In-depth human plasma proteome analysis captures tissue proteins and transfer of protein variants across the placenta.
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ABSTRACT:
SUBMITTER: Pernemalm M
PROVIDER: S-EPMC6519984 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
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Project description:Novel method for plasma proteomics and proteogenomics
2019-04-10 | PXD010899 | Pride
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over forty million patients worldwide. Although most coronavirus disease 2019 (COVID-19) patients have a good prognosis, some develop severe illness. Markers that define disease severity or predict clinical outcome need to be urgently developed as the mortality rate in critical cases is approximately 61.5%. In the present study, we performed in-depth proteome profiling of undepleted plasma from eight COVID-19 patients. Quantitative proteomic analysis using the BoxCar method revealed that 91 out of 1222 quantified proteins were differentially expressed depending on the severity of COVID-19. Importantly, we found 76 proteins, previously not reported, which could be novel prognostic biomarker candidates. Our plasma proteome signatures captured the host response to SARS-CoV-2 infection, thereby highlighting the role of neutrophil activation, complement activation, platelet function, and T cell suppression as well as proinflammatory factors upstream and downstream of interleukin-6, interleukin-1B, and tumor necrosis factor. Consequently, this study supports the development of blood biomarkers and potential therapeutic targets to aid clinical decision-making and subsequently improve prognosis of COVID-19.
| S-EPMC7772338 | biostudies-literature
Project description:BackgroundCoronary heart disease (CHD) and stroke were key outcomes in the Women's Health Initiative (WHI) randomized trials of postmenopausal estrogen and estrogen plus progestin therapy. We recently reported a large number of changes in blood protein concentrations in the first year following randomization in these trials using an in-depth quantitative proteomics approach. However, even though many affected proteins are in pathways relevant to the observed clinical effects, the relationships of these proteins to CHD and stroke risk among postmenopausal women remains substantially unknown.MethodsThe same in-depth proteomics platform was applied to plasma samples, obtained at enrollment in the WHI Observational Study, from 800 women who developed CHD and 800 women who developed stroke during cohort follow-up, and from 1-1 matched controls. A plasma pooling strategy, followed by extensive fractionation prior to mass spectrometry, was used to identify proteins related to disease incidence, and the overlap of these proteins with those affected by hormone therapy was examined. Replication studies, using enzyme-linked-immunosorbent assay (ELISA), were carried out in the WHI hormone therapy trial cohorts.ResultsCase versus control concentration differences were suggested for 37 proteins (nominal P < 0.05) for CHD, with three proteins, beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), and insulin-like growth factor binding protein acid labile subunit (IGFALS) having a false discovery rate < 0.05. Corresponding numbers for stroke were 47 proteins with nominal P < 0.05, three of which, apolipoprotein A-II precursor (APOA2), peptidyl-prolyl isomerase A (PPIA), and insulin-like growth factor binding protein 4 (IGFBP4), have a false discovery rate < 0.05. Other proteins involved in insulin-like growth factor signaling were also highly ranked. The associations of B2M with CHD (P < 0.001) and IGFBP4 with stroke (P = 0.005) were confirmed using ELISA in replication studies, and changes in these proteins following the initiation of hormone therapy use were shown to have potential to help explain hormone therapy effects on those diseases.ConclusionsIn-depth proteomic discovery analysis of prediagnostic plasma samples identified B2M and IGFBP4 as risk markers for CHD and stroke respectively, and provided a number of candidate markers of disease risk and candidate mediators of hormone therapy effects on CHD and stroke.Clinical trials registrationClinicalTrials.gov identifier: NCT00000611.
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Project description:Environmental DNA (eDNA) metabarcoding is an increasingly important tool for surveying biodiversity in marine ecosystems. However, the scale of temporal and spatial variability in eDNA signatures, and how this variation may impact eDNA-based marine biodiversity assessments, remains uncertain. To address this question, we systematically examined variation in vertebrate eDNA signatures across depth (0 m to 10 m) and horizontal space (nearshore kelp forest and surf zone) over three successive days in Southern California. Across a broad range of teleost fish and elasmobranchs, results showed significant variation in species richness and community assemblages between surface and depth, reflecting microhabitat depth preferences of common Southern California nearshore rocky reef taxa. Community assemblages between nearshore and surf zone sampling stations at the same depth also differed significantly, consistent with known habitat preferences. Additionally, assemblages also varied across three sampling days, but 69% of habitat preferences remained consistent. Results highlight the sensitivity of eDNA in capturing fine-scale vertical, horizontal, and temporal variation in marine vertebrate communities, demonstrating the ability of eDNA to capture a highly localized snapshot of marine biodiversity in dynamic coastal environments.
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Project description:The human placenta is a difficult tissue to work with using proteomic technology since it contains large amounts of lipids and glycogen. Both lipids and glycogen are known to interfere with the first step in the two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), the isoelectric focusing. In order to gain the best possible protein separation on 2D-PAGE, an optimized sample preparation protocol for placental proteins was developed. Two different buffers, urea/CHAPS and Hepes, were used for solubilization in combination with six different precipitation methods. The removal of glycogen from the samples by centrifugation was crucial for the final proteome maps. Solubilization with urea/CHAPS in combination with dichloromethane/methanol or acidified acetone proved to be the best precipitation procedures. When applied to clinical placenta samples apolipoprotein A1 was found to be accumulated in the preeclamptic placenta, where it may either have a nutritional effect or act as a modifier of signal transduction.
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Project description:Genetic variants influencing the transcriptome have been extensively studied. However, the impact of the genetic factors on the human proteome is largely unexplored, mainly due to lack of suitable high-throughput methods. Here we present unique and comprehensive identification of genetic variants affecting the human plasma protein profile by combining high-throughput and high-resolution mass spectrometry (MS) with genome-wide SNP data. We identified and quantified the abundance of 1,056 tryptic-digested peptides, representing 163 proteins in the plasma of 1,060 individuals from two population-based cohorts. The abundance level of almost one-fifth (19%) of the peptides was found to be heritable, with heritability ranging from 0.08 to 0.43. The levels of 60 peptides from 25 proteins, 15% of the proteins studied, were influenced by cis-acting SNPs. We identified and replicated individual cis-acting SNPs (combined P value ranging from 3.1 × 10(-52) to 2.9 × 10(-12)) influencing 11 peptides from 5 individual proteins. These SNPs represent both regulatory SNPs and nonsynonymous changes defining well-studied disease alleles such as the ε4 allele of apolipoprotein E (APOE), which has been shown to increase risk of Alzheimer's disease. Our results show that high-throughput mass spectrometry represents a promising method for large-scale characterization of the human proteome, allowing for both quantification and sequencing of individual proteins. Abundance and peptide composition of a protein plays an important role in the etiology, diagnosis, and treatment of a number of diseases. A better understanding of the genetic impact on the plasma proteome is therefore important for evaluating potential biomarkers and therapeutic agents for common diseases.
| S-EPMC3606982 | biostudies-literature
Project description:Craniopharyngiomas are rare epithelial tumors derived from pituitary gland embryonic tissue. This epithelial tumor can be categorized as an adamantinomatous craniopharyngioma (ACP) or papillary craniopharyngioma (PCP) subtype with histopathological and genetic differences. Genomic and transcriptomic profiles of craniopharyngiomas have been investigated; however, the proteomic profile has yet to be elucidated and added to these profiles. Recent improvements in high-throughput quantitative proteomic approaches have introduced new opportunities for a better understanding of these diseases and the efficient discovery of biomarkers. We aimed to confirm subtype-associated proteomic changes between ACP and PCP specimens. We performed a system-level proteomic study using an integrated approach that combines mass spectrometry-based quantitative proteomic, statistical, and bioinformatics analyses. The bioinformatics analysis showed that differentially expressed proteins between ACP and PCP were significantly involved in mitochondrial organization, fatty acid metabolic processes, exocytosis, the inflammatory response, the cell cycle, RNA splicing, cell migration, and neuron development. Furthermore, using network analysis, we identified hub proteins that were positively correlated with ACP and PCP phenotypes. Our findings improve our understanding of the pathogenesis of craniopharyngiomas and provide novel insights that may ultimately translate to the development of craniopharyngioma subtype-specific therapeutics.
| S-EPMC8551227 | biostudies-literature
Project description:Nanoparticles exposed to biological fluids are rapidly surrounded by proteins. It is known that this formed protein corona influences the interplay of nanoparticles with cells or tissue barriers. In this study, we report the impact of a formed human plasma protein corona on the transfer of 80 nm polystyrene (PS) nanoparticles across the human placenta. We used the human ex-vivo placental perfusion model, as it reflects the intact and physiological tissue barrier between mother and unborn. Our results show an enhanced transfer of polystyrenes, exposed to human plasma, across the placenta compared to bovine serum albumin which served as control setting. We isolated nanoparticles before and after tissue exposure and analyzed their protein corona via shotgun proteomics and LC-MS/MS. The corona profile of particles that crossed the placenta highlighted several proteins as possible drivers for elevated tissue transfer. Subsequently two distinct proteins, human albumin and immunoglobulin G, were selected and incubated with the nanoparticles to form a sole protein corona. Strikingly, the protein corona formed by albumin induced significantly the transfer of polystyrenes across the tissue as compared to corona formed by immunoglobulins. To conclude, our study provides a comparative analysis between different formed protein coronas on nanoparticles and a corona dependent transfer behavior of polystyrenes across placental tissue. Our findings suggest that protein corona analyses of nanoparticles might help to understand better their properties at biological barriers.
2020-08-19 | PXD018160 | Pride
Project description:BackgroundNanoparticles, which are exposed to biological fluids are rapidly interacting with proteins and other biomolecules forming a corona. In addition to dimension, charge and material the distinct protein corona influences the interplay of nanoparticles with tissue barriers. In this study we were focused on the impact of in situ formed human plasma protein corona on the transfer of 80 nm polystyrene nanoparticles (PS-particles) across the human placenta. To study materno-to fetal PS transfer we used the human ex vivo placental perfusion approach, which represents an intact and physiological tissue barrier. To analyze the protein corona of PS particles we performed shotgun proteomics of isolated nanoparticles before and after tissue exposure.ResultsHuman plasma incubated with PS-particles of 80 nm and subsequent formed protein corona enhanced the transfer across the human placenta compared to PS-corona formed by bovine serum albumin and dextran which served as a control. Quantitative and qualitative changes of plasma proteins determined the changes in PS transfer across the barrier. Based on the analysis of the PS-proteome two candidate proteins, namely human albumin and immunoglobulin G were tested if these proteins may account for the enhanced PS-transfer across the placenta. Interestingly, the protein corona formed by human albumin significantly induced the transfer of PS-particles across the tissue compared to the formed IgG-corona.ConclusionIn total we demonstrate the PS corona dynamically and significantly evolves upon crossing the human placenta. Thus, the initial composition of PS particles in the maternal circulation is not predictive for their transfer characteristics and performance once beyond the barrier of the placenta. The precise mechanism of these effects remains to be elucidated but highlights the importance of using well designed biological models when testing nanoparticles for biomedical applications.
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Project description:This study investigated polymorphisms in the milk protein genes CSN1S1, CSN2, CSN1S2, CSN3, LALBA, and LGB, and casein haplotypes in Beninese indigenous cattle. Considering 67 animals, DNA sequencing of the genes' exons, flanking regions and parts of the 5'-upstream regions identified 1058 genetic variants including 731 previously unknown. In addition, four novel milk protein variants were detected, including CSN3K (p.Ala66Val), LALBAF (p.Arg58Trp), LGBB1 (p.Ala134Val) and LGBK (p.Thr92Asnfs*13). CSN3K is caused by a novel SNP (BTA6:85656526C>T, exon 4) whereas LALBAF and LGBB1 are due to rs714688595C>T (exon 1) and rs109625649C>T (exon 4), respectively. Regarding LGBK, a frameshift insertion of one adenine residue at BTA11:103257980 (exon 3) induces a premature translation termination resulting in a 46% reduction of the reference protein sequence. The casein polymorphisms formed five main CSN1S1-CSN2-CSN1S2-CSN3 haplotypes including B-A1-A-B, B-A1-A-A and C-A2-A-B which are predominant in the investigated cattle breeds. Moreover, in silico analyses of polymorphisms within the 5'- and 3'- untranslated regions of all six milk proteins revealed effects on microRNA and transcription factor binding sites. This study suggests a large genetic variation of milk protein genes in Beninese cattle, which should be investigated in further studies for their effects on milk production, including quality and yield traits.
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