Differential response of TIMP-3 null mice to the lung insults of sepsis, mechanical ventilation, and hyperoxia

2005 ◽  
Vol 289 (2) ◽  
pp. L244-L251 ◽  
Author(s):  
Erica L. Martin ◽  
Lynda A. McCaig ◽  
Brent Z. Moyer ◽  
M. Cynthia Pape ◽  
Kevin J. Leco ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Cecal Ligation ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Null Mouse ◽  
Similar Response ◽  
Wild Type ◽  
Air Space ◽  
Different Types ◽  
Insight Into

An imbalance in matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) leads to excessive or insufficient tissue breakdown, which is associated with many disease processes. The TIMP-3 null mouse is a model of MMP/TIMP imbalance, which develops air space enlargement and decreased lung function. These mice responded differently to cecal ligation and perforation (CLP)-induced septic lung injury than wild-type controls. The current study addresses whether the TIMP-3 knockout lung is susceptible to different types of insults or only those involving sepsis, by examining its response to lipopolysaccharide (LPS)-induced sepsis, mechanical ventilation (MV), and hyperoxia. TIMP-3 null noninjured controls of each insult consistently demonstrated significantly higher compliance vs. wild-type mice. Null mice treated with LPS had a further significantly increased compliance compared with untreated controls. Conversely, MV and hyperoxia did not alter compliance in the null lung. MMP abundance and activity increased in response to LPS but were generally unaltered following MV or hyperoxia, correlating with compliance alterations. All three insults produced inflammatory cytokines; however, the response of the null vs. wild-type lung was dependent on the type of insult. Overall, this study demonstrated that 1) LPS-induced sepsis produced a similar response in null mice to CLP-induced sepsis, 2) the null lung responded differently to various insults, and 3) the null susceptibility to compliance changes correlated with increased MMPs. In conclusion, this study provides insight into the role of TIMP-3 in response to various lung insults, specifically its importance in regulating MMPs to maintain compliance during a sepsis.

scholarly journals Salicylic Acid Accumulation Controlled by LSD1 Is Essential in Triggering Cell Death in Response to Abiotic Stress

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 962
Author(s):  
Maciej Jerzy Bernacki ◽  
Anna Rusaczonek ◽  
Weronika Czarnocka ◽  
Stanisław Karpiński
Keyword(s):  
Cell Death ◽  
Salicylic Acid ◽  
Abiotic Stress ◽  
Wild Type ◽  
Pr Genes ◽  
Genes Expression ◽  
Salicylic Acid Accumulation ◽  
Cell Death Phenotype ◽  
Insight Into

Salicylic acid (SA) is well known hormonal molecule involved in cell death regulation. In response to a broad range of environmental factors (e.g., high light, UV, pathogens attack), plants accumulate SA, which participates in cell death induction and spread in some foliar cells. LESION SIMULATING DISEASE 1 (LSD1) is one of the best-known cell death regulators in Arabidopsis thaliana. The lsd1 mutant, lacking functional LSD1 protein, accumulates SA and is conditionally susceptible to many biotic and abiotic stresses. In order to get more insight into the role of LSD1-dependent regulation of SA accumulation during cell death, we crossed the lsd1 with the sid2 mutant, caring mutation in ISOCHORISMATE SYNTHASE 1(ICS1) gene and having deregulated SA synthesis, and with plants expressing the bacterial nahG gene and thus decomposing SA to catechol. In response to UV A+B irradiation, the lsd1 mutant exhibited clear cell death phenotype, which was reversed in lsd1/sid2 and lsd1/NahG plants. The expression of PR-genes and the H2O2 content in UV-treated lsd1 were significantly higher when compared with the wild type. In contrast, lsd1/sid2 and lsd1/NahG plants demonstrated comparability with the wild-type level of PR-genes expression and H2O2. Our results demonstrate that SA accumulation is crucial for triggering cell death in lsd1, while the reduction of excessive SA accumulation may lead to a greater tolerance toward abiotic stress.

scholarly journals NMR and LC-MS-Based Metabolomics to Study Osmotic Stress in Lignan-Deficient Flax

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 767
Author(s):  
Kamar Hamade ◽  
Ophélie Fliniaux ◽  
Jean-Xavier Fontaine ◽  
Roland Molinié ◽  
Elvis Otogo Nnang ◽  
...  
Keyword(s):  
Stress Response ◽  
Osmotic Stress ◽  
Biosynthetic Pathway ◽  
Potential Role ◽  
Plant Secondary Metabolites ◽  
Wild Type ◽  
Osmotic Stress Response ◽  
Transgenic Flax ◽  
Insight Into

Lignans, phenolic plant secondary metabolites, are derived from the phenylpropanoid biosynthetic pathway. Although, being investigated for their health benefits in terms of antioxidant, antitumor, anti-inflammatory and antiviral properties, the role of these molecules in plants remains incompletely elucidated; a potential role in stress response mechanisms has been, however, proposed. In this study, a non-targeted metabolomic analysis of the roots, stems, and leaves of wild-type and PLR1-RNAi transgenic flax, devoid of (+) secoisolariciresinol diglucoside ((+) SDG)—the main flaxseed lignan, was performed using 1H-NMR and LC-MS, in order to obtain further insight into the involvement of lignan in the response of plant to osmotic stress. Results showed that wild-type and lignan-deficient flax plants have different metabolic responses after being exposed to osmotic stress conditions, but they both showed the capacity to induce an adaptive response to osmotic stress. These findings suggest the indirect involvement of lignans in osmotic stress response.

Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response to sepsis

2003 ◽  
Vol 285 (6) ◽  
pp. L1222-L1232 ◽  
Author(s):  
Erica L. Martin ◽  
Brent Z. Moyer ◽  
M. Cynthia Pape ◽  
Barry Starcher ◽  
Kevin J. Leco ◽  
...  
Keyword(s):  
Negative Impact ◽  
Cecal Ligation ◽  
Lung Compliance ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Wild Type ◽  
Gelatinase Activity ◽  
Lung Structure ◽  
And Function ◽  
Knockout Animals

Matrix metalloproteinases (MMPs) are degradative enzymes, which act to remodel tissue. Their activity is regulated by the tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the degradation/inhibition activities has been associated with many diseases, including sepsis. We have previously shown that TIMP-3 knockout animals develop spontaneous, progressive air space enlargement. The objectives of this study were to determine the effects of a septic lung stress induced by cecal ligation and perforation (CLP) on lung function, structure, pulmonary surfactant, and inflammation in TIMP-3 null mice. Knockout and wild-type animals were randomized to either sham or CLP surgery, allowed to recover for 6 h, and then euthanized. TIMP-3 null animals exposed to sham surgery had a significant increase in lung compliance when compared with sham wild-type mice. Additionally, the TIMP-3 knockout mice showed a significant increase in compliance following CLP. Rapid compliance changes were accompanied by significantly decreased collagen and fibronectin levels and increased gelatinase (MMP-2 and -9) abundance and activation. Additionally, in situ zymography showed increased airway-associated gelatinase activity in the knockout animals enhanced following CLP. In conclusion, exposing TIMP-3 null animals to sepsis rapidly enhances the phenotypic abnormalities of these mice, due to increased MMP activity induced by CLP.

Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2541-2553 ◽  
Author(s):  
Johanna Laurikkala ◽  
Johanna Pispa ◽  
Han-Sung Jung ◽  
Pekka Nieminen ◽  
Marja Mikkola ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hair Follicles ◽  
Wild Type ◽  
Mutant Mouse Embryos ◽  
Anhidrotic Ectodermal Dysplasia ◽  
Embryonic Morphogenesis ◽  
Hair Follicle Development ◽  
And Function ◽  
Insight Into

X-linked and autosomal forms of anhidrotic ectodermal dysplasia syndromes (HED) are characterized by deficient development of several ectodermal organs, including hair, teeth and exocrine glands. The recent cloning of the genes that underlie these syndromes, ectodysplasin (ED1) and the ectodysplasin A receptor (EDAR), and their identification as a novel TNF ligand-receptor pair suggested a role for TNF signaling in embryonic morphogenesis. In the mouse, the genes of the spontaneous mutations Tabby (Ta) and downless (dl) were identified as homologs of ED1 and EDAR, respectively. To gain insight into the function of this signaling pathway in development of skin and hair follicles, we analyzed the expression and regulation of Eda and Edar in wild type as well as Tabby and Lef1 mutant mouse embryos. We show that Eda and Edar expression is confined to the ectoderm and occurs in a pattern that suggests a role of ectodysplasin/Edar signaling in the interactions between the ectodermal compartments and the formation and function of hair placodes. By using skin explant cultures, we further show that this signaling pathway is intimately associated with interactions between the epithelial and mesenchymal tissues. We also find that Ta mutants lack completely the placodes of the first developing tylotrich hairs, and that they do not show patterned expression of placodal genes, including Bmp4, Lef1, Shh, Ptch and Edar, and the genes for β-catenin and activin A. Finally, we identified activin as a mesenchymal signal that stimulates Edar expression and WNT as a signal that induces Eda expression, suggesting a hierarchy of distinct signaling pathways in the development of skin and hair follicles. In conclusion, we suggest that Eda and Edar are associated with the onset of ectodermal patterning and that ectodysplasin/edar signaling also regulates the morphogenesis of hair follicles.

scholarly journals Using Bcr-Abl to Examine Mechanisms by Which Abl Kinase Regulates Morphogenesis in Drosophila

2008 ◽  
Vol 19 (1) ◽  
pp. 378-393 ◽  
Author(s):  
Traci L. Stevens ◽  
Edward M. Rogers ◽  
Laura M. Koontz ◽  
Donald T. Fox ◽  
Catarina C.F. Homem ◽  
...  
Keyword(s):  
Cell Shape ◽  
Normal Development ◽  
Wild Type ◽  
Nonreceptor Tyrosine Kinase ◽  
Abl Kinase ◽  
Embryonic Morphogenesis ◽  
Dose Dependent ◽  
Shape Changes ◽  
Insight Into

Signaling by the nonreceptor tyrosine kinase Abelson (Abl) plays key roles in normal development, whereas its inappropriate activation helps trigger the development of several forms of leukemia. Abl is best known for its roles in axon guidance, but Abl and its relatives also help regulate embryonic morphogenesis in epithelial tissues. Here, we explore the role of regulation of Abl kinase activity during development. We first compare the subcellular localization of Abl protein and of active Abl, by using a phosphospecific antibody, providing a catalog of places where Abl is activated. Next, we explore the consequences for morphogenesis of overexpressing wild-type Abl or expressing the activated form found in leukemia, Bcr-Abl. We find dose-dependent effects of elevating Abl activity on morphogenetic movements such as head involution and dorsal closure, on cell shape changes, on cell protrusive behavior, and on the organization of the actin cytoskeleton. Most of the effects of Abl activation parallel those caused by reduction in function of its target Enabled. Abl activation leads to changes in Enabled phosphorylation and localization, suggesting a mechanism of action. These data provide new insight into how regulated Abl activity helps direct normal development and into possible biological functions of Bcr-Abl.

scholarly journals Depletion of Cholesteryl Esters Causes Meibomian Gland Dysfunction-Like Symptoms in a Soat1-Null Mouse Model

2021 ◽  
Vol 22 (4) ◽  
pp. 1583
Author(s):  
Igor A. Butovich ◽  
Amber Wilkerson ◽  
Seher Yuksel
Keyword(s):  
Mouse Model ◽  
High Resolution Mass Spectrometry ◽  
Meibomian Gland ◽  
Lipid Homeostasis ◽  
Null Mouse ◽  
Complete Suppression ◽  
Cholesteryl Esters ◽  
Wild Type ◽  
Massive Accumulation

Previous studies on ablation of several key genes of meibogenesis related to fatty acid elongation, omega oxidation, and esterification into wax esters have demonstrated that inactivation of any of them led to predicted changes in the meibum lipid profiles and caused severe abnormalities in the ocular surface and Meibomian gland (MG) physiology and morphology. In this study, we evaluated the effects of Soat1 ablation that were expected to cause depletion of the second largest class of Meibomian lipids (ML)—cholesteryl esters (CE)—in a mouse model. ML of the Soat1-null mice were examined using liquid chromatography high-resolution mass spectrometry and compared with those of Soat1+/− and wild-type mice. Complete suppression of CE biosynthesis and simultaneous accumulation of free cholesterol (Chl) were observed in Soat1-null mice, while Soat1+/− mutants had normal Chl and CE profiles. The total arrest of the CE biosynthesis in response to Soat1 ablation transformed Chl into the dominant lipid in meibum accounting for at least 30% of all ML. The Soat1-null mice had clear manifestations of dry eye and MG dysfunction. Enrichment of meibum with Chl and depletion of CE caused plugging of MG orifices, increased meibum rigidity and melting temperature, and led to a massive accumulation of lipid deposits around the eyes of Soat1-null mice. These findings illustrate the role of Soat1/SOAT1 in the lipid homeostasis and pathophysiology of MG.

scholarly journals Getting into position: the catalytic mechanisms of protein ubiquitylation

2004 ◽  
Vol 379 (3) ◽  
pp. 513-525 ◽  
Author(s):  
Lori A. PASSMORE ◽  
David BARFORD
Keyword(s):  
Protein Interactions ◽  
Regulatory Elements ◽  
Substrate Selection ◽  
Protein Protein Interactions ◽  
Different Types ◽  
Catalytic Mechanisms ◽  
Cellular Pathways ◽  
Ubiquitin Conjugating Enzymes ◽  
Insight Into

The role of protein ubiquitylation in the control of diverse cellular pathways has recently gained widespread attention. Ubiquitylation not only directs the targeted destruction of tagged proteins by the 26 S proteasome, but it also modulates protein activities, protein–protein interactions and subcellular localization. An understanding of the components involved in protein ubiquitylation (E1s, E2s and E3s) is essential to understand how specificity and regulation are conferred upon these pathways. Much of what we know about the catalytic mechanisms of protein ubiquitylation comes from structural studies of the proteins involved in this process. Indeed, structures of ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) have provided insight into their mechanistic details. E3s (ubiquitin ligases) contain most of the substrate specificity and regulatory elements required for protein ubiquitylation. Although several E3 structures are available, the specific mechanistic role of E3s is still unclear. This review will discuss the different types of ubiquitin signals and how they are generated. Recent advances in the field of protein ubiquitylation will be examined, including the mechanisms of E1, E2 and E3. In particular, we discuss the complexity of molecular recognition required to impose selectivity on substrate selection and topology of poly-ubiquitin chains.

scholarly journals The Anatomical Distribution of Mechanoreceptors in Mouse Hind Paw Skin and the Influence of Integrin α1β1 on Meissner-Like Corpuscle Density in the Footpads

2021 ◽  
Vol 15 ◽  
Author(s):  
Valerie Wai ◽  
Lauren Roberts ◽  
Jana Michaud ◽  
Leah R. Bent ◽  
Andrea L. Clark
Keyword(s):  
Sensory Feedback ◽  
Receptive Fields ◽  
Glabrous Skin ◽  
Null Mouse ◽  
Merkel Cells ◽  
Wild Type ◽  
Anatomical Distribution ◽  
Footfall Patterns

Afferent neurons and their mechanoreceptors provide critical sensory feedback for gait. The anatomical distribution and density of afferents and mechanoreceptors influence sensory feedback, as does mechanoreceptor function. Electrophysiological studies of hind paw skin reveal the different types of afferent responses and their receptive fields, however, the anatomical distribution of mechanoreceptor endings is unknown. Also, the role of integrin α1β1 in mechanoreceptor function is unclear, though it is expressed by keratinocytes in the stratum basale where it is likely involved in a variety of mechanotransduction pathways and ion channel functionalities. For example, it has been shown that integrin α1β1 is necessary for the function of TRPV4 that is highly expressed by afferent units. The purpose of this study, therefore, was to determine and compare the distribution of mechanoreceptors across the hind paw skin and the footfall patterns of itga1-null and wild type mice. The itga1-null mouse is lacking the integrin α1 subunit, which binds exclusively to the β1 subunit, thus rendering integrin α1β1 nonfunctional while leaving the numerous other pairings of the β1 subunit undisturbed. Intact hind paws were processed, serially sectioned, and stained to visualize mechanoreceptors. Footfall patterns were analyzed as a first step in correlating mechanoreceptor distribution and functionality. Merkel cells and Meissner-like corpuscles were present, however, Ruffini endings and Pacinian corpuscles were not observed. Meissner-like corpuscles were located exclusively in the glabrous skin of the footpads and digit tips, however, Merkel cells were found throughout hairy and glabrous skin. The increased density of Merkel cells and Meissner-like corpuscles in footpads 1 and 3 and Meissner-like corpuscles in footpad 4 suggests their role in anteroposterior balance, while Meissner-like corpuscle concentrations in digits 2 and 5 support their role in mediolateral balance. Finally, a larger density of Meissner-like corpuscles in footpads 3 and 4 in male itga1-null mice compared to wild type controls paves the way for future site-specific single fiber in vivo recordings to provide insight into the role of integrin α1β1 in tactile mechanotransduction.

scholarly journals The Role of Public-Private Partnerships in Higher Education How Tertiary Institutions in emerging Economies benefit from Public-Private Partnerships

2017 ◽  
Vol 2 (1) ◽  
pp. 1-7
Author(s):  
Ronak Warasthe
Keyword(s):  
Higher Education ◽  
Emerging Economies ◽  
Tertiary Education ◽  
Added Value ◽  
Public Private Partnerships ◽  
Tertiary Institutions ◽  
The Past ◽  
Different Types ◽  
Insight Into

Abstract The number of Public-Private Partnerships in the education sector is growing in developing and emerging economies. Traditionally governments are the main financial contributor to education however, the involvement of the private sector is an increasing one. While more established in primary and secondary education, PPPs in tertiary education are a phenomenon rather slowly growing in the past decades (Patrinos, Barrera-Osorio, & Guaqueta, 2009). There are various concepts of PPPs in higher education each targeting different goals. In order to give an insight into different types of PPPs, the typology according to Mabizela has been briefly displayed and the case of a PPP in Namibia is given. The framework of the partnership was compiled to give an outlook on the practicability of partnerships. The paper exemplifies that both partners within a PPP can benefit from the added value they may generate for their target group. Thus, the benefit depends on quality, relevance and execution of the partnership.

scholarly journals Tłumacz-polemista. Zderzenie paradygmatów w pierwszym polskim wydaniu Orientalizmu Edwarda Saida

2020 ◽  
pp. 116-142
Author(s):  
Weronika Szwebs
Keyword(s):  
Cultural Studies ◽  
Main Text ◽  
Doctoral Thesis ◽  
Critical Attitude ◽  
Additional Information ◽  
Different Types ◽  
The Moment ◽  
Insight Into

Translator as Polemicist: The Clash of Paradigms in the First Polish Edition of Said’s Orientalism The article analyzes the paratextual activity of Witold Kalinowski, the author of the first Polish translation of Edward Said’s Orientalism (1991), paying special attention to his polemical remarks and their relation to the vision of scientific, theoretical discourse. The translator does not strive for invisibility. On the contrary, he uses footnotes and brackets inserted in the main text to comment on different aspects of Said’s work. He signals problems ensuing from the differences between languages and cultures, explains the nature of linguistic difficulties and justifies his own solutions. He also takes on the role of editor and commentator, explaining Said’s allusions, supplementing the discussion with additional information, anticipating readers’ doubts about certain facts that might sound suspicious, and even inserting bracketed additions and clarifications which suggest that the original is unclear or imprecise. Finally, Kalinowski overtly expresses his polemical attitude: he provides certain parts of Said’s discussion with sic! annotation (thus suggesting that the author is wrong) and adds footnotes where he argues with what he sees as the author’s dubious and far-fetched interpretations. The Translator’s Note gives certain insight into the nature of the disagreement between the author and the translator. Explaining why Orientalism is a difficult book to translate, Kalinowski enumerates its troubling features: the combination of different types of discourse and the large number of polemical accents, due to which the book is not fully scientific. The moment of the book’s publication might suggest that such a qualification could have been a result of the then scarce presence of poststructuralist thought and cultural studies in the Polish humanities. However, the analysis of Witold Kalinowski’s articles as well as his doctoral thesis from the 1980s shows both his awareness of the theoretical currents that influenced Orientalism and his critical attitude towards Marxist thought. It is the aversion to the Marxist-inspired interpretations – both Kalinowski’s personal methodological conviction and a widespread attitude in the early post-communist Poland – that seems to be the reason of the clash in the first Polish translation of Said’s work.

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