scholarly journals Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons

Author(s):  
Ryan Insolera ◽  
Péter Lőrincz ◽  
Alec J Wishnie ◽  
Gábor Juhász ◽  
Catherine A Collins

AbstractA healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components due to rupture. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.

PLoS Genetics ◽  
2021 ◽  
Vol 17 (8) ◽  
pp. e1009731
Author(s):  
Ryan Insolera ◽  
Péter Lőrincz ◽  
Alec J. Wishnie ◽  
Gábor Juhász ◽  
Catherine A. Collins

A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.


1995 ◽  
Vol 4 (4) ◽  
pp. 393-400 ◽  
Author(s):  
Olle Lindvall

Cell transplantation is now being explored as a new therapeutic strategy to restore function in the diseased human central nervous system. Neural grafts show long-term survival and function in patients with Parkinson's disease but the symptomatic relief needs to be increased. Cell transplantation seems justified in patients with Huntington's disease and, at a later stage, possibly also in demyelinating disorders. The further development in this research field will require systematic studies in animal experiments but also well-designed clinical trials in small groups of patients.


2020 ◽  
Vol 25 (1) ◽  
pp. 33-38
Author(s):  
A. M. Soldatova ◽  
V. A. Kuznetsov ◽  
T. P. Gizatulina ◽  
L. M. Malishevsky ◽  
S. M. Dyachkov

Aim. To assess the relationship between the prolonged PR interval (≥200 ms) and the long-term survival of patients undergoing cardiac resynchronization therapy (CRT).Material and methods. A total of 85 patients (mean age — 55,1Ѓ}9,9 years; men — 81,2%) with NYHA class II-IV heart failure (HF) were examined. The mean follow-up was 34,0Ѓ}21,2 months. Patients with PR<200 ms (n=52) made up group I, with PR≥200 ms (n=33) — group II. Then the patients were divided into subgroups depending on the QRS duration: ≥150 ms (n=33 in group I and n=14 in group II, respectively) <150 ms (n=19 in group I and n=19 in group II, respectively).Results. In patients of group II, a history of myocardial infarction (MI) was more often registered (p=0,005), left ventricular ejection fraction (LVEF) was lower (p=0,032). In a multivariate analysis, MI (OR 3,217; CI 95% 1,188-8,712; p=0,022) and LVEF value (OR 0,869; CI 95% 0,780-0,968; p=0,011) had a significant relationship with the PR interval prolongation (≥200 ms). The survival of patients of group I was 59,6%, group II — 18,2% (Log-rank test p<0,001). According to Cox regression model, the initial left ventricle end-systolic volume (OR 1,012; 95% CI 1,006-1,017; p<0,001), inferior wall MI (OR 1,690; 95% CI 1,131-2,527; p=0,011) and PR interval ≥200 ms (OR 2,179; 95% CI 1,213–3,915; p=0,009) were associated with long-term mortality. In patients with PR≥200 ms, survival rate was low, regardless of the QRS duration (21,4% in patients with QRS≥150 ms, 15,8% in patients with QRS<150 ms; Log-rank test p=0,698) In patients with PR<200 ms, the survival rate of patients with QRS≥150 ms was 72,7%, and for patients with QRS<150 ms — 36,8% (Log-rank test p=0,031).Conclusion. In HF patients, PR interval prolongation (≥200 ms) is associated with long-term mortality increase. The highest survival rates were observed in patients with PR<200 ms and QRS≥150 ms. In patients with QRS≥150 ms, the presence of PR≥200 ms should be considered as an additional criterion for CRT.


2003 ◽  
Vol 124 (4) ◽  
pp. A736
Author(s):  
Meindert Sosef ◽  
Keishi Sugimachi ◽  
John Baust ◽  
Mehmet Toner

Author(s):  
Olajumoke Ogunsanya

Calls for businesses to act with concern for the environment and society create new operating scenarios in which sustainability concerns must be taken into consideration along with the primary objectives of profitability and competitiveness. These additional obligations contribute to dynamism of the marketplace and make it important for businesses to draw on creativity and innovation to find connections between the unrelated in order to establish new efficiencies that can create competitive advantage and differentiation in the environment they find themselves. The central theme of this chapter is how bisociation informs collective creativity and innovation, and influences sustainability for business organizations competing in an environment that is in a permanent state of flux. This chapter trails a series of concepts to find the relationship between the concept of bisociation, collective creativity and sustainable business practices. The aim is to show how consistent creative thinking and exploration of information in different spaces of thought can proffer innovative solutions organizations require for their long term survival and prosperity.


2007 ◽  
Vol 16 (8) ◽  
pp. 787-798 ◽  
Author(s):  
Hossein Arefanian ◽  
Eric B. Tredget ◽  
Ray V. Rajotte ◽  
Gregory S. Korbutt ◽  
Ron G. Gill ◽  
...  

Type 1 diabetes mellitus (T1DM) is caused by the autoimmune destruction of pancreatic islet β-cells, which are required for the production of insulin. Islet transplantation has been shown to be an effective treatment option for T1DM; however, the current shortage of human islet donors limits the application of this treatment to patients with brittle T1DM. Xenotransplantation of pig islets is a potential solution to the shortage of human donor islets provided xenograft rejection is prevented. We demonstrated that a short-term administration of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs) was highly effective in preventing rejection of neonatal porcine islet (NPI) xenografts in non-autoimmune-prone B6 mice. However, the efficacy of this therapy in preventing rejection of NPI xenografts in autoimmune-prone nonobese diabetic (NOD) mice is not known. Given that the current application of islet transplantation is for the treatment of T1DM, we set out to determine whether a combination of anti-LFA-1 and anti-CD154 mAbs could promote long-term survival of NPI xenografts in NOD mice. Short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs, which we found highly effective in preventing rejection of NPI xenografts in B6 mice, failed to promote long-term survival of NPI xenografts in NOD mice. However, addition of anti-CD4 mAb to short-term treatment of a combination of anti-LFA-1 and anti-CD154 mAbs resulted in xenograft function in 9/12 animals and long-term graft (>100 days) survival in 2/12 mice. Immunohistochemical analysis of islet grafts from these mice identified numerous insulin-producing β-cells. Moreover, the anti-porcine antibody as well as autoreactive antibody responses in these mice was reduced similar to those observed in naive nontransplanted mice. These data demonstrate that simultaneous targeting of LFA-1, CD154, and CD4 molecules can be effective in inducing long-term islet xenograft survival and function in autoimmune-prone NOD mice.


2019 ◽  
Vol 12 ◽  
pp. 1179545X1985836
Author(s):  
Masatomo Ebina ◽  
Kazunori Fujino ◽  
Akira Inoue ◽  
Koichi Ariyoshi ◽  
Yutaka Eguchi

Background:Severe sepsis is commonly associated with mortality among critically ill patients and is known to cause coagulopathy. While antithrombin is an anticoagulant used in this setting, serum albumin levels are known to influence serum antithrombin levels. Therefore, this study aimed to evaluate the outcomes of antithrombin supplementation in patients with sepsis-associated coagulopathy, as well as the relationship between serum albumin levels and the effects of antithrombin supplementation.Methods:This retrospective study evaluated patients who were >18 years of age and had been admitted to either of two intensive care units for sepsis-associated coagulopathy. The groups that did and did not receive antithrombin supplementation were compared for outcomes up to 1 year after admission. Subgroup analyses were performed for patients with serum albumin levels of <2.5 g/dL or ⩾2.5 g/dL.Results:Fifty-one patients received antithrombin supplementation and 163 patients did not. The Cox proportional hazards model revealed that antithrombin supplementation was independently associated with 28-day survival (hazard ratio [HR]: 0.374, P = 0.025) but not with 1 year survival (HR: 0.915, P = 0.752). In addition, among patients with serum albumin levels of <2.5 g/dL, antithrombin supplementation was associated with a significantly lower 28-day mortality rate (9.4% vs 36.8%, P = .009).Conclusion:Antithrombin supplementation may improve short-term survival, but not long-term survival, among patients with sepsis-associated coagulopathy.


1990 ◽  
Vol 73 (3) ◽  
pp. 331-344 ◽  
Author(s):  
Jules M. Nazzaro ◽  
Edward A. Neuwelt

✓ In this analysis, the authors review studies over the last 50 years addressing the association between long-term survival and type of surgical management in adults with supratentorial intermediate or high-grade astrocytomas. Earlier reports are included because they are repeatedly referenced in current works and clearly are an important basis upon which present attitudes are predicated. Because recent work has definitively demonstrated the significance of prognostic variables on outcome, the handling of such factors in studies that investigated survival data according to degree of surgery is emphasized. Study design, experimental methods used, and methods of data analysis are also examined. This analysis shows that there is little justification for dogmatic statements concerning the relationship between increasing patient survival times and aggressive surgical management in adults with supratentorial intermediate or high-grade astrocytomas, if patients receive postoperative radiotherapy.


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