The progenitors of early-type dwarf galaxies in the Virgo cluster

In the here presented thesis, I investigate the possible progenitors of elliptical dwarf galaxies in the Virgo galaxy cluster. For the analysis of the galaxies of the late morphological type, a broadband data set in the u, g, r, i and z filters of the Sloan Digital Sky Survey was used. The photometric and structural properties (e.g. luminosity and radius) of the single morphological subclasses was compared with an existing data set of elliptical dwarf galaxies to explore the possible evolutionary connections. Within the sample, galaxies of the type "blue compact dwarf" - if the contribution of the starburst component is removed - show a remarkably good similarity to the elliptical dwarf galaxies. This agreement in the photometric properties could point to a possible evolutionary connection. The results of the photometry of the entire sample were used as input parameters for an evolutionary synthesis code, which simulates the undisturbed and disturbed evolution of the photometric parameters of the galaxies. By comparing the results of the simulation with the ones of the observations of today's elliptical dwarf galaxies, I am able to restrict the possible progenitors to certain morphological subclasses. In the course of this thesis, I was able to show that apart from "blue compact dwarf galaxies", also the prospective photometric properties of late-type spirals of the type Sd and Sm are in good agreement with today's elliptical dwarf galaxies

Periodate-oxidized ATP stimulates the permeability transition of rat liver mitochondria

AbstractPeriodate-oxidized ADP (oADP) and periodate-oxidized ATP (oATP) stimulate the permeability transition in energized rat liver mitochondria measured as the Ca2+-efflux induced by Ca2+ and Pi. In the presence of Mg2+ and Pi, mitochondria lose intramitochondrial adenine nucleotides at a slow rate. oATP induces a strong decrease of the matrix adenine nucleotides which is inhibited by carboxyatractyloside. Under these conditions, Mg2+ prevents the opening of the permeability transition pore. EGTA prevents the Pi-induced slow efflux of adenine nucleotides, but is without effect on the oATP-induced strong decrease of adenine nucleotides. This oATP-induced strong adenine nucleotide efflux is inhibited by ADP. oATP reduces the increase of matrix adenine nucleotides occurring when the mitochondria are incubated with Mg2+ and ATP. This effect of oATP is also prevented by carboxyatractyloside. oATP is not taken up by the mitochondria. It is suggested that oATP induces a strong efflux of matrix adenine nucleotides by the interaction with the ADP/ATP carrier from the cytosolic side. The induction of the mitochondrial permeability transition by oADP and oATP is attributed to two mechanisms—a strong decrease in the intramitochondrial adenine nucleotide content, especially that of ADP, and a stabilization of the c-conformation of the ADP/ATP carrier

Regulation of Cullin RING E3 Ubiquitin Ligases by CAND1 In Vivo

Cullin RING ligases are multi-subunit complexes consisting of a cullin protein which forms a scaffold onto which the RING protein Rbx1/2 and substrate receptor subunits assemble. CAND1, which binds to cullins that are not conjugated with Nedd8 and not associated with substrate receptors, has been shown to function as a positive regulator of Cullin ligases in vivo. Two models have been proposed to explain this requirement: (i) CAND1 sequesters cullin proteins and thus prevents autoubiquitination of substrate receptors, and (ii) CAND1 is required to promote the exchange of bound substrate receptors. Using mammalian cells, we show that CAND1 is predominantly cytoplasmically localized and that cullins are the major CAND1 interacting proteins. However, only small amounts of CAND1 bind to Cul1 in cells, despite low basal levels of Cul1 neddylation and approximately equal cytoplasmic endogenous protein concentrations of CAND1 and Cul1. Compared to F-box protein substrate receptors, binding of CAND1 to Cul1 in vivo is weak. Furthermore, preventing binding of F-box substrate receptors to Cul1 does not increase CAND1 binding. In conclusion, our study suggests that CAND1 does not function by sequestering cullins in vivo to prevent substrate receptor autoubiquitination and is likely to regulate cullin RING ligase activity via alternative mechanisms

Compound C prevents Hypoxia-Inducible Factor-1α protein stabilization by regulating the cellular oxygen availability via interaction with Mitochondrial Complex I

The transcription factor Hypoxia-Inducible Factor-1α is a master regulator of the cellular response to low oxygen concentration. Compound C, an inhibitor of AMP-activated kinase, has been reported to inhibit hypoxia dependent Hypoxia-Inducible Factor-1α activation via a mechanism that is independent of AMP-activated kinase but dependent on its interaction with the mitochondrial electron transport chain. The objective of this study is to characterize the interaction of Compound C with the mitochondrial electron transport chain and to determine the mechanism through which the drug influences the stability of the Hypoxia-Inducible Factor-1α protein

The role of the cullin-5 e3 ubiquitin ligase in the regulation of insulin receptor substrate-1.

Background. SOCS proteins are known to negatively regulate insulin signaling by inhibiting insulin receptor substrate-1 (IRS1). IRS1 has been reported to be a substrate for ubiquitin-dependent proteasomal degradation. Given that SOCS proteins can function as substrate receptor subunits of Cullin-5 E3 ubiquitin ligases, we examined whether Cullin-5 dependent ubiquitination is involved in the regulation of basal IRS1 protein stability and signal-induced IRS1 degradation. Findings. Our results indicate that basal IRS1 stability varies between cell types. However, the Cullin-5 E3 ligase does not play a major role in mediating IRS1 ubiquitination under basal conditions. Protein kinase C activation triggered pronounced IRS1 destabilization. However, this effect was also independent of the function of Cullin-5 E3 ubiquitin ligases. Conclusions. In conclusion, SOCS proteins do not exert a negative regulatory effect on IRS1 by functioning as substrate receptors for Cullin-5-based E3 ubiquitin ligases both under basal conditions and when IRS1 degradation is induced by protein kinase C activation.Peer Reviewe

Onset of occupational hand eczema among healthcare workers during the SARS‐CoV‐2 pandemic: Comparing a single surgical site with a COVID‐19 intensive care unit

Background As a result of the COVID‐19 outbreak, hygiene regulations have been revised and hand sanitation has been intensified. Objective To investigate the onset of hand eczema during the COVID‐19 pandemic in healthcare workers (HCWs) directly involved in intensive care of COVID‐19 patients and HCWs without direct contact with COVID‐19 patients. Hereby, we aim at increasing awareness about occupational hand eczema and preventive measures that can be adopted. Method A survey was distributed amongst 114 HCWs at a single surgical centre and at a COVID‐19 intensive care unit of the university hospital Ludwig Maximilian University Munich, Germany. Participants were questioned about the daily frequency of hand hygiene prior to and during the pandemic. Participants self‐reported the onset of hand eczema and associated symptoms. Results Our study revealed a significant increase in hand washing, disinfection, and use of hand cream across all participants (P‐value <.001), regardless of having direct contact with COVID‐19 patients. A high prevalence of symptoms associated with acute hand dermatitis of 90.4% was found across all HCWs, whereas hand eczema itself was underreported (14.9%). Conclusion The increase in hand sanitation during the COVID‐19 pandemic impairs the skin of the hands across all HCWs, independent of direct intensive care of affected patients

Structural investigations on the mitochondrial uncouplers niclosamide and FCCP

There has been renewed interest in using mitochondrial uncoupler compounds such as niclosamide and carbonyl cyanide p‐(trifluoromethoxy)phenylhydrazone (FCCP) for the treatment of obesity, hepatosteatosis and diseases where oxidative stress plays a role. However, both FCCP and niclosamide have undesirable effects that are not due to mitochondrial uncoupling, such as inhibition of mitochondrial oxygen consumption by FCCP and induction of DNA damage by niclosamide. Through structure–activity analysis, we identified FCCP analogues that do not inhibit mitochondrial oxygen consumption but still provided good, although less potent, uncoupling activity. We also characterized the functional role of the niclosamide 4′‐nitro group, the phenolic hydroxy group and the anilide amino group in mediating uncoupling activity. Our structural investigations provide important information that will aid further drug development

Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation

One potential approach for treating obesity is to increase energy expenditure in brown and white adipose tissue. Here we aimed to achieve this outcome by targeting mitochondrial uncoupler compounds selectively to adipose tissue, thus avoiding side effects from uncoupling in other tissues. Selective drug accumulation in adipose tissue has been observed with many lipophilic compounds and dyes. Hence, we explored the feasibility of conjugating uncoupler compounds with a lipophilic C8-hydrocarbon chain via an ether bond. We found that substituting the trifluoromethoxy group in the uncoupler FCCP with a C8-hydrocarbon chain resulted in potent uncoupling activity. Nonetheless, the compound did not elicit therapeutic effects in mice, likely as a consequence of metabolic instability resulting from rapid ether bond cleavage. A lipophilic analog of the uncoupler compound 2,6-dinitrophenol, in which a C8-hydrocarbon chain was conjugated via an ether bond in the para-position (2,6-dinitro-4-(octyloxy)phenol), exhibited increased uncoupling activity compared to the parent compound. However, in vivo pharmacokinetics studies suggested that 2,6-dinitro-4-(octyloxy)phenol was also metabolically unstable. In conclusion, conjugation of a hydrophobic hydrocarbon chain to uncoupler compounds resulted in sustained or improved uncoupling activity. However, an ether bond linkage led to metabolic instability, indicating the need to conjugate lipophilic groups via other chemical bonds

Inhibition of Hypoxia-Inducible Factor-1α (HIF-1α) Protein Synthesis by DNA damage inducing agents

10.1371/journal.pone.0010522PLoS ONE55