scholarly journals p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

2020 ◽  
Author(s):  
Sharon A George ◽  
Alexi Kiss ◽  
Sofian N Obaid ◽  
Aileen Venegas ◽  
Trisha Talapatra ◽  
...  
Keyword(s):  
Cardiac Injury ◽  
Mapk Signaling ◽  
Anthracycline Cardiotoxicity ◽  
Genetic Ablation ◽  
Female Mice ◽  
Echocardiographic Parameters ◽  
The Individual ◽  
And Function ◽  
First Time ◽  
Dose Dependent

ABSTRACTBACKGROUNDThe efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38γ and p38δ, remain uncharacterized.OBJECTIVESTo determine the potential cardioprotective effects of p38γ and p38δ genetic deletion in mice subjected to acute DOX treatment.METHODSMale and female wild-type (WT), p38γ-/-, p38δ-/- and p38γ-/-δ-/- mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy.RESULTSSignificantly improved survival was observed in p38δ-/- female mice post-DOX relative to WT females, but not in p38γ-/- or p38γ-/-δ-/- male or female mice. The improved survival in DOX-treated p38δ-/- females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38δ-/- females.CONCLUSIONSp38δ plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38δ targeting could be a potential cardioprotective strategy in anthracycline chemotherapy.NEW AND NOTEWORTHYThis study for the first time identifies the roles of the alternative p38γ and p38δ MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38γ systemic deletion did not affect DOX-cardiotoxicity, p38δ systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38δ-/- females and autophagy was increased.

scholarly journals p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

2020 ◽  
Vol 319 (4) ◽  
pp. H775-H786
Author(s):  
Sharon A. George ◽  
Alexi Kiss ◽  
Sofian N. Obaid ◽  
Aileen Venegas ◽  
Trisha Talapatra ◽  
...  
Keyword(s):  
Structure And Function ◽  
Cardiac Structure ◽  
Male Mice ◽  
Anthracycline Cardiotoxicity ◽  
Genetic Ablation ◽  
Female Mice ◽  
Cardiac Structure And Function ◽  
And Function ◽  
First Time

This study for the first time identifies the sex-specific roles of the alternative p38γ and p38δ MAPK isoforms in promoting doxorubicin (DOX) cardiotoxicity. We show that p38δ and p38γ/δ systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38δ−/− females, and autophagy marker was increased.

Narrow is the Gate to Utopia

Moreana ◽  
2012 ◽  
Vol 49 (Number 187- (1-2) ◽  
pp. 207-226
Author(s):  
Marie-Claire Phélippeau
Keyword(s):  
Social Construction ◽  
Free Will ◽  
Religious Toleration ◽  
Individual Liberty ◽  
The Reformation ◽  
The Individual ◽  
And Function

This study examines the notions of pleasure, individual liberty and consensus in Thomas More’s Utopia. The paradox inherent in Utopia, written before the Reformation, is especially visible in the affirmation of religious toleration coexisting with the need for a strict supervision of the citizens. The dream of an ideal republic is based on a Pauline vision of man which defines the individual mainly as a sinner. Consequently, it is the duty of the republic’s rulers to guide the citizens and establish a consensus. This study tries to determine the part left to the individual’s free will and examines the nature and function of the structures that are supposed to ensure the happiness of each one and of the whole community. The notion of moral hierarchy is asserted as the linchpin of the Utopian social construction.

Victorian Pain

2017 ◽  
Author(s):  
Rachel Ablow
Keyword(s):  
Nineteenth Century ◽  
Victorian Literature ◽  
Social Life ◽  
Charles Darwin ◽  
Harriet Martineau ◽  
The Status ◽  
History Of ◽  
The Individual ◽  
Natural Philosophers ◽  
First Time

The nineteenth century introduced developments in science and medicine that made the eradication of pain conceivable for the first time. This new understanding of pain brought with it a complex set of moral and philosophical dilemmas. If pain serves no obvious purpose, how do we reconcile its existence with a well-ordered universe? Examining how writers of the day engaged with such questions, this book offers a compelling new literary and philosophical history of modern pain. The book provides close readings of novelists Charlotte Brontë and Thomas Hardy and political and natural philosophers John Stuart Mill, Harriet Martineau, and Charles Darwin, as well as a variety of medical, scientific, and popular writers of the Victorian age. The book explores how discussions of pain served as investigations into the status of persons and the nature and parameters of social life. No longer conceivable as divine trial or punishment, pain in the nineteenth century came to seem instead like a historical accident suggesting little or nothing about the individual who suffers. A landmark study of Victorian literature and the history of pain, the book shows how these writers came to see pain as a social as well as a personal problem. Rather than simply self-evident to the sufferer and unknowable to anyone else, pain was also understood to be produced between persons—and even, perhaps, by the fictions they read.

Strategies for Oral Delivery of Metal-Saturated Lactoferrin

2019 ◽  
Vol 20 (11) ◽  
pp. 1046-1051 ◽  
Author(s):  
Przemysław Gajda-Morszewski ◽  
Klaudyna Śpiewak-Wojtyła ◽  
Maria Oszajca ◽  
Małgorzata Brindell
Keyword(s):  
Biological Activity ◽  
Oral Delivery ◽  
Therapeutic Potential ◽  
Structure And Function ◽  
The Difference ◽  
And Function ◽  
First Time

Lactoferrin was isolated and purified for the first time over 50-years ago. Since then, extensive studies on the structure and function of this protein have been performed and the research is still being continued. In this mini-review we focus on presenting recent scientific efforts towards the elucidation of the role and therapeutic potential of lactoferrin saturated with iron(III) or manganese(III) ions. The difference in biological activity of metal-saturated lactoferrin vs. the unmetalated one is emphasized. The strategies for oral delivery of lactoferrin, are also reviewed, with particular attention to the metalated protein.

A University Education

2017 ◽  
Author(s):  
David Willetts
Keyword(s):  
Higher Education ◽  
Modern Society ◽  
University Education ◽  
Modern World ◽  
Controversial Issues ◽  
The Us ◽  
The Individual ◽  
The University ◽  
First Time ◽  
The Relationship

Universities have a crucial role in the modern world. In England, entrance to universities is by nation-wide competition which means English universities have an exceptional influence on schools--a striking theme of the book. This important book first investigates the university as an institution and then tracks the individual on their journey to and through university. In A University Education, David Willetts presents a compelling case for the ongoing importance of the university, both as one of the great institutions of modern society and as a transformational experience for the individual. The book also makes illuminating comparisons with higher education in other countries, especially the US and Germany. Drawing on his experience as UK Minister for Universities and Science from 2010 to 2014, the author offers a powerful account of the value of higher education and the case for more expansion. He covers controversial issues in which he was involved from access for disadvantaged students to the introduction of L9,000 fees. The final section addresses some of the big questions for the future, such as the the relationship between universities and business, especially in promoting innovation.. He argues that the two great contemporary trends of globalisation and technological innovation will both change the university significantly. This is an authoritative account of English universities setting them for the first time in their new legal and regulatory framework.

The Republic

2019 ◽  
pp. 205-229
Author(s):  
Dominic Scott
Keyword(s):  
Political Theory ◽  
Left Behind ◽  
Ideal State ◽  
The Republic ◽  
Individual Justice ◽  
The Individual ◽  
Political Right ◽  
First Time ◽  
The Ideal

This chapter presents a reading of Plato’s Republic. The Republic is among Plato’s most complex works. From its title, the first-time reader will expect a dialogue about political theory, yet the work starts from the perspective of the individual, coming to focus on the question of how, if at all, justice contributes to an agent’s happiness. Only after this question has been fully set out does the work evolve into an investigation of politics—of the ideal state and of the institutions that sustain it, especially those having to do with education. But the interest in individual justice and happiness is never left behind. Rather, the work weaves in and out of the two perspectives, individual and political, right through to its conclusion. All this may leave one wondering about the unity of the work. The chapter shows that, despite the enormous range of topics discussed, the Republic fits together as a coherent whole.

Biosynthetic strategies for tetramic acid formation

2021 ◽  
Author(s):  
Xuhua Mo ◽  
Tobias A. M. Gulder
Keyword(s):  
Molecular Mechanism ◽  
Gene Clusters ◽  
Acid Formation ◽  
Biosynthetic Gene ◽  
Tetramic Acid ◽  
Biosynthetic Gene Clusters ◽  
The Individual ◽  
First Time ◽  
Acid Unit

Over 30 biosynthetic gene clusters for natural tetramate have been identified. This highlight reviews the biosynthetic strategies for formation of tetramic acid unit for the first time, discussing the individual molecular mechanism in detail.

scholarly journals Adolescent and adult laryngotracheal stenosis: a review

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Gerhard Johan Klopper ◽  
Oladele Vincent Adeniyi ◽  
Kate Stephenson
Keyword(s):  
Intensive Care ◽  
Past Century ◽  
Main Body ◽  
Laryngotracheal Stenosis ◽  
Airway Protection ◽  
Interventional Pulmonology ◽  
The Past ◽  
Airway Emergency ◽  
The Individual ◽  
And Function

Abstract Background The larynx has multiple composite functions which include phonation, airway protection, and sensory control of respiration. Stenosis of the larynx and trachea were first recorded by O’Dwyer in 1885 and by Colles in 1886, respectively. Initially, the aetiology of laryngotracheal stenosis was predominantly infective. Currently, the leading cause is iatrogenic injury to the laryngotracheal complex secondary to prolonged ventilation in an intensive care unit. Main body Laryngotracheal stenosis is a complex and diverse disease. It poses a major challenge to the surgeon and can present as an airway emergency. Management typically demands the combined involvement of various disciplines including otorhinolaryngology, cardiothoracic surgery, anaesthesiology, interventional pulmonology, and radiology. Both the disease and its management can impact upon respiration, voice, and swallowing. The incidence of iatrogenic laryngotracheal stenosis has reflected the evolution of airway and intensive care whilst airway surgery has advanced concurrently over the past century. Correction of laryngotracheal stenosis requires expansion of the airway lumen; this is achieved by either endoscopic or open surgery. We review the relevant basic science, aetiopathogenesis, diagnosis, management, and treatment outcomes of LTS. Conclusion The choice of surgical procedure in the management of laryngotracheal stenosis is often dictated by the individual anatomy and function of the larynx and trachea, together with patient factors and available facilities. Regardless of how the surgeon chooses to approach these lesions, prevention of iatrogenic laryngotracheal damage remains of primary importance.

scholarly journals Kinetical Study, Thermo-Mechanical Characteristics and Recyclability of Epoxidized Camelina Oil Cured with Antagonist Structure (Aliphatic/Aromatic) or Functionality (Acid/Amine) Hardeners

Polymers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 2503
Author(s):  
Chiara Di Mauro ◽  
Aratz Genua ◽  
Alice Mija
Keyword(s):  
Disulfide Bonds ◽  
Mechanical Characteristics ◽  
Dicarboxylic Acids ◽  
Thermomechanical Properties ◽  
Chemical Recycling ◽  
Camelina Oil ◽  
Ft Ir ◽  
Tan Δ ◽  
The Individual ◽  
First Time

In an attempt to prepare sustainable epoxy thermosets, this study introduces for the first time the idea to use antagonist structures (aromatic/aliphatic) or functionalities (acid/amine) as hardeners to produce reprocessable resins based on epoxidized camelina oil (ECMO). Two kinds of mixtures were tested: one combines aromatic/aliphatic dicarboxylic acids: 2,2′-dithiodibenzoic acid (DTBA) and 3,3′-dithiodipropionic acid (DTDA); another is the combination of two aromatic structures with acid/amine functionality: DTBA and 4-aminophenyl disulfide (4-AFD). DSC and FT-IR analyses were used as methods to analyze the curing reaction of ECMO with the hardeners. It was found that the thermosets obtained with the dual crosslinked mechanism needed reduced curing temperatures and reprocessing protocols compared to the individual crosslinked thermosets. Thanks to the contribution of disulfide bonds in the network topology, the obtained thermosets showed recycling ability. The final thermomechanical properties of the virgin and mechanical reprocessed materials were analyzed by DMA and TGA. The obtained thermosets range from elastomeric to rigid materials. As an example, the ECMO/DTBA704-AFD30 virgin or reprocessed thermosets have tan δ values reaching 82–83 °C. The study also investigates the chemical recycling and the solvent resistance of these vitrimer-like materials.

scholarly journals The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

2021 ◽  
Vol 22 (15) ◽  
pp. 7923
Author(s):  
Santiago Alvarez-Argote ◽  
Caitlin C. O’Meara
Keyword(s):  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Normal Function ◽  
Cardiac Conduction ◽  
Cell Detection ◽  
Fate Mapping ◽  
The Novel ◽  
Functional Roles ◽  
Macrophage Populations ◽  
And Function

Macrophages were first described as phagocytic immune cells responsible for maintaining tissue homeostasis by the removal of pathogens that disturb normal function. Historically, macrophages have been viewed as terminally differentiated monocyte-derived cells that originated through hematopoiesis and infiltrated multiple tissues in the presence of inflammation or during turnover in normal homeostasis. However, improved cell detection and fate-mapping strategies have elucidated the various lineages of tissue-resident macrophages, which can derive from embryonic origins independent of hematopoiesis and monocyte infiltration. The role of resident macrophages in organs such as the skin, liver, and the lungs have been well characterized, revealing functions well beyond a pure phagocytic and immunological role. In the heart, recent research has begun to decipher the functional roles of various tissue-resident macrophage populations through fate mapping and genetic depletion studies. Several of these studies have elucidated the novel and unexpected roles of cardiac-resident macrophages in homeostasis, including maintaining mitochondrial function, facilitating cardiac conduction, coronary development, and lymphangiogenesis, among others. Additionally, following cardiac injury, cardiac-resident macrophages adopt diverse functions such as the clearance of necrotic and apoptotic cells and debris, a reduction in the inflammatory monocyte infiltration, promotion of angiogenesis, amelioration of inflammation, and hypertrophy in the remaining myocardium, overall limiting damage extension. The present review discusses the origin, development, characterization, and function of cardiac macrophages in homeostasis, cardiac regeneration, and after cardiac injury or stress.

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