scholarly journals ROS and glutathionylation balance cytoskeletal dynamics in neutrophil extracellular trap formation

2017 ◽  
Vol 216 (12) ◽  
pp. 4073-4090 ◽  
Author(s):  
Darko Stojkov ◽  
Poorya Amini ◽  
Kevin Oberson ◽  
Christiane Sokollik ◽  
Andrea Duppenthaler ◽  
...  
Keyword(s):  
Genetic Manipulation ◽  
Genetic Defect ◽  
Underlying Mechanism ◽  
Neutrophil Extracellular Trap ◽  
Pharmacological Agents ◽  
Cytoskeletal Network ◽  
Cytoskeletal Dynamics ◽  
Dna Release ◽  
The One ◽  
Syndrome Protein

The antimicrobial defense activity of neutrophils partly depends on their ability to form neutrophil extracellular traps (NETs), but the underlying mechanism controlling NET formation remains unclear. We demonstrate that inhibiting cytoskeletal dynamics with pharmacological agents or by genetic manipulation prevents the degranulation of neutrophils and mitochondrial DNA release required for NET formation. Wiskott-Aldrich syndrome protein–deficient neutrophils are unable to polymerize actin and exhibit a block in both degranulation and DNA release. Similarly, neutrophils with a genetic defect in NADPH oxidase fail to induce either actin and tubulin polymerization or NET formation on activation. Moreover, neutrophils deficient in glutaredoxin 1 (Grx1), an enzyme required for deglutathionylation of actin and tubulin, are unable to polymerize either cytoskeletal network and fail to degranulate or release DNA. Collectively, cytoskeletal dynamics are achieved as a balance between reactive oxygen species–regulated effects on polymerization and glutathionylation on the one hand and the Grx1-mediated deglutathionylation that is required for NET formation on the other.

scholarly journals Regulation of the one carbon folate cycle as a shared metabolic signature of longevity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrea Annibal ◽  
Rebecca George Tharyan ◽  
Maribel Fides Schonewolff ◽  
Hannah Tam ◽  
Christian Latza ◽  
...  
Keyword(s):  
High Resolution Mass Spectrometry ◽  
Genetic Manipulation ◽  
Underlying Mechanism ◽  
Comparative Approach ◽  
Causal Mechanism ◽  
C Elegans ◽  
Health And Disease ◽  
One Carbon Metabolism ◽  
The One ◽  
Folate Cycle

AbstractThe metabolome represents a complex network of biological events that reflects the physiologic state of the organism in health and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C. elegans to identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle are pervasively regulated in common. We observed similar changes in long-lived mouse models of reduced insulin/IGF signaling. Genetic manipulation of pathway enzymes and supplementation with one carbon metabolites in C. elegans reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection. Such interventions impact the methionine cycle, and reveal methionine restriction as an underlying mechanism. This comparative approach reveals key metabolic nodes to enhance healthy ageing.

Posthuman oder Übermensch. War Nietzsche ein Transhumanist?

2013 ◽  
Vol 42 (1) ◽  
Author(s):  
Michael Skowron
Keyword(s):  
Genetic Manipulation ◽  
Linguistic Analysis ◽  
The Other ◽  
The Internet ◽  
Jürgen Habermas ◽  
Eternal Recurrence ◽  
Different Types ◽  
The Future ◽  
The One ◽  
Michael Sandel

AbstractRecent discussions (especially in the Internet) about the question whether Nietzsche was a Transhumanist or at least a forerunner of the Transhumanist movement have drawn new attention to Nietzsche’s concept of the Overhuman and the relation to the Posthuman. The article is taking a critical stance by turning suggested analogies between education and genetic manipulation of humans into an argument against the latter, by relating self-education to self-overcoming and eternal recurrence of the same (which is excluded by Transhumanists), and by reminding of Nietzsche’s distinction between ‘Overhuman’ and ‘last human’ as two different ways to the future. Linguistic analysis of the epitheta used in speaking of the different ‘types’ in question as well as structural analogies between critical considerations in Michael Sandel and Jürgen Habermas on the one hand, Nietzsche on the other are also evidence that Nietzsche would not have endorsed the technological path to perfection of the human but would emphasize his own way of self-overcoming instead.

Options at the fundamental level for growth regulation in farm livestock

1997 ◽  
Vol 1987 ◽  
pp. 22-22
Author(s):  
P. J. Reeds
Keyword(s):  
Growth Regulation ◽  
Genetic Manipulation ◽  
Growth Promotion ◽  
Cellular Mechanisms ◽  
Pharmacological Agents ◽  
New Developments ◽  
Protein Deposition ◽  
Effective Use ◽  
Farm Livestock ◽  
Stimulation Of

New developments in immunological techniques and increasing expertise in genetic manipulation, especially by gene transfer, have opened up a wide variety of approaches to the manipulation of the growth and metabolism of farm livestock. However, the most effective use of these techniques and the design of new pharmacological agents for growth promotion and nutrient “repartitioning” might well rest on a greater understanding of the factors and cellular mechanisms that coordinate growth and protein anabolism. It is this coordidnation that must be disturbed if persistent gains are to bke made. This greater understanding may well result from an examination of the mechanisms whereby currently available anabolic agents and techniques exert their effects and this paper will draw on these experiences. Growth is clearly a closely coordinated process and this has hampered many attempts to maintain accelerated protein deposition for long periods. For example forced increases in hormonal concentrations often induce hormonal insensitivity. It is possible that understanding and reducing the constraints on growth for example by reducing the levels of suppressive factors rather than concentrating on the active stimulation of anabolic factors may be more effective.

scholarly journals Role of unfolded proteins in lung disease

Thorax ◽  
2020 ◽  
Vol 76 (1) ◽  
pp. 92-99
Author(s):  
Kirsty L Bradley ◽  
Clare A Stokes ◽  
Stefan J Marciniak ◽  
Lisa C Parker ◽  
Alison M Condliffe
Keyword(s):  
Protein Synthesis ◽  
Er Stress ◽  
Respiratory Diseases ◽  
Viral Infections ◽  
Genetic Manipulation ◽  
Experimental Models ◽  
Misfolded Proteins ◽  
Pharmacological Agents ◽  
The Impact

The lungs are exposed to a range of environmental toxins (including cigarette smoke, air pollution, asbestos) and pathogens (bacterial, viral and fungal), and most respiratory diseases are associated with local or systemic hypoxia. All of these adverse factors can trigger endoplasmic reticulum (ER) stress. The ER is a key intracellular site for synthesis of secretory and membrane proteins, regulating their folding, assembly into complexes, transport and degradation. Accumulation of misfolded proteins within the lumen results in ER stress, which activates the unfolded protein response (UPR). Effectors of the UPR temporarily reduce protein synthesis, while enhancing degradation of misfolded proteins and increasing the folding capacity of the ER. If successful, homeostasis is restored and protein synthesis resumes, but if ER stress persists, cell death pathways are activated. ER stress and the resulting UPR occur in a range of pulmonary insults and the outcome plays an important role in many respiratory diseases. The UPR is triggered in the airway of patients with several respiratory diseases and in corresponding experimental models. ER stress has been implicated in the initiation and progression of pulmonary fibrosis, and evidence is accumulating suggesting that ER stress occurs in obstructive lung diseases (particularly in asthma), in pulmonary infections (some viral infections and in the setting of the cystic fibrosis airway) and in lung cancer. While a number of small molecule inhibitors have been used to interrogate the role of the UPR in disease models, many of these tools have complex and off-target effects, hence additional evidence (eg, from genetic manipulation) may be required to support conclusions based on the impact of such pharmacological agents. Aberrant activation of the UPR may be linked to disease pathogenesis and progression, but at present, our understanding of the context-specific and disease-specific mechanisms linking these processes is incomplete. Despite this, the ability of the UPR to defend against ER stress and influence a range of respiratory diseases is becoming increasingly evident, and the UPR is therefore attracting attention as a prospective target for therapeutic intervention strategies.

scholarly journals Successful production of offspring after superovulation and in vitro culture of embryos from domestic ferrets (Mustela putorius furos)

Reproduction ◽  
2001 ◽  
pp. 611-618 ◽  
Author(s):  
ZY Li ◽  
QS Jiang ◽  
YL Zhang ◽  
XM Liu ◽  
JF Engelhardt
Keyword(s):  
Genetic Manipulation ◽  
Blastocyst Stage ◽  
Chorionic Gonadotrophin ◽  
Mustela Putorius ◽  
Cell Stage ◽  
Fetal Bovine ◽  
The One ◽  
Genetic Modelling ◽  
Successful Production

In an effort to expand the use of ferrets as models for genetic disease, several experimental parameters that are required for successful genetic manipulation in this species were investigated. Optimum superovulation (19.3 +/- 0.6 oocytes and embryos per female) was achieved after injections of 100 iu equine chorionic gonadotrophin (eCG) and 150 iu human chorionic gonadotrophin (hCG). The ovulation rate achieved by the treatment was more than double that induced by mating. Mating with a male immediately after hCG treatment did not significantly alter the number of oocytes ovulated or the number of embryos present, indicating that mating is not required for superovulation in ferrets. Of embryos harvested at the one-cell stage, 64.5% and 47.1% developed into blastocysts when cultured in vitro in CZB or TCM-199 plus 10% fetal bovine serum (FBS) media, respectively. In contrast, only 17.1% of embryos cultured in vitro in NCSU-23 developed to the blastocyst stage. Both freshly retrieved and in vitro cultured embryos from cinnamon-coloured parents produced live young when transferred at the eight-cell stage into albino, pseudo-pregnant recipients. The percentage of kits delivered relative to embryos transferred was 61% for freshly retrieved embryos and 32% for embryos cultured in vitro. These results demonstrate successful embryo transfer in ferrets and provide a basis for further study of genetic modelling approaches in this species after embryo manipulation.

Genomic instability and cancer: lessons from analysis of Bloom's syndrome

2009 ◽  
Vol 37 (3) ◽  
pp. 553-559 ◽  
Author(s):  
Miranda Payne ◽  
Ian D. Hickson
Keyword(s):  
Genomic Instability ◽  
Mitotic Chromosome ◽  
Genetic Defect ◽  
Autosomal Recessive Disorder ◽  
Recq Helicase ◽  
Bloom's Syndrome ◽  
Binding Partners ◽  
Bloom’S Syndrome ◽  
Syndrome Protein ◽  
Blm Gene

Bloom's syndrome (BS) is a rare autosomal recessive disorder characterized by genomic instability and cancer predisposition. The underlying genetic defect is mutation of the BLM gene, producing deficiency in the RecQ helicase BLM (Bloom's syndrome protein). The present article begins by introducing BLM and its binding partners before reviewing its known biochemical activities and its potential roles both as a pro-recombinase and as a suppressor of homologous recombination. Finally, the evidence for an emerging role in mitotic chromosome segregation is examined.

Importance of developmental gesture of handwriting in children to better understand writing disabilities: Preliminary study

2016 ◽  
Vol 33 (S1) ◽  
pp. S349-S349
Author(s):  
C. Lopez ◽  
L. Vaivre-douret
Keyword(s):  
Underlying Mechanism ◽  
School Level ◽  
School Age Children ◽  
Control Group ◽  
Healthy Children ◽  
Intervention Process ◽  
Writing Disabilities ◽  
Spatial Measures ◽  
Competing Interest ◽  
The One

IntroductionThere is currently a resurgence of handwriting difficulties in school-age children. Researches in literature focus on kinematics temporal and spatial measures of letters in the writing process and on clinical performances such as the handwriting scale (BHK). This assessment doesn’t consider the organization and the maturation of the handwriting gesture.ObjectivesWe aim to study the developmental organization of the handwriting gesture to provide developmental standards of reference in order to complete performances measures allowing a better understanding of handwriting disabilities.MethodsHealthy children of elementary school aged between 6 and 11 years old are eligible for inclusion. All children are assessed with neuropsychological and neuropsychomotor evaluations and with handwriting assessment (BHK). Two groups are established, the one with handwriting difficulties and the other one (control group) without writing disorder or learning disabilities. The children were matched for age, gender and school level. All children are filmed with a camera suspended over to observe with specific handwriting tasks, the upper limb gesture about segmental organization of fingers, hand, forearm, arm, shoulder and postural organization.ResultsPreliminary findings show significant differences of the segmental organization of the writing gesture between the two groups. We will discuss the identified causes of the handwriting disorders with the analysis of neuropsychomotor and neurological assessments data in correlation with gesture segmental organization.ConclusionDevelopmental organization of the writing gesture is a possible underlying mechanism of handwriting disabilities. Practically, it appears important to improve news tools of evaluations with gestural writing consideration and to implement it in intervention process.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Genome editing of Capsaspora owczarzaki suggests an ancestral function of the Hippo signaling effector YAP/TAZ/Yorkie in cytoskeletal dynamics but not proliferation

2021 ◽  
Author(s):  
Jonathan Eugene Phillips ◽  
Maribel Santos ◽  
Mohammed Kanchwala ◽  
Chao Xing ◽  
Duojia Pan
Keyword(s):  
Cell Proliferation ◽  
Genetic Manipulation ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Animal Development ◽  
Multicellular Aggregates ◽  
Cytoskeletal Regulation ◽  
Cytoskeletal Dynamics ◽  
Ancestral Function ◽  
The Hippo Pathway

Many genes that function in animal development are present in the close unicellular relatives of animals, but little is known regarding the premetazoan function of these genes. Here, we develop techniques for genetic manipulation in the filasterean Capsaspora owczarzaki and use these tools to characterize the Capsaspora ortholog of the Hippo signaling nuclear effector YAP/TAZ/Yorkie (coYki). In contrast to its potent oncogene activity in metazoans, we show that coYki is dispensable for cell proliferation but regulates cytoskeletal dynamics and the morphology of multicellular aggregates in Capsaspora. Our results suggest an ancestral role for the Hippo pathway in cytoskeletal regulation, which was later co-opted to regulate cell proliferation in animals.

scholarly journals At the Crossroads of Apoptosis and Autophagy: Multiple Roles of the Co-Chaperone BAG3 in Stress and Therapy Resistance of Cancer

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 574 ◽  
Author(s):  
Donat Kögel ◽  
Benedikt Linder ◽  
Andreas Brunschweiger ◽  
Silvia Chines ◽  
Christian Behl
Keyword(s):  
Stress Responses ◽  
Physiological Role ◽  
Proteasomal Degradation ◽  
Therapy Resistance ◽  
Major Protein ◽  
Cytoskeletal Dynamics ◽  
Cellular Stress Responses ◽  
Function Expression ◽  
Client Proteins ◽  
The One

BAG3, a multifunctional HSP70 co-chaperone and anti-apoptotic protein that interacts with the ATPase domain of HSP70 through its C-terminal BAG domain plays a key physiological role in cellular proteostasis. The HSP70/BAG3 complex determines the levels of a large number of selective client proteins by regulating their turnover via the two major protein degradation pathways, i.e. proteasomal degradation and macroautophagy. On the one hand, BAG3 competes with BAG1 for binding to HSP70, thereby preventing the proteasomal degradation of its client proteins. By functionally interacting with HSP70 and LC3, BAG3 also delivers polyubiquitinated proteins to the autophagy pathway. BAG3 exerts a number of key physiological functions, including an involvement in cellular stress responses, proteostasis, cell death regulation, development, and cytoskeletal dynamics. Conversely, aberrant BAG3 function/expression has pathophysiological relevance correlated to cardiomyopathies, neurodegeneration, and cancer. Evidence obtained in recent years underscores the fact that BAG3 drives several key hallmarks of cancer, including cell adhesion, metastasis, angiogenesis, enhanced autophagic activity, and apoptosis inhibition. This review provides a state-of-the-art overview on the role of BAG3 in stress and therapy resistance of cancer, with a particular focus on BAG3-dependent modulation of apoptotic signaling and autophagic/lysosomal activity.

scholarly journals Soluble levels of cytosolic tubulin regulate ciliary length control

2011 ◽  
Vol 22 (6) ◽  
pp. 806-816 ◽  
Author(s):  
Neeraj Sharma ◽  
Zachary A. Kosan ◽  
Jannese E. Stallworth ◽  
Nicolas F. Berbari ◽  
Bradley K. Yoder
Keyword(s):  
Primary Cilium ◽  
Cell Types ◽  
Microtubule Network ◽  
Subsequent Increase ◽  
Developmental Defects ◽  
Pharmacological Agents ◽  
Developmental Abnormalities ◽  
Evolutionarily Conserved ◽  
Cytoskeletal Dynamics ◽  
Different Cell Types

The primary cilium is an evolutionarily conserved dynamic organelle important for regulating numerous signaling pathways, and, as such, mutations disrupting ciliogenesis result in a variety of developmental abnormalities and postnatal disorders. The length of the cilium is regulated by the cell through largely unknown mechanisms. Normal cilia length is important, as either shortened or elongated cilia have been associated with disease and developmental defects. Here we explore the importance of cytoskeletal dynamics in regulating cilia length. Using pharmacological approaches in different cell types, we demonstrate that actin depolymerization or stabilization and protein kinase A activation result in a rapid elongation of the primary cilium. The effects of pharmacological agents on cilia length are associated with a subsequent increase in soluble tubulin levels and can be impaired by depletion of soluble tubulin with taxol. In addition, subtle nocodazole treatment was able to induce ciliogenesis under conditions in which cilia are not normally formed and also increases cilia length on cells that have already established cilia. Together these data indicate that cilia length can be regulated through changes in either the actin or microtubule network and implicate a possible role for soluble tubulin levels in cilia length control.

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