Publications

Human pluripotent stem cell -derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitro and in vivo organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single -cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids. Employing the organoid xenograft model of PKD, which spontaneously developed tubular cysts, we demonstrate that minoxidil, a potent autophagy activator and an FDA -approved drug, effectively attenuated cyst formation in vivo. This in vivo organoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.

JTD Keywords: Adenylate kinase, Adult, Animal cell, Animal experiment, Animal model, Animal tissue, Article, Autophagosome, Autophagy, Autophagy (cellular), Calcium homeostasis, Cilia, Cilium, Cohort analysis, Controlled study, Cyclic amp, Dominant polycystic kidney,pluripotent stem-cells,autosomal-dominant,disease,expression,mutations,growth,generation,epithelium,framewor, Enzyme linked immunosorbent assay, Exon, Female, Food and drug administration, Hepatitis a virus cellular receptor 1, Human, Human cell, Humans, Immunohistochemistry, In vitro study, In vivo study, Kidney, Kidney organoid, Kidney polycystic disease, Male, Minoxidil, Mouse, Nonhuman, Organoid, Organoids, Platelet derived growth factor beta receptor, Polycystic kidney diseases, Protein kinase lkb1, Renin, Sequestosome 1, Single cell analysis, Single cell rna seq, Small nuclear rna, Tunel assay, Upregulation, Western blotting, Whole exome sequencing

Many lines of evidence demonstrate a correlation between liver glycogen content and food intake. We previously demonstrated that mice overexpressing protein targeting to glycogen (PTG) specifically in the liver—which have increased glycogen content in this organ—are protected from high-fat diet (HFD)-induced obesity by reduced food intake. However, the use of PTG to increase liver glycogen implies certain limitations. PTG stimulates glycogen synthesis but also inhibits the enzyme responsible for glycogen degradation. Furthermore, as PTG is a regulatory subunit of protein phosphatase 1 (PP1), which regulates many cellular functions, its overexpression could have side effects beyond the regulation of glycogen metabolism. Therefore, it is necessary to determine whether the direct activation of glycogen synthesis, without affecting its degradation or other cellular functions, has the same effects. To this end, we generated mice overexpressing a non-inactivatable form of glycogen synthase (GS) specifically in the liver (9A-MGSAlb mice). Control and 9a-MGSAlb mice were fed a standard diet (SD) or HFD for 16 weeks. Glucose tolerance and feeding behavior were analyzed. 9A-MGSAlb mice showed an increase in hepatic glycogen in fed and fasting conditions. When fed an HFD, these animals preserved their hepatic energy state, had a reduced food intake, and presented a lower body weight and fat mass than control animals, without changes in energy expenditure. Furthermore, 9A-MGSAlb animals showed improved glucose tolerance when fed an SD or HFD. Moreover, liver triacylglycerol levels that were increased after HFD feeding were lower in these mice. These results confirm that increased liver glycogen stores contribute to decreased appetite and improve glucose tolerance in mice fed an HFD. On the basis of our findings, strategies to preserve hepatic glycogen stores emerge as potential treatments for obesity and hyperglycemia.

JTD Keywords: accumulation, atp, attenuates obesity, expression, food intake, glucose, glycogen, glycogen synthase, high-fat diet, homeostasis, hyperglycemia, liver, mgat1, muscle, protein, ptg, Glycogen, Hepatic overexpression, Liver

Epithelial cell divisions are coordinated with cell loss to preserve epithelial integrity. However, how epithelia adapt their rate of cell division to changes in cell number, for instance during homeostatic turnover or wounding, is not well understood. Here, we show that epithelial cells sense local cell density through mechanosensitive E-cadherin adhesions to control G2/M cell-cycle progression. As local cell density increases, tensile forces on E-cadherin adhesions are reduced, which prompts the accumulation of the G2 checkpoint kinase Wee1 and downstream inhibitory phosphorylation of Cdk1. Consequently, dense epithelia contain a pool of cells that are temporarily halted in G2 phase. These cells are readily triggered to divide following epithelial wounding due to the consequent increase in intercellular forces and resulting degradation of Wee1. Our data collectively show that epithelial cell division is controlled by a mechanical G2 checkpoint, which is regulated by cell-density-dependent intercellular forces sensed and transduced by E-cadherin adhesions.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

JTD Keywords: Adherens junction, Cell cycle, Cell division, Cp: cell biology, E-cadherin, Epithelial homeostasis, G2 checkpoint, Mechanical forces, Mechanotransduction, Mitosis, Proliferation

Increased liver glycogen content has been shown to reduce food intake, attenuate obesity, and improve glucose tolerance in a mouse model of high-fat diet (HFD)-induced obesity. Here we studied the contribution of liver glycogen to the regulation of obesity and glucose metabolism in a model of type 2 diabetes and obesity, namely the db/db mouse. To this end, we crossed db/db mice with animals overexpressing protein targeting to glycogen (PTG) in the liver to generate db/db mice with increased liver glycogen content (db/db-PTG). Hepatic PTG overexpression reduced food intake and fat weight and attenuated obesity and hyperglycemia in db/db mice. Db/db-PTG mice showed similar energy expenditure and physical activity to db/db mice. PTG overexpression reduced liver phosphoenolpyruvate carboxykinase (PEPCK) protein levels and repressed hepatic glucose production in db/db mice. Moreover, increased liver glycogen elevated hepatic ATP content in these animals. However, lipid metabolism was not modified by PTG overexpression. In conclusion, increased liver glycogen content ameliorates the diabetic and obesity phenotype in db/db mice.Copyright © 2022 López-Soldado, Guinovart and Duran.

JTD Keywords: atp, db, dyslipidemia, food intake, glucose, homeostasis, liver, metabolism, mouse, receptor, Atp, Db/db, Food intake, Food-intake, Glucose, Glycogen, Liver

Maintaining a balance between excitatory and inhibitory activity is an essential feature of neural networks of the neocortex. In the face of perturbations in the levels of excitation to cortical neurons, synapses adjust to maintain excitatory-inhibitory (EI) balance. In this review, we summarize research on this EI homeostasis in the neocortex, using stroke as our case study, and in particular the loss of excitation to distant cortical regions after focal lesions. Widespread changes following a localized lesion, a phenomenon known as diaschisis, are not only related to excitability, but also observed with respect to functional connectivity. Here, we highlight the main findings regarding the evolution of excitability and functional cortical networks during the process of post-stroke recovery, and how both are related to functional recovery. We show that cortical reorganization at a global scale can be explained from the perspective of EI homeostasis. Indeed, recovery of functional networks is paralleled by increases in excitability across the cortex. These adaptive changes likely result from plasticity mechanisms such as synaptic scaling and are linked to EI homeostasis, providing a possible target for future therapeutic strategies in the process of rehabilitation. In addition, we address the difficulty of simultaneously studying these multiscale processes by presenting recent advances in large-scale modeling of the human cortex in the contexts of stroke and EI homeostasis, suggesting computational modeling as a powerful tool to tie the meso- and macro-scale processes of recovery in stroke patients. Copyright © 2022 Páscoa dos Santos and Verschure.

JTD Keywords: balanced excitation, canonical microcircuit, cerebral-cortex, cortical excitability, cortical reorganization, diaschisis, excitability, excitatory-inhibitory balance, functional networks, homeostatic plasticity, ischemic-stroke, neuronal avalanches, photothrombotic lesions, state functional connectivity, whole-brain models, Algorithm, Biological marker, Brain, Brain cell, Brain cortex, Brain function, Brain radiography, Cerebrovascular accident, Cortical reorganization, Diaschisis, Down regulation, Excitability, Excitatory-inhibitory balance, Fluorine magnetic resonance imaging, Functional networks, Homeostasis, Homeostatic plasticity, Human, Motor dysfunction, Neuromodulation, Plasticity, Pyramidal nerve cell, Review, Simulation, Stroke, Stroke patient, Theta-burst stimulation, Visual cortex

In the recent decades, zinc (Zn) and its alloys have been drawing attention as promising candidates for bioresorbable cardiovascular stents due to its degradation rate more suitable than magnesium (Mg) and iron (Fe) alloys. However, its mechanical properties need to be improved in order to meet the criteria for vascular stents. This work investigates the mechanical properties, biodegradability and biocompatibility of Zn-Mg and Zn-Cu alloys in order to determine a proper alloy composition for optimal stent performance. Nanoindentation measurements are performed to characterize the mechanical properties at the nanoscale as a function of the Zn microstructure variations induced by alloying. The biodegradation mechanisms are discussed and correlated to microstructure, mechanical performance and bacterial/cell response. Addition of Mg or Cu alloying elements refined the microstructure of Zn and enhanced yield strength (YS) and ultimate tensile strength (UTS) proportional to the volume fraction of secondary phases. Zn-1Mg showed the higher YS and UTS and better performance in terms of degradation stability in Hanks’ solution. Zn-Cu alloys presented an antibacterial effect for S. aureus controlled by diffusion mechanisms and by contact. Biocompatibility was dependent on the degradation rate and the nature of the corrosion products.

JTD Keywords: behavior, biocompatibility, biodegradable metals, bioresorbable metals, bioresorbable scaffold, copper, corrosion properties, elastic-modulus, galvanic corrosion, microstructure, nanoindentation, redox homeostasis, zinc, Biocompatibility, Bioresorbable metals, Galvanic corrosion, Nanoindentation, Room-temperature superplasticity, Zinc alloys

[Figure: see text].

JTD Keywords: activation, cell extrusion, contraction, drives, homeostasis, interface, junctions, kinase, tension, Adhesion, Article, Cell membranes, Chemical activation, Cytology, E-cadherin, Epithelial monolayers, Epithelium, Homoeostasis, Human, Mechanical instabilities, Monolayers, Morphological transformations, Morphology, Normal tissue, Oncogenics, Soft substrates, Substrates, Tissue, Tissue mechanics, Tissue morphology, Tumor development

This chapter takes the view that emotions of living machines can be seen from the perspective of self-regulation and appraisal. We will first look at the pragmatic needs to endow machines with emotions and subsequently describe some of the historical background of the science of emotions and its different interpretations and links to affective neuroscience. Subsequently, we argue that emotions can be cast in terms of self-regulation where they provide for a descriptor of the state of the homeostatic processes that maintain the relationship between the agent and its internal and external environment. We augment the notion of homeostasis with that of allostasis which signifies a change from stability through a fixed equilibrium to stability through continuous change. The chapter shows how this view can be used to create complex living machines where emotions are anchored in the need fulfillment of the agent, in this case considering both utilitarian and epistemic needs.

JTD Keywords: Emotion, Motivation, Needs, Appraisal, Self-regulation, Homeostasis, Allostasis, Human–robot interaction, James–Lange theory