Proteasome Lid Bridges Mitochondrial Stress with Cdc53/Cullin1 NEDDylation Status

Cycles of Cdc53/Cullin1 rubylation (a.k.a NEDDylation) protect ubiquitin-E3 SCF (Skp1-Cullin1-F-box protein) complexes from self-destruction and play an important role in mediating the ubiquitination of key protein substrates involved in cell cycle progression, development, and survival. Cul1 rubylation is balanced by the COP9 signalosome (CSN), a multi-subunit derubylase that shows 1:1 paralogy to the 26 S proteasome lid. The turnover of SCF substrates and their relevance to various diseases is well studied, yet, the extent by which environmental perturbations influence Cul1 rubylation/derubylation cycles per se is still unclear. In this study, we show that the level of cellular oxidation serves as a molecular switch, determining Cullin1 rubylation/derubylation ratio. We describe a mutant of the proteasome lid subunit, Rpn11 that exhibits accumulated levels of Cullin1-Rub1 conjugates, a characteristic phenotype of csn mutants. By dissecting between distinct phenotypes of rpn11 mutants, proteasome and mitochondria dysfunction, we were able to recognize the high reactive oxygen species (ROS) production during the transition of cells into mitochondrial respiration, as a checkpoint of Cullin1 rubylation in a reversible manner. Thus, the study adds the rubylation cascade to the list of cellular pathways regulated by redox homeostasis

Opicapone in UK clinical practice: effectiveness, safety and cost analysis in patients with Parkinson's disease.

Aim: This subanalysis of the OPTIPARK study aimed to confirm the effectiveness and safety of opicapone in patients with Parkinson's disease and motor fluctuations in clinical practice specifically in the UK and to assess the impact of opicapone on treatment costs. Methods: Patients received opicapone added to levodopa for 6 months. Clinical outcomes were assessed at 3 and 6 months and treatment costs at 6 months. Results: Most patients' general condition improved at 3 months, with sustained improvements reported at 6 months. Opicapone improved motor and non-motor symptoms at both timepoints, was generally well tolerated and reduced total treatment costs by GBP 3719. Conclusion: Opicapone added to levodopa resulted in clinical improvements and reduced treatment costs across UK clinical practice

Primary skin fibroblasts as a model of Parkinson's disease

Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues

Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-alpha

Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in Mycobacterium tuberculosis (Mtb)-infected lung tissue but is absent in areas of immunopathology. In the microsphere model, PD-1 ligands are up-regulated by infection, and the PD-1/PD-L1 axis is further induced by hypoxia. Inhibition of PD-1 signalling increases Mtb growth, and augments cytokine secretion. TNF-a is responsible for accelerated Mtb growth, and TNF-a neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-a immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-a concentrations. Together, our findings demonstrate that PD-1 regulates the immune response in TB, and inhibition of PD-1 accelerates Mtb growth via excessive TNF-a secretion.</p

Ruthenium polypyridyl complexes and their modes of interaction with DNA : is there a correlation between these interactions and the antitumor activity of the compounds?

Various interaction modes between a group of six ruthenium polypyridyl complexes and DNA have been studied using a number of spectroscopic techniques. Five mononuclear species were selected with formula [Ru(tpy) L1L2](2-n)?, and one closely related dinuclear cation of formula [{Ru(apy)(tpy)}2{l-H2N(CH2)6NH2}]4?. The ligand tpy is 2,20:60,200-terpyridine and the ligand L1 is a bidentate ligand, namely, apy (2,20-azobispyridine), 2-phenylazopyridine, or 2-phenylpyridinylmethylene amine. The ligand L2 is a labile monodentate ligand, being Cl-, H2O, or CH3CN. All six species containing a labile L2 were found to be able to coordinate to the DNA model base 9-ethylguanine by 1H NMR and mass spectrometry. The dinuclear cationic species, which has no positions available for coordination to a DNA base, was studied for comparison purposes. The interactions between a selection of four representative complexes and calf-thymus DNA were studied by circular and linear dichroism. To explore a possible relation between DNA-binding ability and toxicity, all compounds were screened for anticancer activity in a variety of cancer cell lines, showing in some cases an activity which is comparable to that of cisplatin. Comparison of the details of the compound structures, their DNA binding, and their toxicity allows the exploration of structure–activity relationships that might be used to guide optimization of the activity of agents of this class of compounds

Rigid Supersymmetric Backgrounds of Minimal Off-Shell Supergravity

We discuss various aspects of rigid supersymmetry within minimal N=1 off-shell supergravity using the old and new minimal formulations both in Lorentzian and Euclidean signatures. In particular, we construct all rigid supersymmetry backgrounds with a hypersurface orthogonal Killing vector. In the Lorentzian signature we show that AdS_4 provides a rigid supersymmetric background in both formulations albeit with different amounts of preserved supersymmetry. In the Euclidean signature we find new backgrounds of the old-minimal supergravity, including squashed four-spheres and a half-BPS version of flat space.Comment: 40 pages: v2 References added, typos correcte

Thermal AdS(3), BTZ and competing winding modes condensation

We study the thermal physics of AdS(3) and the BTZ black hole when embedded in String theory. The exact calculation of the Hagedorn temperature in TAdS(3) is reinterpreted as the appearance of a winding tachyon both in AdS(3) and BTZ. We construct a dual framework for analyzing the phases of the system. In this dual framework, tachyon condensation and geometric capping appear on the same footing, bridging the usual gap of connecting tachyon condensation to modifications of geometry. This allows us to construct in a natural way a candidate for the unstable phase, analogous to a small black hole in higher dimensions. Additional peculiar effects associated with the Hagedorn temperature and the Hawking-Page transition, some to do with the asymptotic structure of AdS(3) and some with strong curvature effects, are analyzed and explained.Comment: 40 pages, 5 figures, JHEP3 format. v2: added references, minor corrections and clarification

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline