Circadian Entrainment Triggers Maturation of Human In Vitro Islets

Stem-cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human pluripotent stem cells (hPSCs) differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, hPSC-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, hPSC-derived tissues are amenable to functional improvement by circadian modulation

Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3+ regulatory T cells via integrin αvβ8

BACKGROUND & AIMS: The intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut. Transforming growth factor (TGF)-β is a cytokine that maintains intestinal homeostasis, in part by inducing Foxp3(+) regulatory T cells (Tregs) that suppress immune responses. TGF-β is expressed at high levels in the gastrointestinal tract as a latent complex that must be activated. However, the pathways that control TGF-β activation in the intestine are poorly defined. We investigated the cellular and molecular pathways that control activation of TGF-β and induction of Foxp3(+) Tregs in the intestines of mice to maintain immune homeostasis. METHODS: Subsets of intestinal dendritic cells (DCs) were examined for their capacity to activate TGF-β and induce Foxp3(+) Tregs in vitro. Mice were fed oral antigen, and induction of Foxp3(+) Tregs was measured. RESULTS: A tolerogenic subset of intestinal DCs that express CD103 were specialized to activate latent TGF-β, and induced Foxp3(+) Tregs independently of the vitamin A metabolite retinoic acid. The integrin αvβ8, which activates TGF-β, was significantly up-regulated on CD103(+) intestinal DCs. DCs that lack expression of integrin αvβ8 had reduced ability to activate latent TGF-β and induce Foxp3(+) Tregs in vitro and in vivo. CONCLUSIONS: CD103(+) intestinal DCs promote a tolerogenic environment in the intestines of mice via integrin αvβ8-mediated activation of TGF-β

A Multipotent Progenitor Domain Guides Pancreatic Organogenesis

The mammalian pancreas is constructed during embryogenesis by multipotent progenitors, the identity and function of which remain poorly understood. We performed genome-wide transcription factor expression analysis of the developing pancreas to identify gene expression domains that may represent distinct progenitor cell populations. Five discrete domains were discovered. Genetic lineage-tracing experiments demonstrate that one specific domain, located at the tip of the branching pancreatic tree, contains multipotent progenitors that produce exocrine, endocrine, and duct cells in vivo. These multipotent progenitors are Pdx1+Ptf1a+cMycHighCpa1+ and negative for differentiated lineage markers. The outgrowth of multipotent tip cells leaves behind differentiated progeny that form the trunk of the branches. These findings define a multipotent compartment within the developing pancreas and suggest a model of how branching is coordinated with cell type specification. In addition, this comprehensive analysis of >1,100 transcription factors identified genes that are likely to control critical decisions in pancreas development and disease.Molecular and Cellular Biolog

VIPER Integrated MDAO Analysis for Conceptual Design of Supersonic X-Plane Vehicles

A streamlined Multi-Disciplinary Analysis and Optimization (MDAO) process is being developed to provide feedback on conceptual designs and early airspace modeling assessments of unconventional aircraft. This MDAO process has been demonstrated using a Low-Boom Flight Demonstrator (LBFD) like configuration by performing a trade study of various flap sizes. The results of this trade showed that shorter takeoff distances are achieved with increased flap chord and flap deflections. This trend is unlike conventional transport type aircraft which typically show increased required takeoff distances due to the increased drag during its take-off flap configurations. The LBFD like configuration results are attributed to its high engine thrust which overcomes the higher drag associated with these takeoff flap configurations

Hebb repetition effects for non-verbal visual sequences: determinants of sequence acquisition.

We report four experiments premised upon the work of Horton et al. (2008) and Page et al. (2013), and explore conditions under which the visual Hebb repetition effect is observed. Experiment 1 showed that repetition learning is evident when the items comprising the non- repeated (filler) sequences and the repeated (Hebb) sequences are different (no-overlap). However, learning is abolished when the filler and Hebb sequences comprise the same items (full-overlap). Learning of the repeated sequence persisted when repetition spacing was increased to 6 trials (Experiment 2), consistent with that shown for verbal stimuli (Page et al., 2013). In Experiment 3 it was shown that learning for the repeated sequence is accentuated when the output motor response at test is also repeated for the Hebb sequence, but only under conditions of no-overlap. In Experiment 4, repetition spacing was re-examined with a repeated motor output response (a closer methodological analogue to Page et al., 2013). Under these conditions, the gradient of Hebb repetition learning for 6 trial repetition intervals was markedly similar to that for 3 trial intervals. These findings further support the universality of the Hebb repetition effect across memory and are discussed in terms of evidence for amodality within sequence memory

DIAmante TESS AutoRegressive Planet Search (DTARPS): II. Hundreds of New TESS Candidate Exoplanets

The DIAmante TESS AutoRegressive Planet Search (DTARPS) project seeks to identify photometric transiting planets from 976,814 southern hemisphere stars observed in Year 1 of the TESS mission. This paper follows the methodology developed by Melton et al. (Paper I) using light curves extracted and pre-processed by the DIAmante project (Montalto et al. 2020). Paper I emerged with a list of 7,377 light curves with statistical properties characteristic of transiting planets but dominated by False Alarms and False Positives. Here a multistage vetting procedure is applied including: centroid motion and crowding metrics, False Alarm and False Positive reduction, photometric binary elimination, and ephemeris match removal. The vetting produces a catalog of 462 DTARPS Candidates across the southern ecliptic hemisphere and 310 objects in a spatially incomplete Galactic Plane list. Fifty-eight percent were not previously identified as transiting systems. Candidates are flagged for possible blending from nearby stars based on Zwicky Transient Facility data and for possible radial velocity variations based on Gaia satellite data. Orbital periods and planetary radii are refined using astrophysical modeling; the resulting parameters closely match published values for Confirmed Planets. Their properties are discussed in Paper III.Comment: 25 pages, 10 figures, submitted to AAS Journals. Machine Readable Tables and Figure Sets for Tables 1 and 4 are available at https://drive.google.com/drive/folders/1DyxNcNlfcHHAoCdsaipxxIbP5A2FPeyi?usp=share_lin

DIAmante TESS AutoRegressive Planet Search (DTARPS): III. Understanding the DTARPS Candidate Transiting Planet Catalogs

The DIAmante TESS AutoRegressive Planet Search (DTARPS) project, using novel statistical methods, has identified several hundred candidates for transiting planetary systems obtained from 0.9 million Full Frame Image light curves obtained in the TESS Year 1 southern hemisphere survey (Melton et al. 2022a and 2022b). Several lines of evidence, including limited reconnaissance spectroscopy, indicate that at least half are true planets rather than False Positives. Here various population properties of these objects are examined. Half of the DTARPS candidates are hot Neptunes, populating the 'Neptune desert' found in Kepler planet samples. The DTARPS samples also identify dozens of Ultra Short Period planets with orbital periods down to 5 hours, high priority systems for atmospheric transimssion spectroscopy, and planets orbiting low-mass M stars. DTARPS methodology is sufficiently well-characterized at each step that preliminary planet occurrence rates can be estimated. Except for the increase in hot Neptunes, DTARPS planet occurrence rates are consistent with Kepler rates. Overall, DTARPS provides one of the largest and most reliable catalog of TESS exoplanet candidates that can be tapped to improve our understanding of various exoplanetary populations and astrophysical processes.Comment: 29 pages, 16 figures, submitted to the AAS Journals February 13, 202

DIAmante TESS AutoRegressive Planet Search (DTARPS): I. Analysis of 0.9 Million Light Curves

Nearly one million light curves from the TESS Year 1 southern hemisphere extracted from Full Frame Images with the DIAmante pipeline are processed through the AutoRegressive Planet Search statistical procedure. ARIMA models remove trends and lingering autocorrelated noise, the Transit Comb Filter identifies the strongest periodic signal in the light curve, and a Random Forest machine learning classifier is trained and applied to identify the best potential candidates. Classifier training sets include injections of both planetary transit signals and contaminating eclipsing binaries. The optimized classifier has a True Positive Rate of 92.8% and a False Positive Rate of 0.37% from the labeled training set. The result of this DIAmante TESS autoregressive planet search (DTARPS) analysis is a list of 7,377 potential exoplanet candidates. The classifier has a False Positive Rate of 0.3%, a 64% recall rate for previously confirmed exoplanets, and a 78% negative recall rate for known False Positives. The completeness map of the injected planetary signals shows high recall rates for planets with 8 - 30 R(Earth) radii and periods 0.6-13 days and poor completeness for planets with radii < 2 R(Earth) or periods < 1 day. The list has many False Alarms and False Positives that need to be culled with multifaceted vetting operations (Paper II).Comment: 46 pages, 21 figures, submitted to AAS Journals. A Machine Readable Table for Table 3 is available at https://drive.google.com/drive/folders/1DyxNcNlfcHHAoCdsaipxxIbP5A2FPey

Updated fracture incidence rates for the US version of FRAX®

# The Author(s) 2009. This article is published with open access at Springerlink.com Summary On the basis of updated fracture and mortality data, we recommend that the base population values used in the US version of FRAX ® be revised. The impact of suggested changes is likely to be a lowering of 10-year fracture probabilities. Introduction Evaluation of results produced by the US version of FRAX ® indicates that this tool overestimates the likelihood of major osteoporotic fracture. In an attempt to correct this, we updated underlying fracture and mortality rates for the model. Methods We used US hospital discharge data from 2006 t