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"Fernandez, Alvaro"
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Upregulation of Rubicon promotes autosis during myocardial ischemia/reperfusion injury
Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by autophagy from death with autophagy, and whether autophagy contributes to death in cardiomyocytes (CMs) is still controversial. Excessive activation of autophagy induces a morphologically and biochemically defined form of cell death termed autosis. Whether autosis is involved in tissue injury induced under pathologically relevant conditions is poorly understood. In the present study, myocardial ischemia/reperfusion (I/R) induced autosis in CMs, as evidenced by cell death with numerous vacuoles and perinuclear spaces, and depleted intracellular membranes. Autosis was observed frequently after 6 hours of reperfusion, accompanied by upregulation of Rubicon, attenuation of autophagic flux, and marked accumulation of autophagosomes. Genetic downregulation of Rubicon inhibited autosis and reduced I/R injury, whereas stimulation of autosis during the late phase of I/R with Tat-Beclin 1 exacerbated injury. Suppression of autosis by ouabain, a cardiac glycoside, in humanized Na+,K+-ATPase-knockin mice reduced I/R injury. Taken together, these results demonstrate that autosis is significantly involved in I/R injury in the heart and triggered by dysregulated accumulation of autophagosomes due to upregulation of Rubicon.
Journal Article
Batman/Detective comics. Vol. 7, Batmen eternal
\"They were the greatest team of crime-fighters Gotham City has ever known. Now that team has been shattered. Clayface is dead, killed by Batwoman after his path to redemption led to disaster. The Bat-Family-- Nightwing, Red Robin, Batgirl, the Red Hood, Robin and the Dark Knight himself--must decide what to do about their prodigal partner. But Batwoman has been offered control of an army, with Batwing and Azrael following in her footsteps. Now these two rival forces are at each other's throats. As the family feud between cousins Bruce Wayne and Kate Kane threatens to tear Gotham City apart, Cassandra Cain and Stephanie Brown are caught in the crossfire. And behind it all, a sinister cybernetic force is at work to transform Red Robin into the ultimate weapon, and therefore lock Gotham into its worst possible future. To reunite his team and save his city, Batman must trust all those who wear the emblem of the Bat. Because fight or fall, they'll all do so together\"-- Provided by publisher.
Book
The functional and pathologic relevance of autophagy proteases
Autophagy is a well-conserved catabolic process essential for cellular homeostasis. First described in yeast as an adaptive response to starvation, this pathway is also present in higher eukaryotes, where it is triggered by stress signals such as damaged organelles or pathogen infection. Autophagy is characterized at the cellular level by the engulfment of portions of the cytoplasm in double-membrane structures called autophagosomes. Autophagosomes fuse with lysosomes, resulting in degradation of the inner autophagosomal membrane and luminal content. This process is coordinated by complex molecular systems, including the ATG8 ubiquitin-like conjugation system and the ATG4 cysteine proteases, which are implicated in the formation, elongation, and fusion of these autophagic vesicles. In this Review, we focus on the diverse functional roles of the autophagins, a protease family formed by the four mammalian orthologs of yeast Atg4. We also address the dysfunctional expression of these proteases in several pathologic conditions such as cancer and inflammation and discuss potential therapies based on their modulation.
Journal Article
Deus ex machina
\"Batman's team of vigilantes has ghosts in their pasts. And now they have come to roost. When Batman formed a team of fellow vigilantes to help him combat evil in Gotham City, he did it partially to protect his allies from the enemies targeting them. But being on a team makes for more targets, and sometimes the ghosts of your past can become everyone's problem. Azrael was raised to be the perfect assassin by the mysterious Order of St. Dumas...before he rebelled. But when the Order decides to create a more perfect assassin, Azrael and the entire team find themselves in the crosshairs of the deadly A.I. known as Ascalon. This kind of magic and mysticism was part of Bruce Wayne's training when he became Batman. And to save his friends, Bruce will seek the most powerful magical artifact that ever existed. The God Machine can give its bearer any knowledge, answer any question...but in the hands of the World's Greatest Detective, could it be even more dangerous than Ascalon?\"-- Provided by publisher.
Book
Nanosecond Pulsed Electric Field (nsPEF): Opening the Biotechnological Pandora’s Box
Nanosecond Pulsed Electric Field (nsPEF) is an electrostimulation technique first developed in 1995; nsPEF requires the delivery of a series of pulses of high electric fields in the order of nanoseconds into biological tissues or cells. They primary effects in cells is the formation of membrane nanopores and the activation of ionic channels, leading to an incremental increase in cytoplasmic Ca2+ concentration, which triggers a signaling cascade producing a variety of effects: from apoptosis up to cell differentiation and proliferation. Further, nsPEF may affect organelles, making nsPEF a unique tool to manipulate and study cells. This technique is exploited in a broad spectrum of applications, such as: sterilization in the food industry, seed germination, anti-parasitic effects, wound healing, increased immune response, activation of neurons and myocites, cell proliferation, cellular phenotype manipulation, modulation of gene expression, and as a novel cancer treatment. This review thoroughly explores both nsPEF’s history and applications, with emphasis on the cellular effects from a biophysics perspective, highlighting the role of ionic channels as a mechanistic driver of the increase in cytoplasmic Ca2+ concentration.
Journal Article
Rise of the Batmen
\"Follow the adventures of Batman, the world's greatest...teacher?! The Dark Knight and series co-star Batwoman team up to take new proteges Red Robin, Spoiler and the villainous Clayface under their leathery wings! The only problem is, neither new super-instructor knows exactly what they're in for as the attempt to train these wiould-be heroes before a mysterious army takes Gotham for themselves.\"-- Provided by publisher.
Book
Increased autophagy blocks HER2-mediated breast tumorigenesis
Allelic loss of the autophagy gene, beclin 1/BECN1, increases the risk of patients developing aggressive, including human epidermal growth factor receptor 2 (HER2)-positive, breast cancers; however, it is not known whether autophagy induction may be beneficial in preventing HER2-positive breast tumor growth. We explored the regulation of autophagy in breast cancer cells by HER2 in vitro and the effects of genetic and pharmacological strategies to increase autophagy on HER2-driven breast cancer growth in vivo. Our findings demonstrate that HER2 interacts with Beclin 1 in breast cancer cells and inhibits autophagy. Mice with increased basal autophagy due to a genetically engineered mutation in Becn1 are protected from HER2-driven mammary tumorigenesis, and HER2 fails to inhibit autophagy in primary cells derived from these mice. Moreover, treatment of mice with HER2-positive human breast cancer xenografts with the Tat-Beclin 1 autophagy-inducing peptide inhibits tumor growth as effectively as a clinically used HER2 tyrosine kinase inhibitor (TKI). This inhibition of tumor growth is associated with a robust induction of autophagy, a disruption of HER2/Beclin 1 binding, and a transcriptional signature in the tumors distinct from that observed with HER2 TKI treatment. Taken together, these findings indicate that the HER2-mediated inhibition of Beclin 1 and autophagy likely contributes to HER2-mediated tumorigenesis and that strategies to block HER2/Beclin 1 binding and/or increase autophagy may represent a new therapeutic approach for HER2-positive breast cancers.
Journal Article
A lonely place of living
\"The Dark Knight's team of Gotham City vigilantes--including Batwoman, Clayface and Azrael--continue to protect their home in BATMAN: DETECTIVE COMICS VOL. 5! Having exiled herself from Batman's world, former ally Spoiler has nearly destroyed herself trying to expose the corruption of Gotham City's vigilantes. Fortunately for her, help has arrived...but unfortunately for the city, it's in the form of the mysterious Anarky! Is he truly on the side of the people, or is he a dangerous lunatic?\"-- Provided by publisher.
Book
Pathogenic single nucleotide polymorphisms on autophagy-related genes
In recent years, the study of single nucleotide polymorphisms (SNPs) has gained increasing importance in biomedical research, as they can either be at the molecular origin of a determined disorder or directly affect the efficiency of a given treatment. In this regard, sequence variations in genes involved in pro-survival cellular pathways are commonly associated with pathologies, as the alteration of these routes compromises cellular homeostasis. This is the case of autophagy, an evolutionarily conserved pathway that counteracts extracellular and intracellular stressors by mediating the turnover of cytosolic components through lysosomal degradation. Accordingly, autophagy dysregulation has been extensively described in a wide range of human pathologies, including cancer, neurodegeneration, or inflammatory alterations. Thus, it is not surprising that pathogenic gene variants in genes encoding crucial effectors of the autophagosome/lysosome axis are increasingly being identified. In this review, we present a comprehensive list of clinically relevant SNPs in autophagy-related genes, highlighting the scope and relevance of autophagy alterations in human disease.
Journal Article