Structure–property relationships of an additively manufactured 316L stainless steel were explored. A scanning electron microscope and electron backscattered diffraction (EBSD) analysis revealed a ...fine cellular-dendritic (0.5 to 2
μ
m) substructure inside large irregularly shaped grains (~ 100
μ
m). The cellular structure grows along the 〈100〉 crystallographic directions. However, texture analysis revealed that the main 〈100〉 texture component is inclined by ~15 deg from the building direction. X-ray diffraction line profile analysis indicated a high dislocation density of ~1 × 10
15
m
−2
in the as-built material, which correlates well with the observed EBSD microstructure and high-yield strength,
via
the traditional Taylor hardening equation. Significant variations in strain hardening behavior and ductility were observed for the horizontal (HB) and vertical (VB) built samples. Ductility of HB and VB samples measured 49 and 77 pct, respectively. The initial growth texture and subsequent texture evolution during tensile deformation are held responsible for the observed anisotropy. Notably, EBSD analysis of deformed samples showed deformation twins, which predominately form in the grains with 〈111〉 aligned parallel to the loading direction. The VB samples showed higher twinning activity, higher strain hardening rates at high strain, and therefore, higher ductility. Analysis of annealed samples revealed that the observed microstructures and properties are thermally stable, with only a moderate decrease in strength and very similar levels of ductility and anisotropy, compared with the as-built condition.
The reduction in severe and moderate acute malnutrition (SAM and MAM) rates in Pakistan has been sub-optimal compared to other low-and middle-income countries (LMICs). Specially-formulated products ...have been designed globally to manage SAM and MAM, such as ready-to-use therapeutic food (RUTF) and ready-to-use supplementary food (RUSF), with variable efficacies. RUTF is primarily produced and patented in industrialized countries, raising supply challenges in resource-constrained regions with a high burden of acute malnutrition. RUSF minimizes costs by using locally-available ingredients while providing similar nutritional value. In this study, we compared the efficacy, side effects, and compliance of two months of supplementation with either RUTF or RUSF.
Children aged nine months in the rural district of Matiari, Pakistan, with a weight-for-height z-score (WHZ) <-2 received either RUTF (500 kcal sachet) for two months in 2015 or RUSF (520 kcal sachet) for two months in 2018.
The RUSF group had a higher height gain and mid-upper arm circumferences (MUAC) score. Higher compliance was noted with lower side effects in the RUSF group. A higher compliance rate did correlate with the growth parameters in respective groups.
Our study found that both RUTF and RUSF partially improve the anthropometric status of acutely malnourished children, with neither being superior to the other.
Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition of microbiota to motility. However, development of the intestinal circadian clock and detailed ...mechanisms regulating circadian physiology of the intestine remain largely unknown. In this report, we show that both pluripotent stem cell‐derived human intestinal organoids engrafted into mice and patient‐derived human intestinal enteroids possess circadian rhythms and demonstrate circadian phase‐dependent necrotic cell death responses to Clostridium difficile toxin B (TcdB). Intriguingly, mouse and human enteroids demonstrate anti‐phasic necrotic cell death responses to TcdB. RNA‐Seq analysis shows that ~3–10% of the detectable transcripts are rhythmically expressed in mouse and human enteroids. Remarkably, we observe anti‐phasic gene expression of Rac1, a small GTPase directly inactivated by TcdB, between mouse and human enteroids, and disruption of Rac1 abolishes clock‐dependent necrotic cell death responses. Our findings uncover robust functions of circadian rhythms regulating clock‐controlled genes in both mouse and human enteroids governing organism‐specific, circadian phase‐dependent necrotic cell death responses, and lay a foundation for human organ‐ and disease‐specific investigation of clock functions using human organoids for translational applications.
SYNOPSIS
How rhythmicity of gene expression in the gut epithelium develops and which molecular mechanisms contribute to its maintenance remains unclear. This analysis of mouse and human organoid models uncovers species‐specific oscillatory behavior of circadian genes in the intestine.
Maturation of pluripotent stem cell‐derived human intestinal organoids is required to develop robust circadian rhythms.
Approximately 3–10% of transcripts in mouse and human intestinal enteroids are clock‐controlled genes.
Phase set enrichment analysis uncovers eight conserved rhythmic signaling pathways.
Rac1 small GTPase oscillations are anti‐phasic between mouse and human enteroids, regulating distinct necrotic cell death responses to Clostridium difficile toxin B.
Mouse and human 3D in vitro models show tissue maturation to determine species‐specific circadian rhytms in the intestine.
Circadian clock-gated cell division cycles are observed from cyanobacteria to mammals via intracellular molecular connections between these two oscillators. Here we demonstrate WNT-mediated ...intercellular coupling between the cell cycle and circadian clock in 3D murine intestinal organoids (enteroids). The circadian clock gates a population of cells with heterogeneous cell-cycle times that emerge as 12-hr synchronized cell division cycles. Remarkably, we observe reduced-amplitude oscillations of circadian rhythms in intestinal stem cells and progenitor cells, indicating an intercellular signal arising from differentiated cells governing circadian clock-dependent synchronized cell division cycles. Stochastic simulations and experimental validations reveal Paneth cell-secreted WNT as the key intercellular coupling component linking the circadian clock and cell cycle in enteroids.
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•The circadian clock gates cell-cycle progression in the intestinal epithelium•The circadian clock is less robust in intestinal stem and progenitor cells•WNT secreted from Paneth cells couples the circadian clock and cell cycle
Paneth cell-dependent circadian secretion of WNT is a key mechanism linking circadian rhythms and cell-cycle progression in murine enteroids. This finding implicates Paneth cells as local pacemakers that regulate the timing of cell divisions in intestinal stem cells and progenitor cells in the context of circadian rhythmicity.
More than one-fifth of the world's population live in extreme poverty, where a lack of safe water and adequate sanitation enables high rates of enteric infections and diarrhoea to continue unabated. ...Although oral rehydration therapy has greatly reduced diarrhoea-associated mortality, enteric infections still persist, disrupting intestinal absorptive and barrier functions and resulting in up to 43% of stunted growth, affecting one-fifth of children worldwide and one-third of children in developing countries. Diarrhoea in children from impoverished areas during their first 2 years might cause, on average, an 8 cm growth shortfall and 10 IQ point decrement by the time they are 7-9 years old. A child's height at their second birthday is therefore the best predictor of cognitive development or 'human capital'. To this 'double burden' of diarrhoea and malnutrition, data now suggest that children with stunted growth and repeated gut infections are also at increased risk of developing obesity and its associated comorbidities, resulting in a 'triple burden' of the impoverished gut. Here, we Review the growing evidence for this triple burden and potential mechanisms and interventions that must be understood and applied to prevent the loss of human potential and unaffordable societal costs caused by these vicious cycles of poverty.
The gastrointestinal (GI) tract is innervated by the enteric nervous system (ENS), an extensive neuronal network that traverses along its walls. Due to local reflex circuits, the ENS is capable of ...functioning with and without input from the central nervous system. The functions of the ENS range from the propulsion of food to nutrient handling, blood flow regulation, and immunological defense. Records of it first being studied emerged in the early 19th century when the submucosal and myenteric plexuses were discovered. This was followed by extensive research and further delineation of its development, anatomy, and function during the next two centuries. The morbidity and mortality associated with the underdevelopment, infection, or inflammation of the ENS highlight its importance and the need for us to completely understand its normal function. This review will provide a general overview of the ENS to date and connect specific GI diseases including short bowel syndrome with neuronal pathophysiology and current therapies. Exciting opportunities in which the ENS could be used as a therapeutic target for common GI diseases will also be highlighted, as the further unlocking of such mechanisms could open the door to more therapy-related advances and ultimately change our treatment approach.
Background: DNA methylation is an epigenetic mechanism central to development and maintenance of complex mammalian tissues, but our understanding of its role in intestinal development is limited. ...Results: We use whole genome bisulfite sequencing, and find that differentiation of mouse colonic intestinal stem cells to intestinal epithelium is not associated with major changes in DNA methylation. However, we detect extensive dynamic epigenetic changes in intestinal stem cells and their progeny during the suckling period, suggesting postnatal epigenetic development in this stem cell population. We find that postnatal DNA methylation increases at 3' CpG islands (CGIs) correlate with transcriptional activation of glycosylation genes responsible for intestinal maturation. To directly test whether 3' CGI methylation regulates transcription, we conditionally disrupted two major DNA methyltransferases, Dnmt1 or Dnmt3a, in fetal and adult intestine. Deficiency of Dnmt1 causes severe intestinal abnormalities in neonates and disrupts crypt homeostasis in adults, whereas Dnmt3a loss was compatible with intestinal development. These studies reveal that 3' CGI methylation is functionally involved in the regulation of transcriptional activation in vivo, and that Dnmt1 is a critical regulator of postnatal epigenetic changes in intestinal stem cells. Finally, we show that postnatal 3' CGI methylation and associated gene activation in intestinal epithelial cells are significantly altered by germ-free conditions. Conclusions: Our results demonstrate that the suckling period is critical for epigenetic development of intestinal stem cells, with potential important implications for lifelong gut health, and that the gut microbiome guides and/or facilitates these postnatal epigenetic processes.
Environmental enteric dysfunction (EED) is a subclinical syndrome of intestinal inflammation, malabsorption and barrier disruption that is highly prevalent in low- and middle-income countries in ...which poverty, food insecurity and frequent exposure to enteric pathogens impair growth, immunity and neurodevelopment in children. In this Review, we discuss advances in our understanding of EED, intestinal adaptation and the gut microbiome over the 'first 1,000 days' of life, spanning pregnancy and early childhood. Data on maternal EED are emerging, and they mirror earlier findings of increased risks for preterm birth and fetal growth restriction in mothers with either active inflammatory bowel disease or coeliac disease. The intense metabolic demands of pregnancy and lactation drive gut adaptation, including dramatic changes in the composition, function and mother-to-child transmission of the gut microbiota. We urgently need to elucidate the mechanisms by which EED undermines these critical processes so that we can improve global strategies to prevent and reverse intergenerational cycles of undernutrition.
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