Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity

The intestinal epithelium must balance efficient absorption of nutrients with partitioning commensals and pathogens from the bodies’ largest immune system. If this crucial barrier fails, inappropriate immune responses can result in inflammatory bowel disease or chronic infection. Enteroendocrine cells represent 1% of this epithelium and have classically been studied for their detection of nutrients and release of peptide hormones to mediate digestion. Intriguingly, enteroendocrine cells are the key sensors of microbial metabolites, can release cytokines in response to pathogen associated molecules and peptide hormone receptors are expressed on numerous intestinal immune cells; thus enteroendocrine cells are uniquely equipped to be crucial and novel orchestrators of intestinal inflammation. In this review, we introduce enteroendocrine chemosensory roles, summarize studies correlating enteroendocrine perturbations with intestinal inflammation and describe the mechanistic interactions by which enteroendocrine and mucosal immune cells interact during disease; highlighting this immunoendocrine axis as a key aspect of innate immunity

The contributions of maternal age heterogeneity to variance in lifetime reproductive output

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in van Daalen, S. F., Hernandez, C. M., Caswell, H., Neubert, M. G., & Gribble, K. E. The contributions of maternal age heterogeneity to variance in lifetime reproductive output. American Naturalist,199(5), (2022): 603-616, https://doi.org/10.1086/718716.Variance among individuals in fitness components reflects both genuine heterogeneity between individuals and stochasticity in events experienced along the life cycle. Maternal age represents a form of heterogeneity that affects both the mean and the variance of lifetime reproductive output (LRO). Here, we quantify the relative contribution of maternal age heterogeneity to the variance in LRO using individual-level laboratory data on the rotifer Brachionus manjavacas to parameterize a multistate age × maternal age matrix model. In B. manjavacas, advanced maternal age has large negative effects on offspring survival and fertility. We used multistate Markov chains with rewards to quantify the contributions to variance in LRO of heterogeneity and of the stochasticity inherent in the outcomes of probabilistic transitions and reproductive events. Under laboratory conditions, maternal age heterogeneity contributes 26% of the variance in LRO. The contribution changes when mortality and fertility are reduced to mimic more ecologically relevant environments. Over the parameter space where populations are near stationarity, maternal age heterogeneity contributes an average of 3% of the variance. Thus, the contributions of maternal age heterogeneity and individual stochasticity can be expected to depend strongly on environmental conditions; over most of the parameter space, the variance in LRO is dominated by stochasticity.K.E.G. was supported by grant 5K01AG049049 from the National Institute on Aging, by National Science Foundation (NSF) CAREER grant IOS-1942606, and by the Bay and Paul Foundations. H.C. and S.F.v.D. were supported by the European Research Council through Advanced Grants 322829 and 788195 and by the Dutch Research Council through grant ALWOP.2015.100. S.F.v.D. was furthermore supported by the Postdoctoral Scholar Program at Woods Hole Oceanographic Institution, with funding provided by the Doherty Foundation. C.M.H. was supported by an NSF Graduate Research Fellowship. M.G.N. received funding from the Paul MacDonald Fye Chair for Excellence in Oceanography at the Woods Hole Oceanographic Institution

Electrical activity-triggered glucagon-like peptide-1 secretion from primary murine L-cells

Glucagon like peptide 1 (GLP-1) based therapies are now widely used for the treatment of type 2 diabetes. Developing our understanding of intestinal GLP-1 release may facilitate the development of new therapeutics aimed at targeting the GLP-1 producing L-cells. This study was undertaken to characterise the electrical activity of primary L-cells and the importance of voltage gated sodium and calcium channels for GLP-1 secretion. Primary murine L-cells were identified and purified using transgenic mice expressing a fluorescent protein driven by the proglucagon promoter. Fluorescent L-cells were identified within primary colonic cultures for patch clamp recordings. GLP-1 secretion was measured from primary colonic cultures. L-cells purified by flow cytometry were used to measure gene expression by microarray and quantitative RT-PCR. Electrical activity in L-cells was due to large voltage gated sodium currents, inhibition of which by tetrodotoxin reduced both basal and glutamine-stimulated GLP-1 secretion. Voltage gated calcium channels were predominantly of the L-type, Q-type and T-type, by expression analysis, consistent with the finding that GLP-1 release was blocked both by nifedipine and ω-conotoxin MVIIC. We observed large voltage-dependent potassium currents, but only a small chromanol sensitive current that might be attributable to KCNQ1. GLP-1 release from primary L-cells is linked to electrical activity and activation of L-type and Q-type calcium currents. The concept of an electrically excitable L-cell provides a basis for understanding how GLP-1 release may be modulated by nutrient, hormonal and pharmaceutical stimuli

Children's scale errors: A by-product of lexical development?

Scale errors occur when young children seriously attempt to perform an action on an object which is impossible due to its size. Children vary substantially in the incidence of scale errors with many factors potentially contributing to these differences, such as age and the type of scale errors. In particular, the evidence for an inverted U-shaped curve of scale errors involving the child's body (i.e., body scale errors), which would point to a developmental stage, is mixed. Here we re-examine how body scale errors vary with age and explore the possibility that these errors would be related to the size and properties of children's lexicon. A large sample of children aged 18-30 months (N = 125) was tested in a scale error elicitation situation. Additionally, parental questionnaires were collected to assess children's receptive and expressive lexicon. Our key findings are that scale errors linearly decrease with age in childhood, and are more likely to be found in early talkers rather than in less advanced ones. This suggests that scale errors do not correspond to a developmental stage, and that one determinant of these errors is the speed of development of the linguistic and conceptual system, as a potential explanation for the individual variability in prevalence

Essential role of syntaxin-binding protein-1 in the regulation of glucagon-like peptide-1 secretion

Circadian secretion of the incretin, glucagon-like peptide-1 (GLP-1), correlates with expression of the core clock gene, Bmal1, in the intestinal L-cell. Several SNARE proteins known to be circadian in pancreatic α- and β-cells are also necessary for GLP-1 secretion. However, the role of the accessory SNARE, Syntaxin binding protein-1 (Stxbp1; also known as Munc18-1) in the L-cell is unknown. The aim of this study was to determine whether Stxbp1 is under circadian regulation in the L-cell and its role in the control of GLP-1 secretion. Stxbp1 was highly-enriched in L-cells, and STXBP1 was expressed in a subpopulation of L-cells in mouse and human intestinal sections. Stxbp1 transcripts and protein displayed circadian patterns in mGLUTag L-cells line, while chromatin-immunoprecipitation revealed increased interaction between BMAL1 and Stxbp1 at the peak time-point of the circadian pattern. STXBP1 recruitment to the cytosol and plasma membrane within 30 minutes of L-cell stimulation was also observed at this time-point. Loss of Stxbp1 in vitro and in vivo led to reduced stimulated GLP-1 secretion at the peak time-point of circadian release, and impaired GLP-1 secretion ex vivo. In conclusion, Stxbp1 is a circadian regulated exocytotic protein in the intestinal L-cell that is an essential regulatory component of GLP-1 secretion.Wellcome Trust MR

Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression

Key points α‐ and β‐cells express both Nav1.3 and Nav1.7 Na+ channels but in different relative amounts. The differential expression explains the different properties of Na+ currents in α‐ and β‐cells. Nav1.3 is the functionally important Na+ channel α subunit in both α‐ and β‐cells. Islet Nav1.7 channels are locked in an inactive state due to an islet cell‐specific factor. Mouse pancreatic β‐ and α‐cells are equipped with voltage‐gated Na+ currents that inactivate over widely different membrane potentials (half‐maximal inactivation (V0.5) at −100 mV and −50 mV in β‐ and α‐cells, respectively). Single‐cell PCR analyses show that both α‐ and β‐cells have Nav1.3 (Scn3) and Nav1.7 (Scn9a) α subunits, but their relative proportions differ: β‐cells principally express Nav1.7 and α‐cells Nav1.3. In α‐cells, genetically ablating Scn3a reduces the Na+ current by 80%. In β‐cells, knockout of Scn9a lowers the Na+ current by >85%, unveiling a small Scn3a‐dependent component. Glucagon and insulin secretion are inhibited in Scn3a−/− islets but unaffected in Scn9a‐deficient islets. Thus, Nav1.3 is the functionally important Na+ channel α subunit in both α‐ and β‐cells because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Nav1.7 sequence in brain and islets is identical and yet the V0.5 for inactivation is >30 mV more negative in β‐cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation

Performance of a quasi-steady, multi megawatt, coaxial plasma thruster

The Los Alamos National Laboratory Coaxial Thruster Experiment (CTX) has been upgraded to enable the quasisteady operation of magnetoplasmadynamic (MPD) type thrusters at power levels from 2 to 40 MW for 10 ms. Diagnostics include an eight position, three axis magnetic field probe to measure magnetic field fluctuations during the pulse; a triple Langmuir probe to measure ion density, electron temperature, and plasma potential; and a time-of-flight neutral particle spectrometer to measure specific impulse. Here we report on the experimental observations and associated analysis and interpretation of long-pulse, quasisteady, coaxial thruster performance in the CTX device

LKB1 and AMPK differentially regulate pancreatic β-cell identity.

Fully differentiated pancreatic β cells are essential for normal glucose homeostasis in mammals. Dedifferentiation of these cells has been suggested to occur in type 2 diabetes, impairing insulin production. Since chronic fuel excess ("glucotoxicity") is implicated in this process, we sought here to identify the potential roles in β-cell identity of the tumor suppressor liver kinase B1 (LKB1/STK11) and the downstream fuel-sensitive kinase, AMP-activated protein kinase (AMPK). Highly β-cell-restricted deletion of each kinase in mice, using an Ins1-controlled Cre, was therefore followed by physiological, morphometric, and massive parallel sequencing analysis. Loss of LKB1 strikingly (2.0-12-fold, E<0.01) increased the expression of subsets of hepatic (Alb, Iyd, Elovl2) and neuronal (Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamate signaling. These changes were partially recapitulated by the loss of AMPK, which also up-regulated β-cell "disallowed" genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E<0.01). Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P=1.3×10(-33)) and hypoxia-regulated (HIF1; P=2.5×10(-16)) transcription factors. In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain β-cell identity by suppressing alternate pathways leading to neuronal, hepatic, and other characteristics. Selective targeting of these enzymes may provide a new approach to maintaining β-cell function in some forms of diabetes.-Kone, M., Pullen, T. J., Sun, G., Ibberson, M., Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S., Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J., Thorens, B., Reimann, F., Gribble, F., McGinty, J. A., Chen, L., French, P. M., Birzele, F., Hildebrandt, T., Uphues, I., Rutter, G. A. LKB1 and AMPK differentially regulate pancreatic β-cell identity