position, race, ethnicity, and gender; (3) the development of a parallel line of inquiry into occupational health inequities; and (4) the dearth of precise data with which to explore the relationships between work and health status. Finally, we summarize opportunities for advancing health equity and monitoring progress that could be achieved if researchers and practitioners more robustly include work in their efforts to understand and address health inequities.

To better understand human health and disease, researchers create a wide variety of mouse models that carry human DNA. With recent advances in genome engineering, the targeted replacement of mouse genomic regions with orthologous human sequences has become increasingly viable, ranging from finely tuned humanisation of individual nucleotides and amino acids to the incorporation of many megabases of human DNA. Here, we examine emerging technologies for targeted genomic humanisation, we review the spectrum of existing genomically humanised mouse models and the insights such models have provided, and consider the lessons learned for designing such models in the future. Generation of transgenic mice has become routine in studying gene function and disease mechanisms, but often this is not enough to fully understand human biology. Here, the authors review the current state of the art of targeted genomic humanisation strategies and their advantages over classic approaches.

Bipotent axial stem cells residing in the caudal epiblast during late gastrulation generate neuroectodermal and presomitic mesodermal progeny that coordinate somitogenesis with neural tube formation, but the mechanism that controls these two fates is not fully understood. Retinoic acid (RA) restricts the anterior extent of caudal fibroblast growth factor 8 (Fgf8) expression in both mesoderm and neural plate to control somitogenesis and neurogenesis, however it remains unclear where RA acts to control the spatial expression of caudal Fgf8. Here, we found that mouse Raldh2-/- embryos, lacking RA synthesis and displaying a consistent small somite defect, exhibited abnormal expression of key markers of axial stem cell progeny, with decreased Sox2+ and Sox1+ neuroectodermal progeny and increased Tbx6+ presomitic mesodermal progeny. The Raldh2-/- small somite defect was rescued by treatment with an FGF receptor antagonist. Rdh10 mutants, with a less severe RA synthesis defect, were found to exhibit a small somite defect and anterior expansion of caudal Fgf8 expression only for somites 1-6, with normal somite size and Fgf8 expression thereafter. Rdh10 mutants were found to lack RA activity during the early phase when somites are small, but at the 6-somite stage RA activity was detected in neural plate although not in presomitic mesoderm. Expression of a dominant-negative RA receptor in mesoderm eliminated RA activity in presomitic mesoderm but did not affect somitogenesis. Thus, RA activity in the neural plate is sufficient to prevent anterior expansion of caudal Fgf8 expression associated with a small somite defect. Our studies provide evidence that RA restriction of Fgf8 expression in undifferentiated neural progenitors stimulates neurogenesis while also restricting the anterior extent of the mesodermal Fgf8 mRNA gradient that controls somite size, providing new insight into the mechanism that coordinates somitogenesis with neurogenesis.

The epizootic prion disease of cattle, bovine spongiform encephalopathy (BSE), caused variant Creutzfeldt-Jakob disease (vCJD) in humans following dietary exposure. Codon 129 polymorphism of the human prion protein gene ( PRNP ), encoding either methionine (M) or valine (V), dictates the propagation of distinct human prion strains and up to now all but one neuropathologically confirmed vCJD patients have had a 129MM genotype. Concordant with this genetic association, transgenic modelling has established that human PrP 129V is incompatible with the vCJD prion strain and that depending on codon 129 genotype, primary human infection with BSE prions may, in addition to vCJD, result in sporadic CJD-like or novel phenotypes. In 2016 we saw the first neuropathologically confirmed case of vCJD in a patient with a codon 129MV genotype. This patient’s neuropathology and molecular strain type were pathognomonic of vCJD but their clinical presentation and neuroradiological features were more typical of sporadic CJD, suggestive of possible co-propagation of another prion strain. Here we report the transmission properties of prions from the brain and lymphoreticular tissues of the 129MV vCJD patient. Primary transmissions into transgenic mice expressing human PrP with different codon 129 genotypes mainly produced neuropathological and molecular phenotypes congruent to those observed in the same lines of mice challenged with prions from 129MM vCJD patient brain, indicative that the vCJD prion strain was the dominant propagating prion strain in the patient’s brain. Remarkably however, some transgenic mice challenged with 129MV vCJD patient brain propagated a novel prion strain type which at secondary passage was uniformly lethal in mice of all three PRNP codon 129 genotypes after similar short mean incubation periods. These findings establish that cattle BSE prions can trigger the co-propagation of distinct prion strains in humans.

Sex-specific initiation of meiosis in the fetal ovary has been suggested to require retinoic acid (RA) for induction of Stra8 , with expression of the RA-degrading enzyme Cyp26b1 in fetal testis delaying meiosis until postnatal development. In this study, we investigate Raldh2 −/− mice lacking RA synthesis and signalling in mesonephros and adjacent gonad and reveal that Stra8 expression in the fetal ovary does not require RA signalling. In contrast to previous observations, we find that Stra8 is expressed in the absence of physiologically detectable levels of RA. Ketoconazole inhibition of Cyp26b1 in Raldh2 −/− testis allows RA-independent induction of Stra8 , but only when the mesonephros remains attached, pointing to a non-RA signal from the mesonephros that induces Stra8 in the adjacent gonad. These findings demonstrate that Cyp26b1 prevents the onset of meiosis by metabolizing a substrate other than RA that controls Stra8 expression, thus changing the paradigm for how studies on Cyp26 function are conducted. Retinoic acid is thought to initiate meiosis in the fetal ovary via Stra8 expression, and Cyp26b1 metabolism of retinoic acid prevents meiosis in the testis. In this study, mice lacking retinoic acid synthesis exhibit Stra8 induction, suggesting that a Cyp26b1 substrate other than retinoic acid controls Stra8 expression.

Metabolic reprogramming is an active regulator of stem cell fate choices, and successful stem cell differentiation in different compartments requires the induction of oxidative phosphorylation. However, the mechanisms that promote mitochondrial respiration during stem cell differentiation are poorly understood. Here we demonstrate that Stat3 promotes muscle stem cell myogenic lineage progression by stimulating mitochondrial respiration in mice. We identify Fam3a, a cytokine-like protein, as a major Stat3 downstream effector in muscle stem cells. We demonstrate that Fam3a is required for muscle stem cell commitment and skeletal muscle development. We show that myogenic cells secrete Fam3a, and exposure of Stat3-ablated muscle stem cells to recombinant Fam3a in vitro and in vivo rescues their defects in mitochondrial respiration and myogenic commitment. Together, these findings indicate that Fam3a is a Stat3-regulated secreted factor that promotes muscle stem cell oxidative metabolism and differentiation, and suggests that Fam3a is a potential tool to modulate cell fate choices. Induction of mitochondrial oxidative respiration is required for stem cell differentiation, but the mechanisms underlying this process are poorly understood. Here, the authors report that Stat3 promotes muscle stem cell differentiation by stimulating mitochondrial respiration via Fam3a.

The well-being of health workers is essential to provide health promotion, prevention, and care. There is mounting evidence, though, that the wellbeing of health workers is not being protected as it should be. Surveys have indicated health workers, including clinicians, community health workers, public health workers, mental health workers, emergency medical responders, long-term care workers, as well as those in support roles, have been experiencing high levels of physical injury, harassment, stress, and burnout. Many such workers shared their intentions to leave their positions or the field altogether. Media reports have described heart-wrenching cases of physicians and nurses who died by suicide, and surveys have indicated unprecedented levels of poor mental health among health workers.In 2021, the American Rescue Plan funded new research, intervention development, training, education, and dissemination, largely in response to the mental health crisis unfolding due to the COVID-19 pandemic. Since that time, the U.S. Centers for Disease Control and Prevention (CDC), the National Academy of Medicine, the U.S. Surgeon General, organized labor, and numerous other leaders and stakeholders have called for urgent action. This supplement was conceived by the CDC's National institute for Occupational Safety and Health (NIOSH) to rapidly communicate the latest science guiding the development of responsive mental health and well-being resources for health workers.Health workers, who already faced difficult and chronically stressful working conditions, experienced profound, negative mental health effects as a result of the pandemic-even more than other essential workers (Health Workers Face a Mental Health Crisis | VitalSigns | CDC). The connection between mental health outcomes and how work is designed, organized, and managed is becoming increasingly clear. There is a growing body of science supporting the improvement of workplace mental health through healthy work design and systems-level well-being efforts within organizations. This supplement directly contributes to this literature in the context of the health sector.In this supplement, several contributions explore the theme of Health Worker Mental Health: Addressing the Current Crisis and Building a Sustainable Future. The work presented in this supplement covers three main areas of interest: 1 ) updated data describing concerning trends in the state of health worker mental health and well-being, 2) original research and a systematic review that describe evidence-informed interventions aimed at improving health worker mental health and well-being, and 3) perspectives from organizations that are taking action to make equitable changes at the organization, state, and national levels.

Action to address workforce functioning and productivity requires a broader approach than the traditional scope of occupational safety and health. Focus on “well-being” may be one way to develop a more encompassing objective. Well-being is widely cited in public policy pronouncements, but often as “. . . and well-being” (e.g., health and well-being). It is generally not defined in policy and rarely operationalized for functional use. Many definitions of well-being exist in the occupational realm. Generally, it is a synonym for health and a summative term to describe a flourishing worker who benefits from a safe, supportive workplace, engages in satisfying work, and enjoys a fulfilling work life. We identified issues for considering well-being in public policy related to workers and the workplace.