| 1. |
- Baranowski, Bartosz, et al.
(författare)
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Protein family neighborhood analyzer-ProFaNA
- 2023
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Ingår i: PeerJ. - 2167-8359. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Functionally related genes are well known to be often grouped in close vicinity in the genomes, particularly in prokaryotes. Notwithstanding the diverse evolutionary mechanisms leading to this phenomenon, it can be used to predict functions of uncharacterized genes. Methods: Here, we provide a simple but robust statistical approach that leverages the vast amounts of genomic data available today. Considering a protein domain as a functional unit, one can explore other functional units (domains) that significantly often occur within the genomic neighborhoods of the queried domain. This analysis can be performed across different taxonomic levels. Provisions can also be made to correct for the uneven sampling of the taxonomic space by genomic sequencing projects that often focus on large numbers of very closely related strains, e.g., pathogenic ones. To this end, an optional procedure for averaging occurrences within subtaxa is available. Results: Several examples show this approach can provide useful functional predictions for uncharacterized gene families, and how to combine this information with other approaches. The method is made available as a web server at http://bioinfo.sggw.edu.pl/neighborhood_analysis.
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| 2. |
- Barbara Sahlin, K., et al.
(författare)
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Short-term effect of induced alterations in testosterone levels on fasting plasma amino acid levels in healthy young men
- 2021
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Ingår i: Life. - : MDPI AG. - 0024-3019 .- 2075-1729. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Long term effect of testosterone (T) deficiency impairs metabolism and is associated with muscle degradation and metabolic disease. The association seems to have a bidirectional nature and is not well understood. The present study aims to investigate the early and unidirectional metabolic effect of induced T changes by measuring fasting amino acid (AA) levels in a human model, in which short-term T alterations were induced. We designed a human model of 30 healthy young males with pharmacologically induced T changes, which resulted in three time points for blood collection: (A) baseline, (B) low T (3 weeks post administration of gonadotropin releasing hormone antagonist) and (C) restored T (2 weeks after injection of T undecanoate). The influence of T on AAs was analyzed by spectrophotometry on plasma samples. Levels of 9 out of 23 AAs, of which 7 were essential AAs, were significantly increased at low T and are restored upon T supplementation. Levels of tyrosine and phenylalanine were most strongly associated to T changes. Short-term effect of T changes suggests an increased protein breakdown that is restored upon T supplementation. Fasting AA levels are able to monitor the early metabolic changes induced by the T fluctuations.
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| 3. |
- Betancourt, Lazaro Hiram, et al.
(författare)
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The human melanoma proteome atlas-Defining the molecular pathology
- 2021
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Ingår i: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 11:7, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients.
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| 4. |
- Giwercman, Aleksander, et al.
(författare)
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Novel protein markers of androgen activity in humans : proteomic study of plasma from young chemically castrated men
- 2022
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Ingår i: eLife. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reliable biomarkers of androgen activity in humans are lacking. The aim of this study was, therefore, to identify new protein markers of biological androgen activity and test their predictive value in relation to low vs normal testosterone values and some androgen deficiency linked pathologies. Methods: Blood samples from 30 healthy GnRH antagonist treated males were collected at three time points: (1) before GnRH antagonist administration; (2) 3 weeks later, just before testosterone undecanoate injection, and (3) after additional 2 weeks. Subsequently, they were analyzed by mass spectrometry to identify potential protein biomarkers of testosterone activity. Levels of proteins most significantly associated with testosterone fluctuations were further tested in a cohort of 75 hypo- and eugonadal males suffering from infertility. Associations between levels of those markers and cardiometabolic parameters, bone mineral density as well as androgen receptor (AR) CAG repeat lengths, were explored. Results: Using receiver operating characteristic analysis, 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6), and fructose-bisphosphate aldolase (ALDOB), as well as a Multi Marker Algorithm, based on levels of 4HPPD and IGFBP6, were shown to be best predictors of low (<8 nmol/l) vs normal (>12 nmol/l) testosterone. They were also more strongly associated with metabolic syndrome and diabetes than testosterone levels. Levels of ALDOB and 4HPPD also showed association with AR CAG repeat lengths. Conclusions: We identified potential new protein biomarkers of testosterone action. Further investigations to elucidate their clinical potential are warranted. Funding: The work was supported by ReproUnion2.0 (grant no. 20201846), which is funded by the Interreg V EU program.
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| 5. |
- Koczkowska, Magdalena, et al.
(författare)
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Personalized health risk assessment based on single-cell RNA sequencing analysis of a male with 45, X/48, XYYY karyotype
- 2022
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Numeric sex chromosome abnormalities are commonly associated with an increased cancer risk. Here, we report a 14-year-old boy with a rare mosaic 45, X/48, XYYY karyotype presenting with subtle dysmorphic features and relative height deficiency, requiring growth hormone therapy. As only 12 postnatal cases have been described so far with very limited follow-up data, to assess the proband's long-term prognosis, including cancer risk, we performed high-throughput single-cell RNA sequencing (scRNA-seq) analysis. Although comprehensive cytogenetic analysis showed seemingly near perfect balance between 45, X and 48, XYYY cell populations, scRNA-seq revealed widespread differences in genotype distribution among immune cell fractions, specifically in monocytes, B- and T-cells. These results were confirmed at DNA level by digital-droplet PCR on flow-sorted immune cell types. Furthermore, deregulation of predominantly autosomal genes was observed, including TCL1A overexpression in 45, X B-lymphocytes and other known genes associated with hematological malignancies. Together with the standard hematological results, showing increased fractions of monocytes and CD4+/CD8+T lymphocytes ratio, long-term personalized hemato-oncological surveillance was recommended in the reported patient.
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| 6. |
- Krysińska, Marianna, et al.
(författare)
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Pan-kinome of Legionella expanded by a bioinformatics survey
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenic Legionella bacteria are notorious for delivering numerous effector proteins into the host cell with the aim of disturbing and hijacking cellular processes for their benefit. Despite intensive studies, many effectors remain uncharacterized. Motivated by the richness of Legionella effector repertoires and their oftentimes atypical biochemistry, also by several known atypical Legionella effector kinases and pseudokinases discovered recently, we undertook an in silico survey and exploration of the pan-kinome of the Legionella genus, i.e., the union of the kinomes of individual species. In this study, we discovered 13 novel (pseudo)kinase families (all are potential effectors) with the use of non-standard bioinformatic approaches. Together with 16 known families, we present a catalog of effector and non-effector protein kinase-like families within Legionella, available at http://bioinfo.sggw.edu.pl/kintaro/. We analyze and discuss the likely functional roles of the novel predicted kinases. Notably, some of the kinase families are also present in other bacterial taxa, including other pathogens, often phylogenetically very distant from Legionella. This work highlights Nature’s ingeniousness in the pathogen–host arms race and offers a useful resource for the study of infection mechanisms.
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| 7. |
- Lasota, Dorota, et al.
(författare)
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Alcohol and the Risk of Railway Suicide
- 2020
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Ingår i: International journal of environmental research and public health. - : MDPI AG. - 1660-4601. ; 17:19
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Tidskriftsartikel (refereegranskat)abstract
- Suicide is one of the ten most common causes of death in the world. Of all deaths from suicide, 22% can be attributed to the use of alcohol, which means that every fifth suicide would not occur if alcohol were not consumed by the population. People under the influence of alcohol choose more radical and effective methods of dying by suicide, e.g., throwing themselves under a moving vehicle, such as a train. The presented analysis aimed to determine important risk factors affecting railway suicide in Poland and their relation to the state of alcohol intoxication of the victims, and the relationship between ethyl alcohol consumption and the phenomenon of suicide. Documentation obtained from the Department of Forensic Medicine at the Medical University of Warsaw, in the form of death registers and forensic medical records concerning examination and autopsy, was analyzed. This made it possible to identify suicide victims from among pedestrian victims of railway accidents recorded during the period under study. The research was carried out using unidimensional and multidimensional statistical analyses with IBM SPSS Statistics, version 25. Sober suicide victims were statistically significantly older than victims under the influence of alcohol; alcohol concentration was correlated with the age of the victims-the older the victims were, the higher the alcohol concentration. A significantly higher number of deaths attributed to suicide by sober victims was observed in autumn compared to other seasons. Multidimensional analysis showed a statistically significant effect of age and season on the probability of dying by suicide under the influence of alcohol-this probability decreases with the age of the victims and is also significantly lower in autumn. The observed relationship between age and the presence of alcohol in suicide victims can be the cause of railway suicides. Knowledge of the mechanisms of seasonal variability of suicidal behavior can help to develop effective strategies to prevent railway suicides. It is necessary to improve the system of reporting railway suicides, as only reliable statistics provide the possibility of assessing both the scale of the problem and the effectiveness of actions taken.
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| 8. |
- Lüscher, Bernhard, et al.
(författare)
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ADP-ribosyltransferases, an update on function and nomenclature
- 2022
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Ingår i: The FEBS Journal. - : John Wiley & Sons. - 1742-464X .- 1742-4658. ; 289:23, s. 7399-7410
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Tidskriftsartikel (refereegranskat)abstract
- ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.
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| 9. |
- Park, Gina J., et al.
(författare)
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The mechanism of RNA capping by SARS-CoV-2
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 609:7928, s. 793-800
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Tidskriftsartikel (refereegranskat)abstract
- The RNA genome of SARS-CoV-2 contains a 5′ cap that facilitates the translation of viral proteins, protection from exonucleases and evasion of the host immune response1–4. How this cap is made in SARS-CoV-2 is not completely understood. Here we reconstitute the N7- and 2′-O-methylated SARS-CoV-2 RNA cap (7MeGpppA2′-O-Me) using virally encoded non-structural proteins (nsps). We show that the kinase-like nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain5 of nsp12 transfers the RNA to the amino terminus of nsp9, forming a covalent RNA–protein intermediate (a process termed RNAylation). Subsequently, the NiRAN domain transfers the RNA to GDP, forming the core cap structure GpppA-RNA. The nsp146 and nsp167 methyltransferases then add methyl groups to form functional cap structures. Structural analyses of the replication–transcription complex bound to nsp9 identified key interactions that mediate the capping reaction. Furthermore, we demonstrate in a reverse genetics system8 that the N terminus of nsp9 and the kinase-like active-site residues in the NiRAN domain are required for successful SARS-CoV-2 replication. Collectively, our results reveal an unconventional mechanism by which SARS-CoV-2 caps its RNA genome, thus exposing a new target in the development of antivirals to treat COVID-19.
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| 10. |
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