scholarly journals Model systems in SDHx-related pheochromocytoma/paraganglioma

2021 ◽  
Author(s):  
Krisztina Takács-Vellai ◽  
Zsolt Farkas ◽  
Fanni Ősz ◽  
Gordon W. Stewart
Keyword(s):  
Adrenal Gland ◽  
Tca Cycle ◽  
Metastatic Potential ◽  
Dna Demethylation ◽  
Neuroendocrine Cells ◽  
Model Systems ◽  
Energy Deficit ◽  
Model Organisms ◽  
Developmental Abnormalities ◽  
Parasympathetic Ganglia

AbstractPheochromocytoma (PHEO) and paraganglioma (PGL) (together PPGL) are tumors with poor outcomes that arise from neuroendocrine cells in the adrenal gland, and sympathetic and parasympathetic ganglia outside the adrenal gland, respectively. Many follow germline mutations in genes coding for subunits of succinate dehydrogenase (SDH), a tetrameric enzyme in the tricarboxylic acid (TCA) cycle that both converts succinate to fumarate and participates in electron transport. Germline SDH subunit B (SDHB) mutations have a high metastatic potential. Herein, we review the spectrum of model organisms that have contributed hugely to our understanding of SDH dysfunction. In Saccharomyces cerevisiae (yeast), succinate accumulation inhibits alpha-ketoglutarate-dependent dioxygenase enzymes leading to DNA demethylation. In the worm Caenorhabditis elegans, mutated SDH creates developmental abnormalities, metabolic rewiring, an energy deficit and oxygen hypersensitivity (the latter is also found in Drosophila melanogaster). In the zebrafish Danio rerio, sdhb mutants display a shorter lifespan with defective energy metabolism. Recently, SDHB-deficient pheochromocytoma has been cultivated in xenografts and has generated cell lines, which can be traced back to a heterozygous SDHB-deficient rat. We propose that a combination of such models can be efficiently and effectively used in both pathophysiological studies and drug-screening projects in order to find novel strategies in PPGL treatment.

Abstract 426: Laminin Downregulation Facilitates Cardiomyocyte Coupling in situ to Increase Contractile Function

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Ayla Sessions ◽  
Gaurav Kaushik ◽  
Adam Engler
Keyword(s):  
Basement Membrane ◽  
Contractile Function ◽  
Current Model ◽  
Model Systems ◽  
Model Organisms ◽  
Muscle Physiology ◽  
Heart Tube ◽  
Age Related ◽  
New Evidence

Aging is associated with extensive remodeling of the heart, including basement membrane extracellular matrix (ECM) components that surround cardiomyocytes. Remodeling is thought to contribute to impaired cardiac mechanotransduction, but the contribution of specific basement membrane ECM components to age-related cardiac remodeling is unclear, owing to current model systems being complex and slow to age. To investigate the effect of basement membrane remodeling on mechanical function in genetically tractable, rapidly aging, and simple model organisms, we employed Drosophila melanogaster, which has a simple trilayered heart tube composed of only basement membrane ECM. We observed differential regulation of collagens between laboratory Drosophila strains , i.e. yellow-white ( yw ) and white-1118 ( w 1118 ), leading to changes in muscle physiology, which were linked to severity of dysfunction with age. Therefore, we sought to understand the extent to which basement membrane ECM modulates lateral cardiomyocyte coupling and contractile function during aging. Cardiac-restricted knockdown of ECM genes Pericardin , Laminin A , and Viking in Drosophila prevented age-associated heart tube restriction and increased contractility, even under viscous load. Most notably, reduction of Laminin A expression decreased levels of other genes that co-assemble in ECM, leading to overall preservation of contractile velocity and extension of median organismal lifespan by 3 weeks or 39%. These data provide new evidence of a direct link between basement membrane ECM homeostasis, contractility, and maintenance of lifespan.

Abstract 371: Down Regulation of ECM Genes Laminin and Collagen IV Lead to Preserved Cardiac Function With Age and Increased Lifespan in Drosophila

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Ayla O Sessions
Keyword(s):  
Diastolic Dysfunction ◽  
High Speed ◽  
Current Model ◽  
Collagen Iv ◽  
Model Systems ◽  
Model Organisms ◽  
Heart Tube ◽  
Ecm Remodeling ◽  
Intercalated Discs ◽  
And Performance

Increased deposition of extracellular matrix (ECM) is observed in all advanced age heart failure patients, but current model systems are complex and slow to age. To investigate the effect of extracellular remodeling on mechanical function in genetically tractable, rapidly aging, and simple model organisms, we employed Drosophila melanogaster, which has a simple trilayered heart tube. We found that two common wildtype strains of Drosophila, i.e. yellow-white (yw) and white-1118 (w1118), exhibit different cytoskeletal and ECM remodeling with age. Using a recently developed nanoindentation method to measure cardiomyocyte stiffness and high speed optical imaging to assess contractility of intact Drosophila hearts, we found that yw flies had stiffer intercalated discs (ICD) and exhibited diastolic dysfunction with age. On the other hand, w1118 flies had a shorter lifespan compared to yw, did not exhibit ICD stiffening, had a less severe diastolic dysfunction, and showed an increase in ECM layer thickness between ventral muscle (VM) and cardiomyocyte (CM) layers of the heart tube. To modulate ECM and assess its effect in the aged w1118 flies, we knocked-down ECM genes LamininA and Viking (homologous to Collagen IV). Both ECM KD genotypes exhibited diastolic dilation with increased fractional shortening at adult (1wk) and aged (5wk) time points. The LamininA KD resulted in decreased cardiomyocyte stiffness correlating with increased relaxation velocities in adult flies and preservation of shortening and relaxation velocities in aged flies over controls. However, both the LamininA and Collagen IV KD flies experienced a basal increase in the decoupling of their cardiomyocytes as determined by heart period variance and % fibrillar heart-beats. These conductance issues were not enough to counteract the increased cardiac output and performance with age, and the Collagen IV KD outlived controls by 1.5 weeks median survival and the LamininA KD by 3 weeks. This suggests that the cell-ECM contacts in the basement membrane are intimately tied not only to the coupling of the cardiomyocytes of the Drosophila heart tube but also to cytoskeletal remodeling, but perhaps different ECM proteins have different mechanisms for interacting with the cardiomyocyte cytoskeleton.

scholarly journals A circadian clock in Saccharomyces cerevisiae

2010 ◽  
Vol 107 (5) ◽  
pp. 2043-2047 ◽  
Author(s):  
Zheng Eelderink-Chen ◽  
Gabriella Mazzotta ◽  
Marcel Sturre ◽  
Jasper Bosman ◽  
Till Roenneberg ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Genetic Model ◽  
Circadian Clocks ◽  
Model Systems ◽  
Model Organisms ◽  
Biological Clocks ◽  
Experimental Systems ◽  
Fundamental Biological Process ◽  
Free Running ◽  
And Behavior

Circadian timing is a fundamental biological process, underlying cellular physiology in animals, plants, fungi, and cyanobacteria. Circadian clocks organize gene expression, metabolism, and behavior such that they occur at specific times of day. The biological clocks that orchestrate these daily changes confer a survival advantage and dominate daily behavior, for example, waking us in the morning and helping us to sleep at night. The molecular mechanism of circadian clocks has been sketched out in genetic model systems from prokaryotes to humans, revealing a combination of transcriptional and posttranscriptional pathways, but the clock mechanism is far from solved. Although Saccharomyces cerevisiae is among the most powerful genetic experimental systems and, as such, could greatly contribute to our understanding of cellular timing, it still remains absent from the repertoire of circadian model organisms. Here, we use continuous cultures of yeast, establishing conditions that reveal characteristic clock properties similar to those described in other species. Our results show that metabolism in yeast shows systematic circadian entrainment, responding to cycle length and zeitgeber (stimulus) strength, and a (heavily damped) free running rhythm. Furthermore, the clock is obvious in a standard, haploid, auxotrophic strain, opening the door for rapid progress into cellular clock mechanisms.

scholarly journals Collecting eco-evolutionary data in the dark: Impediments to subterranean research and how to overcome them

2020 ◽  
Author(s):  
Stefano Mammola ◽  
Enrico Lunghi ◽  
Helena Bilandžija ◽  
Pedro Cardoso ◽  
Volker Grimm ◽  
...  
Keyword(s):  
Model Systems ◽  
Ex Situ ◽  
Model Organisms ◽  
Physiological Tolerance ◽  
Advantages And Disadvantages ◽  
General Scientific ◽  
Experimental Model Systems ◽  
Scientific Questions ◽  
Subterranean Species

(1) Caves and other subterranean habitats fulfill the requirements of experimental model systems to address general questions in ecology and evolution. Yet, the harsh working conditions of these environments and the uniqueness of the subterranean organisms have challenged most attempts to pursuit standardized research(2) Two main obstacles have synergistically hampered previous attempts. First, there is a habitat impediment related to the objective difficulties of exploring subterranean habitats and our inability to access the network of fissures that represent the elective habitat for the so-called “cave species.” Second, there is a biological impediment illustrated by the rarity of most subterranean species and their low physiological tolerance, often limiting sample size and complicating lab experiments.(3) We explore the advantages and disadvantages of four general experimental setups (in-situ, quasi in-situ, ex-situ, and in-silico) in the light of habitat and biological impediments. We also discuss the potential of indirect approaches to research. Furthermore, using bibliometric data, we provide a quantitative overview of the model organisms that scientists have exploited in the study of subterranean life.(4) Our over-arching goal is to promote caves as model systems where one can perform standardised scientific research. This is important not only to achieve an in-depth understanding of the functioning of subterranean ecosystems but also to fully exploit their long-discussed potential in addressing general scientific questions with implications beyond the boundaries of this discipline.

scholarly journals Immunohistochemical heterogeneity of nerve cells in the human adrenal gland with special reference to substance P.

1996 ◽  
Vol 44 (4) ◽  
pp. 369-375 ◽  
Author(s):  
M Colombo-Benkmann ◽  
L Klimaschewski ◽  
C Heym
Keyword(s):  
Substance P ◽  
Adrenal Gland ◽  
Special Reference ◽  
Adrenal Medulla ◽  
Enteric Neurons ◽  
Double Labeling ◽  
Parasympathetic Ganglia ◽  
Calcitonin Gene ◽  
Rate Limiting ◽  
Adrenal Innervation

Neurons in the human adrenal medulla, stained by the NADH-diaphorase reaction, were counted and their neurochemical markers were investigated by double labeling immunofluorescence with special reference to substance P. The findings indicate a significant participation of intramedullary nerve cell bodies in human adrenal innervation with 40.4 neurons/mm3 adrenal medulla. Substance P-immunoreactive neurons, which made up approximately 20% of all neurons, exhibited heterogeneity by co-localization of immunoreactivities for dynorphin, for cholecystokinin, and for neurofilament triplet. Substance-P-immunolabeled neurons were always nonreactive for calcitonin gene-related peptide, for vasoactive intestinal polypeptide, or for tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis. These chemical phenotypes of intramedullary neurons reveal immunohistochemical similarities with postganglionic neurons in parasympathetic ganglia or with enteric neurons, suggesting a hitherto unrecognized functional significance of the intrinsic nervous system in the human adrenal gland.

An overview of glossiphoniid leech development

2001 ◽  
Vol 79 (2) ◽  
pp. 218-232 ◽  
Author(s):  
David A Weisblat ◽  
Françoise Z Huang
Keyword(s):  
Model Systems ◽  
Model Organisms ◽  
Consensus Tree ◽  
Comparative Development ◽  
Experimental Embryology ◽  
Molecular Studies ◽  
Research Questions ◽  
Per Se ◽  
Molecular Phylogenies ◽  
Development And Evolution

Dramatic advances in understanding the development of selected "model" organisms, coupled with the realization that genes which regulate development are often conserved between diverse taxa, have renewed interest in comparative development and evolution. Recent molecular phylogenies seem to be converging on a new consensus "tree," according to which higher bilaterians fall into three major groups, Deuterostoma, Ecdysozoa, and Lophotrochozoa. Commonly studied model systems for development fall almost exclusively within the first two of these groups. Glossiphoniid leeches (phylum Annelida) offer certain advantages for descriptive and experimental embryology per se, and can also serve to represent the lophotrochozoan clade. We present an overview of the development of glossiphoniid leeches, highlighting some current research questions and the potential for comparative cellular and molecular studies.

Selective autonomic stimulation of canine trachealis with dimethylphenylpiperazinium

1981 ◽  
Vol 51 (2) ◽  
pp. 428-437 ◽  
Author(s):  
A. R. Leff ◽  
N. M. Munoz
Keyword(s):  
Adrenal Gland ◽  
Contractile Response ◽  
Sympathetic Innervation ◽  
Adrenergic Stimulation ◽  
Parasympathetic Ganglia ◽  
Regional Administration ◽  
Adrenal Secretion ◽  
Stimulation Of

The response of canine tracheal muscle to autonomic stimulation with 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) was studied isometrically in 39 dogs in vivo. Intra-arterial (ia) DMPP (2.5 X 10(-4) to 2.5 X 10(-2) mg/kg) caused selective dose related contraction [maximum 30.1 +/- 6.5 gram-force (gf)/cm] due to regional stimulation of parasympathetic ganglia. This contraction was blocked by regional administration of atropine 10(-3) mg/kg ia and hexamethonium 5 X 10(-2) mg/kg ia. Nonselective intravenous (iv) administration of DMPP 2.5 X 10(-2) mg/kg caused parasympathetic tracheal contraction [+13.4 +/- 1.64 gf/cm] followed by later sympathetic relaxation [-11.8 +/- 2.3 gf/cm]; 0.5 mg/kg iv atropine abolished contraction but did not affect relaxation. The role of the adrenal gland vs. direct sympathetic innervation in producing tracheal relaxation after sympathetic stimulation was also studied. Tracheal relaxation to 2.5 X 10(-2) mg/kg iv DMPP was -18.2 +/- 4.0 gf/cm before adrenalectomy (ADX) and -4.3 +/- 0.9 gf/cm afterward (P less than 0.001). In contrast, tracheal contraction resulting from alpha-adrenergic stimulation after 2.5 X 10(-2) mg/kg iv DMPP in beta-blocked (BB) dogs was not significantly altered by ADX. At 2.5 X 10(-1) mg/kg iv DMPP, the alpha-adrenergic contractile response was still 70% of the response prior to ADX. We conclude that sympathetic tracheal relaxation in dogs is predominantly mediated by circulating catecholamine from the adrenal gland, but that alpha-adrenergic contraction after BB results predominantly from direct sympathetic innervation and is not greatly augmented by adrenal secretion. We also report a new method for selective stimulation of airway cholinergic nerves in vivo without systemic effects.

scholarly journals In situ Metabolite Mass Spectrometry Imaging: New Insights into the Adrenal Gland

2020 ◽  
Vol 52 (06) ◽  
pp. 435-447
Author(s):  
Fengxia Li ◽  
Annette Feuchtinger ◽  
Axel Walch ◽  
Na Sun
Keyword(s):  
Mass Spectrometry ◽  
Adrenal Gland ◽  
Mass Spectrometry Imaging ◽  
Neuroendocrine Cells ◽  
Adrenal Tumors ◽  
Analytical Methodology ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Clinically Significant

AbstractThe adrenal gland integrates catecholamine-producing neuroendocrine cells and steroid-producing cells with mesenchymal origin in a structured manner under one capsule and is a key regulator for vital bioactivity. In addition to adrenal-specific disease, dysregulation of adrenal hormones is associated with systemic effects, leading to undesirable metabolic and cardiovascular consequences. Mass spectrometry imaging (MSI) technique can simultaneously measure a broad range of biomolecules, including metabolites and hormones, which has enabled the study of tissue metabolic and hormone alterations in adrenal and adrenal-related diseases. Furthermore, this technique coupled with labeled immunohistochemistry staining has enabled the study of the pathophysiological adaptation of the adrenal gland under normal and abnormal conditions at different molecular levels. This review discusses the recent applications of in situ MSI in the adrenal gland. For example, the combination of formalin-fixed paraffin-embedded tissue microarray and MSI to tissues from patient cohorts has facilitated the discovery of clinically relevant prognostic biomolecules and generated promising hypotheses for new sights into physiology and pathophysiology of adrenal gland. MSI also has enabled the discovery of clinically significant tissue molecular (i. e., biomarker) and pathway changes in adrenal disease, particularly in adrenal tumors. In addition, MSI has advanced the ability to optimally identify and detect adrenal gland specific molecules. Thus, as a novel analytical methodology, MSI has provided unprecedented capabilities for in situ tissue study.

scholarly journals Neuronal glucose metabolism is impaired while astrocytic TCA cycling is unaffected at symptomatic stages in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

2018 ◽  
Vol 39 (9) ◽  
pp. 1710-1724 ◽  
Author(s):  
Tesfaye W Tefera ◽  
Karin Borges
Keyword(s):  
Spinal Cord ◽  
Glucose Metabolism ◽  
Mouse Model ◽  
Tca Cycle ◽  
Energy Deficit ◽  
Acetate Metabolism ◽  
Resonance Spectroscopy ◽  
Symptomatic Disease ◽  
The Tca Cycle ◽  
Disease Stages

Although alterations in energy metabolism are known in ALS, the specific mechanisms leading to energy deficit are not understood. We measured metabolite levels derived from injected [1-13C]glucose and [1,2-13C]acetate (i.p.) in cerebral cortex and spinal cord extracts of wild type and hSOD1G93A mice at onset and mid disease stages using high-pressure liquid chromatography, 1H and 13C nuclear magnetic resonance spectroscopy. Levels of spinal and cortical CNS total lactate, [3-13C]lactate, total alanine and [3-13C]alanine, but not cortical glucose and [1-13C]glucose, were reduced mostly at mid stage indicating impaired glycolysis. The [1-13C]glucose-derived [4-13C]glutamate, [4-13C]glutamine and [2-13C]GABA amounts were diminished at mid stage in cortex and both time points in spinal cord, suggesting decreased [3-13C]pyruvate entry into the TCA cycle. Lack of changes in [1,2-13C]acetate-derived [4,5-13C]glutamate, [4,5-13C]glutamine and [1,2-13C]GABA levels indicate unchanged astrocytic 13C-acetate metabolism. Reduced levels of leucine, isoleucine and valine in CNS suggest compensatory breakdown to refill TCA cycle intermediate levels. Unlabelled, [2-13C] and [4-13C]GABA concentrations were decreased in spinal cord indicating that impaired glucose metabolism contributes to hyperexcitability and supporting the use of treatments which increase GABA amounts. In conclusion, CNS glucose metabolism is compromised, while astrocytic TCA cycling appears to be normal in the hSOD1G93A mouse model at symptomatic disease stages.

scholarly journals Microbial Adhesion and Biofilm Formation on Microfiltration Membranes: A Detailed Characterization Using Model Organisms with Increasing Complexity

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
L. Vanysacker ◽  
C. Denis ◽  
P. Declerck ◽  
A. Piasecka ◽  
I. F. J. Vankelecom
Keyword(s):  
Membrane Fouling ◽  
Biofilm Formation ◽  
Bacterial Community Composition ◽  
Microbial Interactions ◽  
Model Systems ◽  
Model Organisms ◽  
Microbial Adhesion ◽  
Membrane Biofouling ◽  
Microfiltration Membranes ◽  
Cell Densities

Since many years, membrane biofouling has been described as the Achilles heel of membrane fouling. In the present study, an ecological assay was performed using model systems with increasing complexity: a monospecies assay usingPseudomonas aeruginosaorEscherichia coliseparately, a duospecies assay using both microorganisms, and a multispecies assay using activated sludge with or without spikedP. aeruginosa. The microbial adhesion and biofilm formation were evaluated in terms of bacterial cell densities, species richness, and bacterial community composition on polyvinyldifluoride, polyethylene, and polysulfone membranes. The data show that biofouling formation was strongly influenced by the kind of microorganism, the interactions between the organisms, and the changes in environmental conditions whereas the membrane effect was less important. The findings obtained in this study suggest that more knowledge in species composition and microbial interactions is needed in order to understand the complex biofouling process. This is the first report describing the microbial interactions with a membrane during the biofouling development.

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