Distinct fibroblast subsets regulate lacteal integrity through YAP/TAZ-induced VEGF-C in intestinal villi

Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFR beta(+) IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake. Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment. Our findings demonstrate the heterogeneity of IntSCs and reveal that distinct subsets of villi fibroblasts regulate lacteal integrity through YAP/TAZ-induced VEGF-C secretion, providing new insights into the dynamic regulatory mechanisms behind lymphangiogenesis and lymphatic remodeling.Peer reviewe

Metabolic flux between organs measured by arteriovenous metabolite gradients

Mammalian organs convert dietary nutrients into circulating metabolites and share them to maintain whole-body metabolic homeostasis. While the concentrations of circulating metabolites have been frequently measured in a variety of pathophysiological conditions, the exchange flux of circulating metabolites between organs is not easily measurable due to technical difficulties. Isotope tracing is useful for measuring such fluxes for a metabolite of interest, but the shuffling of isotopic atoms between metabolites requires mathematical modeling. Arteriovenous metabolite gradient measurements can complement isotope tracing to infer organ-specific net fluxes of many metabolites simultaneously. Here, we review the historical development of arteriovenous measurements and discuss their advantages and limitations with key example studies that have revealed metabolite exchange flux between organs in diverse pathophysiological contexts

Study of an Atmospheric Refractivity Estimation from a Clutter Using Genetic Algorithm

In this paper, a method for estimating atmospheric refractivity from sea and land clutters is proposed. To estimate the atmospheric refractivity, clutter power spectrums based on an artificial tri-linear model are calculated using an Advanced Refractive Prediction System (AREPS) simulator. Then, the clutter power spectrums are again obtained based on the measured atmospheric refractivity data using the AREPS simulator. In actual operation, this spectrum from measured reflectivity can be replaced with real-time clutter spectrums collected from radars. A cost function for the genetic algorithm (GA) is then defined based on the difference between the two clutter power spectrums to predict the atmospheric refractivity using the artificial tri-linear model. The optimum variables of the tri-linear model are determined at a minimum cost in the GA process. The results demonstrate that atmospheric refractivity can be predicted using the proposed method from the clutter powers

Dietary Fructose and Fructose-Induced Pathologies

The consumption of fructose as sugar and high-fructose corn syrup has markedly increased during the past several decades. This trend coincides with the exponential rise of metabolic diseases, including obesity, nonalcoholic fatty liver disease, cardiovascular disease, and diabetes. While the biochemical pathways of fructose metabolism were elucidated in the early 1990s, organismal-level fructose metabolism and its whole-body pathophysiological impacts have been only recently investigated. In this review, we discuss the history of fructose consumption, biochemical and molecular pathways involved in fructose metabolism in different organs and gut microbiota, the role of fructose in the pathogenesis of metabolic diseases, and the remaining questions to treat such diseases

Radiation from a Cavity-Backed Circular Aperture Array Antenna Enclosed by an FSS Radome

Radiation from a cavity-backed circular aperture array antenna enclosed by a frequency selective surface (FSS) radome is studied using the hybrid analysis method, by combining the mode matching method, the ray tracing technique, and Huygens’s principle. The equivalent magnetic surface currents on the apertures are derived from the aperture electromagnetic fields, which are calculated based on the mode matching method. The rays are generated from the equivalent magnetic surface currents and used to analyze the FSS radome based on the ray tracing technique. After being obtained from both the mode matching method and the ray tracing technique, electromagnetic fields on an outermost radome are transformed into the equivalent electric and magnetic surface currents using Huygens’s principle. The radiated fields are computed from the equivalent surface currents and compared with the measured data

Analysis of a Low-Earth Orbit Satellite Downlink Considering Antenna Radiation Patterns and Space Environment in Interference Situations

This paper investigates a low-Earth orbit (LEO) satellite downlink for high-speed data communication in interference situations. A choke ring horn type antenna is used as the data transmitting antenna with an isoflux pattern in the LEO satellite, which has a beam coverage of ±51.6° and a bore-sight gain of 4.4 dBi at 8 GHz. The receiving antenna on the ground station is a parabolic type antenna with a diameter of 11.3 m, and it has a half-power beam width (HPBW) of 0.2° with a maximum gain of 59 dBi at 8 GHz. The jamming-to-signal ratio (J/S) is calculated assuming that the LEO satellite transmits signals to the ground station, and an elevation angle of the interference source varies from 0° to 90° at an altitude of 10 km. Applying antenna characteristics, such as HPBWs and side lobes, to the calculated space wave path loss makes it possible to predict the J/S results according to the location of the interference source and the satellite. The results show that it is necessary to consider the space environment to accurately analyze the LEO satellite downlink, especially at the low elevation angle of the satellite

Hyperactivation of YAP/TAZ Drives Alterations in Mesangial Cells through Stabilization of N-Myc in Diabetic Nephropathy

SIGNIFICANCE STATEMENT: Mesangial cells (MCs) in the kidney are essential to maintaining glomerular integrity, and their impairment leads to major glomerular diseases including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying mechanism is poorly understood. We show that YAP/TAZ are increased in MCs of patients with DN and two animal models of DN. High glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse MCs recapitulates the hallmarks of DN. Activated YAP/TAZ bind and stabilize N-Myc, one of the Myc family. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and to MC impairments. Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis. BACKGROUND: Mesangial cells (MCs) in the kidney are central to maintaining glomerular integrity, and their impairment leads to major glomerular diseases, including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying molecular mechanism is poorly understood. METHODS: Immunolocalization of YAP/TAZ and pathological features of PDGFRβ + MCs were analyzed in the glomeruli of patients with DN, in Zucker diabetic fatty rats, and in Lats1/2i ΔPβ mice. RiboTag bulk-RNA sequencing and transcriptomic analysis of gene expression profiles of the isolated MCs from control and Lats1/2iΔPβ mice were performed. Immunoprecipitation analysis and protein stability of N-Myc were performed by the standard protocols. RESULTS: YAP and TAZ, the final effectors of the Hippo pathway, are highly increased in MCs of patients with DN and in Zucker diabetic fatty rats. Moreover, high glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse model MCs recapitulates the hallmarks of DN, including excessive proliferation of MCs and extracellular matrix deposition, endothelial cell impairment, glomerular sclerosis, albuminuria, and reduced glomerular filtration rate. Mechanistically, activated YAP/TAZ bind and stabilize N-Myc protein, one of the Myc family of oncogenes. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and eventually to MC impairments and DN pathogenesis. CONCLUSIONS: Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.11Nsciescopu

Glucagon regulates the stability of REV-ERBα to modulate hepatic glucose production in a model of lung cancer-associated cachexia.

Lung adenocarcinoma is associated with cachexia, which manifests as an inflammatory response that causes wasting of adipose tissue and skeletal muscle. We previously reported that lung tumor-bearing (TB) mice exhibit alterations in inflammatory and hormonal signaling that deregulate circadian pathways governing glucose and lipid metabolism in the liver. Here, we define the molecular mechanism of how de novo glucose production in the liver is enhanced in a model of lung adenocarcinoma. We found that elevation of serum glucagon levels stimulates cyclic adenosine monophosphate production and activates hepatic protein kinase A (PKA) signaling in TB mice. In turn, we found that PKA targets and destabilizes the circadian protein REV-ERBα, a negative transcriptional regulator of gluconeogenic genes, resulting in heightened de novo glucose production. Together, we identified that glucagon-activated PKA signaling regulates REV-ERBα stability to control hepatic glucose production in a model of lung cancer-associated cachexia