The tumor suppressor BAP1 interacts with chromatin-associated proteins and regulates cell proliferation, but its mechanism of action and regulation remain poorly defined. We show that the ...ubiquitin-conjugating enzyme UBE2O multi-monoubiquitinates the nuclear localization signal of BAP1, thereby inducing its cytoplasmic sequestration. This activity is counteracted by BAP1 autodeubiquitination through intramolecular interactions. Significantly, we identified cancer-derived BAP1 mutations that abrogate autodeubiquitination and promote its cytoplasmic retention, indicating that BAP1 autodeubiquitination ensures tumor suppression. The antagonistic relationship between UBE2O and BAP1 is also observed during adipogenesis, whereby UBE2O promotes differentiation and cytoplasmic localization of BAP1. Finally, we established a putative targeting consensus sequence of UBE2O and identified numerous chromatin remodeling factors as potential targets, several of which tested positive for UBE2O-mediated ubiquitination. Thus, UBE2O defines an atypical ubiquitin-signaling pathway that coordinates the function of BAP1 and establishes a paradigm for regulation of nuclear trafficking of chromatin-associated proteins.
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•UBE2O ubiquitinates BAP1 on its NLS, and regulates its subcellular localization•The mechanism of BAP1 autodeubiquitination is disrupted in cancer•UBE2O and BAP1 have antagonistic roles in cell-cycle regulation and differentiation•UBE2O targets itself and a subset of chromatin regulators
Mashtalir et al. show that an atypical ubiquitin ligase UBE2O regulates the nucleocytoplasmic transport of the tumor suppressor BAP1. The autocatalytic removal of the ubiquitin from BAP1 can counteract UBE2O activity. The identifications of cancer-derived BAP1 mutations also suggest that BAP1 autodeubiquitination ensures tumor suppression.
Specimens of Garra rufa were collected from a warm river and a cool stream in the Bingöl Province, Turkey, once a month over a period of one year. The effects of month, season, gender and location on ...the fatty acid composition in the muscle and the lipid content were investigated and dietary marker fatty acids were used to obtain dietary preferences in different locations (Ilıcalar, Garip) and periods. Total lipid change was seasonally significant (ANOSIM-R=0.49) at both locations and 18:1ω9, 20:5ω3 and 20:6ω3 were the most abundant dietary fatty acids. Although G. rufa are predominantly herbivores, they can also feed omnivorously on mixed diets depending on the presence and absence of their primary diet. The effect of season was significant on fatty acid composition, regardless of the location (Pperm=0.001). Significant seasonal changes in all the fatty acid compositions could be attributed to seasonal changes in the abundance and diversity of dietary sources in the environment due to the effect of temperature.
Electrolyte abnormalities are not uncommon in coronavirus disease 2019 (COVID-19). Several studies have suggested that various electrolyte imbalances seem to have an impact on disease prognosis. ...However, no study has primarily focused on the effect of baseline electrolyte abnormalities on disease outcome. In this study, we assessed the validity of the hypothesis that baseline electrolyte imbalances may be related to unfavourable outcomes in hospitalized COVID-19 patients. Design of the study was retrospective and observational. We included 408 hospitalized individuals with COVID-19 over 18 years old. Baseline levels of sodium, potassium, calcium and chloride were assessed and the effects of abnormalities in these electrolytes on requirement for intensive care unit and mechanical ventilation, hospitalization duration and treatment outcome were evaluated. Patients were clustered based on electrolyte levels and clusters were compared according to outcome variables. Frequency of other severe disease indices was compared between the clusters. Lastly, we evaluated the independent factors related to COVID-19-associated deaths with multivariate analyses. In all, 228 (55.8%) of the patients had at least one electrolyte imbalance at baseline. Hyponatraemia was the most frequent electrolyte abnormality. Patients with hyponatraemia, hypochloraemia or hypocalcaemia had, respectively, more frequent requirement for intensive care unit and mechanical ventilation, higher mortality rate and longer hospitalization. The clusters associated with electrolyte abnormalities had unfavourable outcomes. Also, Clinical and laboratory features associated with severe disease were detected more often in those clusters. Hyponatraemia was an independent factor related to death from COVID-19 (OR 10.33; 95% CI 1.62–65.62; p 0.01). Furthermore, baseline electrolyte imbalances, primarily hyponatraemia, were related to poor prognosis in COVID-19 and baseline electrolyte assessment would be beneficial for evaluating the risk of severe COVID-19.
•More than half of the hospitalized COVID-19 patients had electrolyte abnormalities.•Hyponatraemia was the most frequent electrolyte anomaly.•Hyponatraemia, hypochloraemia and hypocalcaemia were related to unfavorable outcomes in COVID-19 patients.•Hyponatraemia is one of the independent factors related to death from COVID-19.
The ability of abundantly available heartwood of
Areca catechu to adsorb cadmium(II) ions from aqueous solution has been investigated through batch experiments at room temperature. Various sorption ...parameters such as contact time, initial concentration of cadmium(II) ion, solution pH and amount of the biomass on the adsorption capacity, were studied. The adsorbent was found to be effective for quantitative removal of cadmium(II) ions in acidic conditions and equilibrium has been achieved in 30
min at pH 6.0. The equilibrium adsorption data were fitted to Langmuir, Freundlich and Dubinin–Radushkevich adsorption isotherm models and the model parameters were evaluated. The kinetic study showed that the pseudo-second-order rate equation better described the biosorption process. The FT-IR spectrum analysis revealed that hydroxyl, carboxyl, amide and amine groups were major cadmium(II) binding groups.
SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein ...(S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.
Neuronal cell death contributes significantly to the pathology of traumatic brain injury (TBI) irrespective of the mode or severity of the injury. Activation of a pro-survival protein, Akt, is known ...to be regulated by an E3 ligase TRAF6 through a process of ubiquitination-coupled phosphorylation at its T308 residue. Here we show that upregulation of a pro-apototic protein, GADD34, attenuates TRAF6-mediated Akt activation in a controlled cortical impact model of TBI in mice. TBI induces the expression of GADD34 by stimulating binding of a stress inducible transcription factor, ATF4, to the GADD34 promoter. GADD34 then binds with TRAF6 and prevents its interaction with Akt. This event leads to retention of Akt in the cytosol and prevents phosphorylation at the T308 position. Finally, in vivo depletion of GADD34 using a lentiviral knockdown approach leads to a rescue of Akt activation and markedly attenuates TBI-induced cell death.
DNA topoisomerase II completely removes DNA intertwining, or catenation, between sister chromatids before they are segregated during cell division. How this occurs throughout the genome is poorly ...understood. We demonstrate that in yeast, centromeric plasmids undergo a dramatic change in their topology as the cells pass through mitosis. This change is characterized by positive supercoiling of the DNA and requires mitotic spindles and the condensin factor Smc2. When mitotic positive supercoiling occurs on decatenated DNA, it is rapidly relaxed by topoisomerase II. However, when positive supercoiling takes place in catenated plasmid, topoisomerase II activity is directed toward decatenation of the molecules before relaxation. Thus, a topological change on DNA drives topoisomerase II to decatenate molecules during mitosis, potentially driving the full decatenation of the genome.
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