The Homeodomain-Containing Transcription Factors Arx and Pax4 Control Enteroendocrine Subtype Specification in Mice

Intestinal hormones are key regulators of digestion and energy homeostasis secreted by rare enteroendocrine cells. These cells produce over ten different hormones including GLP-1 and GIP peptides known to promote insulin secretion. To date, the molecular mechanisms controlling the specification of the various enteroendocrine subtypes from multipotent Neurog3+ endocrine progenitor cells, as well as their number, remain largely unknown. In contrast, in the embryonic pancreas, the opposite activities of Arx and Pax4 homeodomain transcription factors promote islet progenitor cells towards the different endocrine cell fates. In this study, we thus investigated the role of Arx and Pax4 in enteroendocrine subtype specification. The small intestine and colon of Arx- and Pax4-deficient mice were analyzed using histological, molecular, and lineage tracing approaches. We show that Arx is expressed in endocrine progenitors (Neurog3+) and in early differentiating (ChromograninA−) GLP-1-, GIP-, CCK-, Sct- Gastrin- and Ghrelin-producing cells. We noted a dramatic reduction or a complete loss of all these enteroendocrine cell types in Arx mutants. Serotonin- and Somatostatin-secreting cells do not express Arx and, accordingly, the differentiation of Serotonin cells was not affected in Arx mutants. However, the number of Somatostatin-expressing D-cells is increased as Arx-deficient progenitor cells are redirected to the D-cell lineage. In Pax4-deficient mice, the differentiation of Serotonin and Somatostatin cells is impaired, as well as of GIP and Gastrin cells. In contrast, the number of GLP-1 producing L-cells is increased concomitantly with an upregulation of Arx. Thus, while Arx and Pax4 are necessary for the development of L- and D-cells respectively, they conversely restrict D- and L-cells fates suggesting antagonistic functions in D/L cell allocation. In conclusion, these finding demonstrate that, downstream of Neurog3, the specification of a subset of enteroendocrine subtypes relies on both Arx and Pax4, while others depend only on Arx or Pax4

The Lantern, 2013-2014

• Strikes • Pietro di Venezia • To the Lover of Small Things • Jim\u27s Big Day • Akademiks • Redamancy • A Love Poem for Arctia Caja • Mother River • The Lyrics to Your Song • Nerves • Gemini Season • White Interface • The Last Time I Played with Dolls • The Mechanic • My Goldfish • Put Down Your Hammer • Strip • Hollywood • Identity • The Grey Zone • Sophia • When I Became a Poet • Unbroken • The Veteran Aeronaut • I Have Running Water but They had the Stars • Not A Nigga • Mother, Adam, Eve • From Fragile Seeds: A Palindrome • Conspiring, The Spires • Finally Working Out What Goes Where (God, For Example, is in His Kingdom) • Identity Crisis • Affection • Patience • An Enchanting Lost Cause • False Starts • Soggy Rice, Lukewarm Water • The Glow • Heat • 9-14 • Filigree • Diane Arbus • Touched • Dying Alive • Just Another Drunkard on the Train • Dinner • The French Legionnaire • Conspiracy and Theory • 1249am • Colored Pencils • Sea Glass • Roundtrip • The Muse Heard Music • Lacrimosa • The Allegory of the Maze • The Stars on Stuart Road • To Isabella • For Want of a Potato Chip • Termite Nests • Saving a Rose • Today and Yesterday • A Foggy New York • Cat; Wurtzburg • Embrace • Faces • Geisha • Pacis Leo • Patterns • Te-Whanganui-a-Tara (The Dock)https://digitalcommons.ursinus.edu/lantern/1180/thumbnail.jp

Reduced fire severity offers near-term buffer to climate-driven declines in conifer resilience across the western United States

Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration. © 2023 the Author(s)

Design for structural and energy performance of long span buildings using geometric multi-objective optimization

This paper addresses the potential of multi-objective optimization (MOO) in conceptual design to help designers generate and select solutions from a geometrically diverse range of high-performing building forms. With a focus on the long span building typology, this research employs a MOO approach that uses both finite element structural modeling and building energy simulations simultaneously to generate optimized building shapes that are not constrained to regular, rectilinear geometric configurations. Through a series of case studies that explore performance tradeoffs of enclosed arches and static overhangs in different climates, this paper shows how MOO can yield architecturally expressive, high-performing designs, which makes the process more attractive to designers searching for creative forms. It also provides new insight into specific design responses to various climatic constraints, since optimization that considers both structure and energy can shift best solutions in unexpected ways. Finally, by displaying performance results in terms of embodied and operational energy, this paper presents new data showing how considerations of structural material efficiency compare in magnitude to total building energy usage. Together, these three contributions can influence current sustainable design strategies for building typologies that have significant structural requirements. Keywords: Multi-objective optimization; Conceptual design; Embodied energy; Operational energy; Design tradeoff

Design for structural and energy performance of long span buildings using geometric multi-objective optimization

This paper addresses the potential of multi-objective optimization (MOO) in conceptual design to help designers generate and select solutions from a geometrically diverse range of high-performing building forms. With a focus on the long span building typology, this research employs a MOO approach that uses both finite element structural modeling and building energy simulations simultaneously to generate optimized building shapes that are not constrained to regular, rectilinear geometric configurations. Through a series of case studies that explore performance tradeoffs of enclosed arches and static overhangs in different climates, this paper shows how MOO can yield architecturally expressive, high-performing designs, which makes the process more attractive to designers searching for creative forms. It also provides new insight into specific design responses to various climatic constraints, since optimization that considers both structure and energy can shift best solutions in unexpected ways. Finally, by displaying performance results in terms of embodied and operational energy, this paper presents new data showing how considerations of structural material efficiency compare in magnitude to total building energy usage. Together, these three contributions can influence current sustainable design strategies for building typologies that have significant structural requirements. Keywords: Multi-objective optimization; Conceptual design; Embodied energy; Operational energy; Design tradeoff

Data-driven approximation algorithms for rapid performance evaluation and optimization of civil structures

This paper explores the use of data-driven approximation algorithms, often called surrogate modeling, in the early-stage design of structures. The use of surrogate models to rapidly evaluate design performance can lead to a more in-depth exploration of a design space and reduce computational time of optimization algorithms. While this approach has been widely developed and used in related disciplines such as aerospace engineering, there are few examples of its application in civil engineering. This paper focuses on the general use of surrogate modeling in the design of civil structures and examines six model types that span a wide range of characteristics. Original contributions include novel metrics and visualization techniques for understanding model error and a new robustness framework that accounts for variability in model comparison. These concepts are applied to a multi-objective case study of an airport terminal design that considers both structural material volume and operational energy consumption. Key Words: surrogate modelling, machine learning, approximation, structural desig

Identification of the <em>Drosophila</em> and <em>Tribolium</em> receptors for the recently discovered insect RYamide neuropeptides

One year ago, we discovered a new family of insect RYamide neuropeptides, which has the C-terminal consensus sequence FFXXXRYamide, and which is widely occurring in most insects, including the fruitfly Drosophila melanogaster and the red flour beetle Tribolium castaneum (F. Hauser et al., J. Proteome Res. 9 (2010) 5296-5310). Here, we identify a Drosophila G-protein-coupled receptor (GPCR) coded for by gene CG5811 and its Tribolium GPCR ortholog as insect RYamide receptors. The Drosophila RYamide receptor is equally well activated (EC(50), 1×10(-9)M) by the two Drosophila RYamide neuropeptides: RYamide-1 (PVFFVASRYamide) and RYamide-2 (NEHFFLGSRYamide), both contained in a preprohormone coded for by gene CG40733. The Tribolium receptor shows a somewhat higher affinity to Tribolium RYamide-2 (ADAFFLGPRYamide; EC(50), 5×10(-9)M) than to Tribolium RYamide-1 (VQNLATFKTMMRYamide; EC(50), 7×10(-8)M), which might be due to the fact that the last peptide does not completely follow the RYamide consensus sequence rule. There are other neuropeptides in insects that have similar C-terminal sequences (RWamide or RFamide), such as the FMRFamides, sulfakinins, myosuppressins, neuropeptides F, and the various short neuropeptides F. Amazingly, these neuropeptides show no cross-reactivity to the Tribolium RYamide receptor, while the Drosophila RYamide receptor is only very slightly activated by high concentrations (>10(-6)M) of neuropeptide F and short neuropeptide F-1, showing that the two RYamide receptors are quite specific for activation by insect RYamides, and that the sequence FFXXXRYamide is needed for effective insect RYamide receptor activation. Phylogenetic tree analyses and other amino acid sequence comparisons show that the insect RYamide receptors are not closely related to any other known insect or invertebrate/vertebrate receptors, including mammalian neuropeptide Y and insect neuropeptide F and short neuropeptide F receptors. Gene expression data published in Flybase (www.flybase.org) show that the Drosophila CG5811 gene is significantly expressed in the hindgut of adult flies, suggesting a role of insect RYamides in digestion or water reabsorption

Conditional deletion of neurogenin-3 using Nkx2.1iCre results in a mouse model for the central control of feeding, activity and obesity

SUMMARY The ventral hypothalamus acts to integrate visceral and systemic information to control energy balance. The basic helix-loop-helix transcription factor neurogenin-3 (Ngn3) is required for pancreatic β-cell development and has been implicated in neuronal development in the hypothalamus. Here, we demonstrate that early embryonic hypothalamic inactivation of Ngn3 (also known as Neurog3) in mice results in rapid post-weaning obesity that is associated with hyperphagia and reduced energy expenditure. This obesity is caused by loss of expression of Pomc in Pomc- and Cart-expressing (Pomc/Cart) neurons in the arcuate nucleus, indicating an incomplete specification of anorexigenic first order neurons. Furthermore, following the onset of obesity, both the arcuate and ventromedial hypothalamic nuclei become insensitive to peripheral leptin treatment. This conditional mouse mutant therefore represents a novel model system for obesity that is associated with hyperphagia and underactivity, and sheds new light upon the roles of Ngn3 in the specification of hypothalamic neurons controlling energy balance