Caenorhabditis elegans comes of age

A report of the European C. elegans 2008 meeting, Seville, Spain, 29 March-2 April 2008

Protective effects of the thioredoxin and glutaredoxin systems in dopamine-induced cell death

Although the etiology of sporadic Parkinson disease (PD) is unknown, it is well established that oxidative stress plays an important role in the pathogenic mechanism. The thioredoxin (Trx) and glutaredoxin (Grx) systems are two central systems upholding the sulfhydryl homeostasis by reducing disulfides and mixed disulfides within the cell and thereby protecting against oxidative stress. By examining the expression of redox proteins in human postmortem PD brains, we found the levels of Trx1 and thioredoxin reductase 1 (TrxR1) to be significantly decreased. The human neuroblastoma cell line SH-SY5Y and the nematode Caenorhabditis elegans were used as model systems to explore the potential protective effects of the redox proteins against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. 6-OHDA is highly prone to oxidation, resulting in the formation of the quinone of 6-OHDA, a highly reactive species and powerful neurotoxin. Treatment of human cells with 6-OHDA resulted in an increased expression of Trx1, TrxR1, Grx1, and Grx2, and small interfering RNA for these genes significantly increased the cytotoxic effects exerted by the 6-OHDA neurotoxin. Evaluation of the dopaminergic neurons in C. elegans revealed that nematodes lacking trxr-1 were significantly more sensitive to 6-OHDA, with significantly increased neuronal degradation. Importantly, both the Trx and the Grx systems were also found to directly mediate reduction of the 6-OHDA-quinone in vitro and thus render its cytotoxic effects. In conclusion, our results suggest that the two redox systems are important for neuronal survival in dopamine-induced cell death. © 2014 Elsevier Inc.A.P.F. was supported by Stiftelsen Lars Hiertas Minne and Karolinska Institutet research grants. Research in the Swoboda laboratory was supported by the Swedish Research Council (VR) and the NordForsk Nordic network for C. elegans research. A.M.-V. was supported by the Instituto de Salud Carlos III (Projects PI050065 and PI080557, cofinanced by the Fondo Social Europeo, FEDER) and Junta de Andalucía (Projects P07-CVI-02697 and P08-CVI-03629), Spain. Some C. elegans strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440).Peer Reviewe

Assessment of subclinical cardiac changes in structure and function by cardiovascular magnetic resonance

Background: The early identification of disease can benefit patients clinically and provide a powerful research tool. This thesis aims to identify subclinical cardiac change using cardiovascular magnetic resonance (CMR) in both disease and health and evaluate its diagnostic and prognostic uses. Methods: We have prospectively recruited and conducted multi-parametric CMR in 50 patients with hypertrophic cardiomyopathy (HCM), 40 endurance athletes and 100 asymptomatic patients with type 2 diabetes mellitus. Results: Study 1 and 2 evaluated CMR in the early diagnosis of HCM. Study 1 demonstrated the diagnostic accuracy of extracellular volume (ECV) mapping is superior to volumetric methods of differentiating HCM from athletic left ventricular (LV) hypertrophy. Study 2 demonstrated that ECV expansion could be detected prior to overt hypertrophy or impairment of contractile function in patients with HCM. Study 3 demonstrated that LV torsion is lower in endurance athletes than controls and is predominantly influenced by lactate threshold and intensity of training. Study 4 and 5 investigated the role of CMR in identifying patients with type 2 diabetes at risk of heart failure and silent myocardial infarction. Study 4 found that the increased risk of heart failure in patients with type 2 diabetes was mediated by ECV expansion and diffuse fibrosis. There was a high rate of silent myocardial infarction (17 %) which was unrelated to heart failure risk. In study 5 we developed a simple screening tool, using measures that can be carried out in a cardiology clinic, for the detection of silent myocardial infarction in type 2 diabetes. Conclusions: CMR is able to detect subclinical change in both tissue characteristics and function of the heart. This can aid the early and appropriate diagnosis of disease and identify those at the highest risk of adverse outcomes

eulerForce: Force-directed Layout for Euler Diagrams

Euler diagrams use closed curves to represent sets and their relationships. They facilitate set analysis, as humans tend to perceive distinct regions when closed curves are drawn on a plane. However, current automatic methods often produce diagrams with irregular, non-smooth curves that are not easily distinguishable. Other methods restrict the shape of the curve to for instance a circle, but such methods cannot draw an Euler diagram with exactly the required curve intersections for any set relations. In this paper, we present eulerForce, as the first method to adopt a force-directed approach to improve the layout and the curves of Euler diagrams generated by current methods. The layouts are improved in quick time. Our evaluation of eulerForce indicates the benefits of a force-directed approach to generate comprehensible Euler diagrams for any set relations in relatively fast time

Redox-dependent and redox-independent functions of Caenorhabditis elegans thioredoxin 1

Thioredoxins (TRX) are traditionally considered as enzymes catalyzing redox reactions. However, redox-independent functions of thioredoxins have been described in different organisms, although the underlying molecular mechanisms are yet unknown. We report here the characterization of the first generated endogenous redox-inactive thioredoxin in an animal model, the TRX-1 in the nematode Caenorhabditis elegans. We find that TRX-1 dually regulates the formation of an endurance larval stage (dauer) by interacting with the insulin pathway in a redox-independent manner and the cGMP pathway in a redox-dependent manner. Moreover, the requirement of TRX-1 for the extended longevity of worms with compromised insulin signalling or under calorie restriction relies on TRX-1 redox activity. In contrast, the nuclear translocation of the SKN-1 transcription factor and increased LIPS-6 protein levels in the intestine upon trx-1 deficiency are strictly redox-independent. Finally, we identify a novel function of C. elegans TRX-1 in male food-leaving behaviour that is redox-dependent. Taken together, our results position C. elegans as an ideal model to gain mechanistic insight into the redox-independent functions of metazoan thioredoxins, overcoming the limitations imposed by the embryonic lethal phenotypes of thioredoxin mutants in higher organisms.NIH Office of Research Infrastructure P40 OD010440Spanish Ministry of Economy and Competitiveness BFU2015- 64408-PFondo Social Europeo BFU2015- 64408-PNational Institute of Allergy and Infectious Diseases of the National Institutes of Health R01AI07640