Protein termini are determinants of protein stability. Proteins bearing degradation signals, or degrons, at their amino‐ or carboxyl‐termini are eliminated by the N‐ or C‐degron pathways, ...respectively. We aimed to elucidate the function of C‐degron pathways and to unveil how normal proteomes are exempt from C‐degron pathway‐mediated destruction. Our data reveal that C‐degron pathways remove mislocalized cellular proteins and cleavage products of deubiquitinating enzymes. Furthermore, the C‐degron and N‐degron pathways cooperate in protein removal. Proteome analysis revealed a shortfall in normal proteins targeted by C‐degron pathways, but not of defective proteins, suggesting proteolysis‐based immunity as a constraint for protein evolution/selection. Our work highlights the importance of protein termini for protein quality surveillance, and the relationship between the functional proteome and protein degradation pathways.
SYNOPSIS
Proteins with degradation signals (degron) at their amino‐ or carboxyl‐termini are eliminated by the N‐ or C‐degron pathways, respectively. Proteome‐wide analyses suggest functions of human C‐degrons signals in protein quality surveillance, as well as interplay with N‐degron‐dependent mechanisms.
The Global Protein Stability (GPS) random peptide platform enables context‐independent characterization of degron features.
The activity of C‐degrons is tuned by their surrounding sequences.
Gly/C‐degron shortage is limited to functional eukaryotic proteomes accessible to C‐degron pathways.
C‐degron pathways clear products of proteases and mislocalized cellular proteins.
Mitochondrial localization of MIC19 is dually safeguarded by the N‐ and C‐degron pathways.
Coronaviral diGly‐ending proteins evade C‐degron pathway‐mediated degradation.
Proteome‐wide analyses suggest functions of C‐terminal degradation signals in protein quality surveillance as well as interplay with N‐degron‐dependent mechanisms.
Abstract
Clinical trials showed pangenotypic direct-acting antivirals’ (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, ...glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only < 1% exhibited elevated total bilirubin or aminotransferase levels with both regimens. Five drug discontinuations occurred due to AEs (bilirubin elevation: 3; dermatological issues: 2). Pangenotypic DAAs GLE/PIB and SOF/VEL are effective and well tolerated, achieving high SVR12 rates for patients with all HCV genotypes.
This paper applies the quantile Granger causality test, to explore whether the economic policy uncertainty (EPU) is affected by the crude oil price (COP) shocks in BRICS countries. The empirical ...results of the causal link present asymmetrical features, such that when the oil markets experience supply shocks, there is a positive influence on the EPU in China, India and Brazil. Moreover, a declining COP has an impact on the EPU in Russia and South Africa. Our findings are consistent with the real business cycle model of the oil price shocks, under the influence of the channels that determine the supply and demand. The BRICS EPU also has an impact on the oil market, but their degree of significance varies, and is related to the demand for oil. Understanding the relationship between EPU and oil markets in BRICS countries can assist policymakers to rebalance of the energy landscape, and also aid in the stabilization of national economies.
•We explore the role of crude oil price (COP) shocks in economic policy uncertainty (EPU).•We employed the quantile Granger causality test for estimations.•The empirical results of causal link present asymmetrical features.•Our findings are consistent with the real business cycle model of oil price shocks.
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•A simple, fast and green process for isolation of CPC was established.•CPC recovery from disrupted algae using IL-ATPS was developed.•The extraction efficiency of CPC obtained was ...99%.•The partition coefficient for CPC in this study was 36.6.•The separation factor achieved in IL-ATPS was 5.8.
An aqueous two-phase system (ATPS) with ionic liquids (ILs) was used for the isolate of C-phycocyanin (CPC) from Spirulina platensis microalga. Various imidazolium ILs and potassium salts were studied. The effect of ILs-ATPS on the extraction efficiency of CPC was also studied. The experimental parameters like pH, loading volume, algae concentration, temperature, and alkyl chain length of IL were well-covered in this report. The experimental results showed that the extraction efficiency, the partition coefficient, and the separation factor for CPC were 99%, 36.6, and 5.8, respectively, for an optimal pH value of 7 and a temperature of 308 K. The order of extraction efficiency for CPC using IL-ATPS was: 1-octyl-3-methylimidazolium bromide (C8MIM-Br) > 1-hexyl-3-methylimidazolium bromide (C6MIM-Br) > 1-butyl-3-methylimidazolium bromide (C4MIM-Br). The isolation process followed the pseudo second-order kinetic model and the thermodynamic results were obviously spontaneous.
In the emergency department, it is important to rapidly identify the toxic substances that have led to acute poisoning because different toxicants or toxins cause poisoning through different ...mechanisms, requiring disparate therapeutic strategies and precautions against contraindicating actions, and diverse directions of clinical course monitoring and prediction of prognosis. Ambient ionization mass spectrometry, a state‐of‐the‐art technology, has been proved to be a fast, accurate, and user‐friendly tool for rapidly identifying toxicants like residual pesticides on fruits and vegetables. In view of this, developing an analytical platform that explores the application of such a cutting‐edge technology in a novel direction has been initiated a research program, namely, the rapid identification of toxic substances which might have caused acute poisoning in patients who visit the emergency department and requires an accurate diagnosis for correct clinical decision‐making to bring about corresponding data‐guided management. This review includes (i) a narrative account of the breakthrough in emergency toxicology brought about by the advent of ambient ionization mass spectrometry and (ii) a thorough discussion about the clinical implications and technical limitations of such a promising innovation for promoting toxicological tests from tier two‐level to tier one level.
Background
Prior studies indicated a link between urinary catheter use and urinary complications, highlighting the need for comprehensive, gender‐specific investigations. This study explored the ...association through a national retrospective cohort, emphasizing gender disparities and long‐term outcomes.
Methods
Our study utilized data from the entire population covered by Taiwan's National Health Insurance Research Database from 2000 to 2017. We included 148,304 patients who had undergone Foley catheter placement and their propensity‐scores matched controls in the study. We evaluated urinary complications, which encompassed urinary tract cancer, urolithiasis, urethral stricture, obstructive uropathy, reflux uropathy, fistula, diverticulum, caruncle, false passage, prolapsed urethral mucosa, urinary tract rupture, and urinary tract infection. These were assessed using the Fine and Gray sub‐distribution proportional hazards model to compare between the Foley and non‐Foley groups. Sensitivity analyses were conducted with different matching ratios.
Results
In the study, the non‐Foley group presented a marginally higher mean age (75.24 ± 10.47 years) than the Foley group (74.09 ± 10.47 years). The mean duration of Foley catheterization was 6.1 ± 4.19 years. Men with Foley catheterization exhibited the highest adjusted sub‐distribution hazard ratios for urinary tract cancer (6.57, 95% CI: 5.85–7.37), followed by women with Foley catheterization (4.48, 95% CI: 3.98–5.05), and men without catheterization (1.58, 95% CI: 1.39–1.8) in comparison with women without the procedure. Furthermore, men with Foley catheterization were found to be at the greatest risk for complications such as urolithiasis, urethral stricture, obstructive and reflux uropathy, fistula, diverticulum, caruncle, false passage, prolapsed urethral mucosa, and urinary tract rupture. Conversely, women with urinary catheterization were most susceptible to urinary tract infections.
Conclusions
The evidence confirms that urinary catheterization significantly increases urinary complications, particularly among men. Our study underscores the crucial need for healthcare providers to carefully evaluate the necessity of catheterization, aim to shorten its duration whenever feasible, and strictly adhere to established protocols to minimize complications.
Mitochondria play essential roles in regulating cellular functions. Some drug treatments and molecular interventions have been reported to have off-target effects damaging mitochondria and causing ...severe side effects. The development of a database for the management of mitochondrial toxicity-related molecules and their targets is important for further analyses. To correlate chemical, biological and mechanistic information on clinically relevant mitochondria-related toxicity, a comprehensive mitochondrial toxicity database (MitoTox) was developed. MitoTox is an electronic repository that integrates comprehensive information about mitochondria-related toxins and their targets. Information and data related to mitochondrial toxicity originate from various sources, including scientific journals and other electronic databases. These resources were manually verified and extracted into MitoTox. The database currently contains over 1400 small-molecule compounds, 870 mitochondrial targets, and more than 4100 mitochondrial toxin-target associations. Each MitoTox data record contains over 30 fields, including biochemical properties, therapeutic classification, target proteins, toxicological data, mechanistic information, clinical side effects, and references. MitoTox provides a fully searchable database with links to references and other databases. Potential applications of MitoTox include toxicity classification, prediction, reference and education. MitoTox is available online at http://www.mitotox.org.
Coronavirus Disease 2019 (COVID-19) has been the most severe public health challenge in this century. Two years after its emergence, the rapid development and deployment of effective COVID-19 ...vaccines have successfully controlled this pandemic and greatly reduced the risk of severe illness and death associated with COVID-19. However, due to its ability to rapidly evolve, the SARS-CoV-2 virus may never be eradicated, and there are many important new topics to work on if we need to live with this virus for a long time. To this end, we hope to provide essential knowledge for researchers who work on the improvement of future COVID-19 vaccines. In this review, we provided an up-to-date summary for current COVID-19 vaccines, discussed the biological basis and clinical impact of SARS-CoV-2 variants and subvariants, and analyzed the effectiveness of various vaccine booster regimens against different SARS-CoV-2 strains. Additionally, we reviewed potential mechanisms of vaccine-induced severe adverse events, summarized current studies regarding immune correlates of protection, and finally, discussed the development of next-generation vaccines.
To determine the association of prior traumatic brain injury (TBI) with subsequent diagnosis of neurodegeneration disease.
All studies from 1980 to 2016 reporting TBI as a risk factor for diagnoses ...of interest were identified by searching PubMed, Embase, study references, and review articles. The data and study design were assessed by 2 investigators independently. A meta-analysis was performed by RevMan 5.3.
There were 18 studies comprising 3,263,207 patients. Meta-analysis revealed a significant association of prior TBI with subsequent dementia. The pooled odds ratio (OR) for TBI on development of dementia, FTD and TDP-43 associated disease were 1.93 (95% CI 1.47-2.55, p < 0.001), 4.44 (95% CI 3.86-5.10, p < 0.001), and 2.97 (95% CI 1.35-6.53, p < 0.001). However, analyses of individual diagnoses found no evidence that the risk of Alzheimer's disease, and Parkinson's disease in individuals with previous TBI compared to those without TBI.
History of TBI is not associated with the development of subsequent neurodegeneration disease. Care must be taken in extrapolating from these results because no suitable criteria define post TBI neurodegenerative processes. Therefore, further research in this area is needed to confirm these questions and uncover the link between TBI and neurodegeneration disease.
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