The Blood Proteoform Atlas: A reference map of proteoforms in human hematopoietic cells
Open accessAbstract
Human biology is tightly linked to proteins, yet most measurements do not precisely determine alternatively spliced sequences or posttranslational modifications. Here, we present the primary structures of ~30,000 unique proteoforms, nearly 10 times more than in previous studies, expressed from 1690 human genes across 21 cell types and plasma from human blood and bone marrow. The results, compiled in the Blood Proteoform Atlas (BPA), indicate that proteoforms better describe protein-level biology and are more specific indicators of differentiation than their corresponding proteins, which are more broadly expressed across cell types. We demonstrate the potential for clinical application, by interrogating the BPA in the context of liver transplantation and identifying cell and proteoform signatures that distinguish normal graft function from acute rejection and other causes of graft dysfunction.
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- Findingcitation
The count of experimentally determined proteoforms was about ten times higher than in earlier reports.
“The number of experimentally determined proteoforms exceeded that of previous reports by ~10-fold (16)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Tran JC, Nature 480, 254– 258 (2011). 22037311 PMC3237778 source
Not checked in the free run.
- Findingown data
Uniqueness was significantly more pronounced at the proteoform level than at the protein level (χ2(21)=0.519, P=4.73×10−14).
“which shows that uniqueness is significantly more pronounced with proteoform-level information [χ2(21) = 0.519, P = 4.73 × 10−14].”
Quote in the paperSubstantial claim - Findingcitation
A proteogenomic database built from the HBA contained 50,177 protein sequences and 95,979 transcripts reconstructed from RNA-seq data for 19 cell types.
“From the HBA, we generated a proteogenomic database with 50,177 protein sequences, corresponding to 95,979 transcripts reconstructed from RNA sequencing (RNA-seq) data for 19 cell types (table S3) (7).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Uhlen M, Science 366, eaax9198 (2019).31857451 source
Not checked in the free run.
- Findingown data
Most proteins (81%) appeared in two or more cell types.
“The histogram in Fig. 2C shows that most proteins are shared between two or more cell types (81%).”
Quote in the paperSubstantial claim - Findingown data
Protein-level and proteoform-level data both grouped differentiated cell types along the main branches of hematopoiesis with the same confidence in t-SNE analysis.
“Both protein and proteoform data clustered differentiated cell types along primary branches of hematopoiesis at the same level of confidence upon t-SNE analysis.”
Quote in the paperSubstantial claim
- Findingown data
Most proteoforms (58%) were found in only one cell type.
“In contrast, the majority of proteoforms (58%) were identified in only one cell type (Fig. 2D)”
Quote in the paperSubstantial claim - Findingown data
The clustering distance for proteoforms was an order of magnitude larger than that for proteins.
“The high number of unique proteoforms per cell type is evident, and the clustering distance for proteoforms is one order of magnitude higher than for proteins.”
Quote in the paperSubstantial claim - Findingown data
The protein accumulation curve showed that about 80% of possible protein identifications were made from the analyzed cell types with current workflows.
“However, the accumulation curve for proteins shows that ~80% of possible protein identifications (fig. S3) were made from the analyzed cell types using current workflows.”
Quote in the paperSubstantial claim - Findingown data
When 12 cell types shared between BPA and HBA were searched, the HBA database yielded slightly fewer proteins and proteoforms (801 proteins, 4,344 proteoforms) than the UniProtKB/Swiss-Prot database (887 proteins, 4,993 proteoforms).
“Searching 12 cell types shared between the BPA and the HBA, we identified slightly fewer proteins and proteoforms using the HBA database search (801 proteins and 4344 proteoforms; table S4) than with the human UniProtKB/Swiss-Prot database (887 proteins and 4993 proteoforms; table S5).”
Quote in the paperSubstantial claim - Findingown data
In the BPA, each protein corresponded on average to 17.5 proteoforms.
“For the BPA, the average number of proteoforms arising from each “protein” (i.e., proteoform hits mapped back to their corresponding human gene) was 17.5.”
Quote in the paperNot a substantial claim - Findingown data
Fifteen proteoforms were significantly increased in non-AR.
“On the other hand, 15 proteoforms were significantly increased in non-AR (table S10).”
Quote in the paperSubstantial claim - Findingown data
The expression heatmap separated the two cell groups by more than 66% of the total clustering distance.
“The same pattern is observed in the expression heatmap generated from the standardized intensities scores (Fig. 3C), separating the two cell groups by >66% of the total clustering distance.”
Quote in the paperNot a substantial claim - Findingown data
In a validation cohort of 59 patient PBMCs (TX=36, ADNR=10, AR=13), statistical analysis confirmed significantly up-regulated proteoforms in the TX or non-AR groups.
“Statistical analysis comparing AR and non-AR or TX and non-TX populations confirmed significantly up-regulated proteoforms from the TX or non-AR groups (Fig. 4, F and G, and table S10).”
Quote in the paperSubstantial claim - Findingcitation
Commonly enriched pathways between groups included T cell activation and graft migration, including RHO GTPase effectors.
“Between the groups, we found some commonly enriched pathways involved in T cell activation and graft migration, including RHO GTPase effectors (36).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] El Masri R, Delon J, Nat. Rev. Immunol. 21, 499– 513 (2021). 33547421 source
Not checked in the free run.
- Findingown data
TX-specific pathways included regulated exocytosis, platelet degranulation, and cytoskeletal organization.
“TX-specific pathways include regulated exocytosis, platelet degranulation, and cytoskeletal organization.”
Quote in the paperNot a substantial claim - Findingown data
One PF4 proteoform, PFR18631, was observed in six cell types: platelets, plasma, B cells, T cells, and HSCs.
“Consistent with a narrower distribution of proteoforms, one proteoform of PF4, PFR18631, was observed in six cell types (platelets, plasma, B cells, T cells, and HSCs).”
Quote in the paperNot a substantial claim - Findingown data
Proteoform PFR1464 from thymosin beta-4 was about 10-fold higher in naïve B cells than in memory B cells.
“The proteoform PFR1464 from thymosin beta-4 (Fig. 3F) was elevated by ~10-fold in naïve B cells relative to memory cells”
Quote in the paperNot a substantial claim - Findingown data
In 75 liver transplant recipients, untargeted quantitative TDP of PBMC lysates identified 198 differentially expressed proteoforms from 99 proteins.
“We identified a total of 198 differentially expressed proteoforms (DEPs) from 99 proteins (Fig. 4, C and D)”
Quote in the paperSubstantial claim - Findingown data
Proteoform PFR1215 from S100A was higher in memory B cells than in naïve B cells.
“whereas proteoform PFR1215 from the protein S100A (Fig. 3G) was increased in memory relative to naïve B cells.”
Quote in the paperNot a substantial claim - Findingown data
By mapping about 57,000 redundant proteoforms in human blood, bone marrow, plasma, and major hematopoietic cell types, the study advanced fundamental knowledge of human protein components.
“By mapping ~57,000 redundant proteoforms present in human blood, bone marrow, plasma, and within main hematopoietic cell types, we have advanced fundamental knowledge of protein components present in the human body.”
Quote in the paperSubstantial claim - Interpretationown data
The results indicate that proteoforms are better cell-type markers than protein-level assignments alone.
“These results indicate that proteoforms are better markers of a cell type than monitoring gene expression using just protein-level assignments.”
Quote in the paperSubstantial claim - Interpretationown data
Without cell type-specific RNA splicing information, a few abundant isoforms are missed.
“However, a few abundant isoforms are missed without cell type–specific RNA splicing information.”
Quote in the paperSubstantial claim - Interpretationown data
Many proteins or proteoforms were shared by bone marrow cells or by their mature blood forms, indicating that these cell types are distinct.
“Many proteins or proteoforms are shared by cells from the bone marrow or between their mature forms in the blood, indicating that these cell types are distinct (Fig. 3, A and B).”
Quote in the paperSubstantial claim - Interpretationreasoning
The study likely accounts for at most about 3% of human proteoforms from 1 to 59 kDa.
“Hence, this study likely accounts for at most ~3% of human proteoforms distributed from 1 to 59 kDa (fig. S3)”
Quote in the paperSubstantial claim - Interpretationown data
Modeling suggests that saturating primary hematopoietic cells would reveal more than 50,000 additional proteoforms in the 1-59 kDa size range.
“This modeling indicates that saturation of primary hematopoietic cells would uncover >50,000 additional proteoforms in this size regime.”
Quote in the paperSubstantial claim - Study design and conductown data
Quantitative results were consistent between spectral counting and intact proteoform quantification.
“Quantitative results were consistent using spectral counting and intact proteoform quantification methods in both cases.”
Quote in the paperNot a substantial claim - Interpretationown data
The small-cohort results suggest that clinically relevant immunoproteoforms are present in select blood cell populations.
“and (ii) clinically relevant immunoproteoforms are present in select blood cell populations.”
Quote in the paperSubstantial claim - Premisecitation
Acute rejection results from an imbalance of immune activation from cellular and humoral antidonor responses over immune quiescence suppressor mechanisms.
“AR arises from an imbalance of immune activation (IA) related to cellular and humoral antidonor responses (e.g., effector CD4+, cytotoxic CD8+ T cells, and donor-specific antibodies) over immune quiescence (IQ) suppressor countermechanisms (e.g., regulatory T cells) (27–30).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [27] Moreau A, Varey E, Anegon I, Cuturi MC, Cold Spring Harb. Perspect. Med. 3, a015461 (2013). 24186491 PMC3808773 source
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- cites [28] Ronca V, Wootton G, Milani C, Cain O, Front. Immunol. 11, 2155 (2020). 32983177 PMC7492390 source
Not checked in the free run.
- cites [29] Pons JA, Transplantation 86, 1370– 1378 (2008). 19034005 source
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- cites [30] Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G, Front. Immunol. 10, 43 (2019). 30804926 PMC6371029 source
Not checked in the free run.
- Interpretationnone given
The study provided cell- and proteoform-specific information in organ transplantation as a potential clinical application.
“Here, both cell- and proteoform-specific information in the context of organ transplantation were provided as a potential clinical application.”
Quote in the paperNot a substantial claim - Interpretationcitation
A reference map of human proteoforms can serve at the protein level a role similar to single-cell RNA-seq at the transcript level for understanding spatial and temporal protein dynamics in human tissue.
“A reference map of human proteoforms can serve a similar function at the protein level as we seek to understand the spatial and temporal dynamics of proteins operative in human tissue (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] HuBMAP Consortium, Nature 574, 187– 192 (2019). 31597973 PMC6800388 source
Not checked in the free run.
- Interpretationown data
The small-cohort results suggest that leukocyte proteoform levels might have diagnostic value for immune activation versus immune quiescence in liver transplantation.
“The results from this small cohort suggest that in the clinical context of liver transplantation (i) leukocyte proteoform levels might have diagnostic value for IA versus IQ”
Quote in the paperSubstantial claim- Rests on an assumption: The balance between immune activation and immune quiescence that relates to acute rejection risk is difficult to determine in liver transplant recipients without objective markers.
- May combine two claims. 38
- Classified as probably not a substantial claim. 8
May combine two claims.
Findingown dataAcross 21 blood and bone marrow cell types plus plasma, the authors cataloged 29,620 distinct proteoforms and 1,690 proteins.
“Table 1 captures a total of 29,620 nonredundant proteoforms and 1690 proteins (i.e., specific genes assigned from proteoform spectral matches) across 21 different human hematopoietic cell types and plasma.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe BPA covers 8.3% of the total human proteome (20,395 genes) and 16% of the predicted sub-30 kDa proteome in UniProtKB/Swiss-Prot.
“The BPA currently provides 8.3% coverage (fig. S3) of the total human proteome (20,395 genes) and 16% of the predicted proteome <30 kDa in UniProtKB/Swiss-Prot.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA proteoform was found in an average of 2.19 cell types, while a protein was found in an average of 6.51.
“The average number of cell types in which a proteoform was found was 2.19, whereas for proteins it was 6.51.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe mean number of nonredundant proteoforms per cell type was 1,346, compared with 76 for proteins.
“The mean number of identified nonredundant proteoforms per cell type was 1346, compared with only 76 for proteins (more statistical measures are presented in table S7).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong the discovered proteoforms, lysine acetylation and C- or N-terminal cleavage were the most frequent modifications, while coding polymorphisms and alternative splicing were less common.
“Many proteoforms discovered have posttranslational modifications; lysine acetylation (32.9%) and C- and N-terminal cleavage (30.6%) are the two most common, with coding polymorphisms (7.6%) or alternative splicing (3.8%) being minority occurrences”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenAbout 93% of identified proteoforms were smaller than 20 kDa, even though the GELFrEE fractions analyzed contained proteins up to 50 kDa.
“Despite the accelerating pace of development for TDP, most identified proteoforms (~93%) are <20 kDa, even analyzing GELFrEE fractions containing proteins up to 50 kDa.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn t-SNE analysis, antigen-presenting cells separated from lymphoid lineage cells; lymphoid cells clustered together; and three pre-B cell types from bone marrow formed a distinct cluster.
“The cluster of antigen-presenting cells (monocytes, macrophages, and dendritic cells) was separated from lymphoid lineage cells [T cells, B cells, and natural killer (NK) cells]. Additionally, the lymphoid lineage clustered together, and the three pre-B cell types from bone marrow formed a distinct cluster (Fig. 2, A and B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMost proteoforms found with the HBA database were also in UniProtKB/Swiss-Prot (82.7%); 2.2% (114) were HBA-only, and 49 (0.96%) were newly identified proteoforms confidently assigned to transcript isoform or sequence variation.
“Most proteoforms observed with the HBA database were shared with the UniProtKB/ Swiss-Prot database (82.7%), while 2.2% (114) of proteoforms were only in the HBA database (fig. S2), and of these, 49 (0.96%) represented newly identified proteoforms that are confidently assigned to being derived from transcript isoform or sequence variation (table S6).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe proteoform collector's curve did not plateau, with only about 37% of projected proteoforms identified.
“In contrast, the collector’s curve for proteoforms did not reach a plateau (fig. S3), with just ~37% of projected proteoforms identified.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAcross all BPA cell types, PFR1464 was more abundant in naïve B cells, while PFR1215 was more widely observed across cell types.
“Expanding this comparison to all cell types in the BPA, we observe that PFR1464 is more abundant in naïve B cells, whereas PFR1215 is more widely observed in different cell types (Fig. 3H).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingcitationAll panel proteoforms were identified in T cells, 23 in B cells, and 22 in NK cells.
“All proteoforms from the panel were identified in T cells, 23 in B cells, and 22 in NK cells–collectively the most abundant PBMC types (41).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Kleiveland CR, in The Impact of Food Bioactives on Health: In Vitro and Ex Vivo Models, Verhoeckx K, Eds. (Springer, 2015), pp. 161– 167. 29787039
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Findingown dataHBA transcriptome data showed high CAVIN2 expression in PBMCs, supporting the results.
“Moreover, transcriptome data from the HBA point to the CAVIN2 gene as highly expressed in PBMCs, supporting the results.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThree proteoform clusters were observed: one up-regulated in naïve and memory B cells, one up-regulated in pre-B cells, and one with a random regulation pattern.
“Three clusters of proteoforms were observed: (i) those up-regulated in naïve and memory B cells, (ii) those up-regulated in pre-B cells, and (iii) those with a random regulation pattern.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPFR1215 was low in naïve B cells and high in pre-B and memory B cells.
“Exploring the presence of these two proteoforms in the five B cell subtypes showed that PFR1215 is present at low levels in naïve B cells and at high levels in pre-B cells and memory B cells (Fig. 3E).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPFR1464 was mainly present in naïve B cells and low in pre-B cells.
“PFR1464 is present mainly in naïve B cells and has low levels in pre-B cells (Fig. 3E).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataProteoforms related to ACTB, PFN1, and PF4 were statistically significant in TX and non-AR groups, supporting the discovery-stage experiments.
“Proteoforms related to ACTB, PFN1, and PF4 were statistically significant in TX and non-AR groups, supporting the discovery-stage experiments.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe three non-AR proteoforms with higher q values were CAVIN2 positions 297-343 (PFR70141), HMGB1 positions 107-214 (PFR69103), and canonical N-terminally acetylated PFN1 (PFR1439).
“The three proteoforms with the higher q values were a piece of serum deprivation-response protein (CAVIN2) from amino acid positions 297 to 343, PFR70141; a C-terminal portion of high mobility group protein B1 (HMGB1) from amino acid positions 107 to 214, PFR69103; and the canonical sequence of profilin-1 (PFN1) N-terminally acetylated, PFR1439.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe TX-up-regulated proteoforms were PF4 N-terminally truncated with five extra amino acids (PFR18631), canonical HMGN2 (PFR1006), and a C-terminal ACTB fragment from positions 330 to 375 (PFR69028).
“The proteoforms differentially regulated in TX were platelet factor 4 (PF4) N-terminally truncated with five extra amino acids, PFR18631; nonhistone chromosomal protein HMG-17 (HMGN2) canonical sequence, PFR1006; and a C terminus part of cytoplasmic actin 1 (ACTB) from amino acid positions 330 to 375, PFR69028.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA second PF4 proteoform, PFR18628, was identified in 11 cell types, and its protein P02776 in 15 cell types.
“A second proteoform, PFR18628, was identified in 11 cell types, and the corresponding protein (P02776) in 15 different cell types.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMost panel proteoforms had a narrower cell-type distribution than their proteins; for example, PFR70141 from CAVIN2 was only in NK, naïve B, B, and T cells, while protein O95810 was also in platelets, PBMCs, and HSCs.
“Most proteoforms are found in a narrower range of cell types; for example, PFR70141 from the CAVIN2 gene was only identified in NK cells, naïve B cells, B cells, and T cells, while at the protein level (O95810) it was additionally observed in platelets, PBMCs, and hematopoietic stem cells (HSCs).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong mature B cells, 10 proteoforms had higher relative abundance in naïve B cells and 50 were elevated in memory B cells.
“A closer look into the differentially regulated proteoforms from the mature B cells showed 10 proteoforms with increased relative abundance in naïve B cells, with 50 elevated in memory B cells (Fig. 3D).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingcitationPFR18631 has four extra N-terminal amino acids (FASA) compared with PFR18628, which maps to the canonical UniProtKB/Swiss-Prot isoform and was not differentially expressed.
“This proteo form has four extra amino acids (FASA) on the N terminus compared with PFR18628, which maps to the canonical isoform in UniProtKB/UniprotKB/Swiss-prot (42) and was not differentially expressed.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Gupta SK, Hassel T, Singh JP, Proc. Natl. Acad. Sci. U.S.A 92, 7799– 7803 (1995). 7644496 PMC41233 source
Not checked in the free run.
May combine two claims.
Findingown dataPF4 had two proteoforms in the 24-proteoform panel, and only PFR18631 was 1.9-fold up-regulated in TX versus non-TX.
“Notably, the protein PF4 had two proteoforms in the 24 proteoform panel, and only PFR18631 was 1.9-fold up-regulated in the TX group compared with the non-TX group.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe results suggest that RNA splicing generates only a small number of newly detectable proteoforms below 30 kDa, and these come from an average of four introns.
“These results indicate that RNA splicing produces only a handful of new detectable proteoforms <30 kDa, which are expressed from an average of just four introns.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe estimated number of proteoforms in a human cell type was about 1.1 million, close to an earlier estimate.
“From this, we estimated the number of proteoforms to be ~1.1 million in a human cell type, close to a previous estimation (22).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Aebersold R, Nat. Chem. Biol. 14, 206– 214 (2018). 29443976 PMC5837046 source
Not checked in the free run.
May combine two claims.
Interpretationown dataFive panel proteoforms were identified in red blood cells, neutrophils, and plasma, suggesting nonspecific cell proteoforms.
“Five were identified in red blood cells (RBCs), neutrophils, and plasma, suggesting nonspecific cell proteoforms.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationHuman biology is closely tied to proteins, and mass spectrometry-based proteomics has linked phenotype to protein-level biology.
“Human biology is tightly linked to proteins, and mass spectrometry-based proteomics has established a strong linkage between phenotype and protein-level biology (1, 2).”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationProtein isoforms differ by cell type.
“Protein isoforms vary by cell type (11, 12).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationMeasuring proteoforms can fill these gaps by capturing the full molecular composition of proteins and refining phenotypic correlations.
“Measurement of proteoforms (8) can close these gaps by capturing the complete molecular composition of proteins, refining phenotypic correlations.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Smith LM, Kelleher NL; Consortium for Top Down Proteomics, Nat. Methods 10, 186– 187 (2013). 23443629 PMC4114032 source
Not checked in the free run.
May combine two claims.
PremisecitationTop-down proteomics avoids inferring proteins from shotgun peptide data and provides cell- and proteoform-specific information.
“In this study, we used top-down proteomics (TDP) (16), which avoids the problem of inferring proteins using peptide data from shotgun proteomics analysis (17), to obtain cell- and proteoform-specific information (18) from the major cell types present in the blood and bone marrow.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16] Tran JC, Nature 480, 254– 258 (2011). 22037311 PMC3237778 source
Not checked in the free run.
- cites [17] Nesvizhskii AI, Aebersold R, Mol. Cell. Proteomics 4, 1419– 1440 (2005). 16009968 source
Not checked in the free run.
- cites [18] Smith LM, Kelleher NL, Science 359, 1106– 1107 (2018). 29590032 PMC5944612 source
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May combine two claims.
PremisecitationLiver transplantation is an area of unmet need, and acute rejection episodes limit survival.
“One area of unmet need is organ transplantation, in particular liver transplantation (LT), where episodes of acute rejection (AR) limit survival (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Levitsky J, Clin. Gastroenterol. Hepatol. 15, 584– 593.e2 (2017). 27567694 PMC5326609 source
Not checked in the free run.
May combine two claims.
PremisecitationTop-down proteomics still has limitations in protein separation and coverage of large proteoforms above 30 kDa.
“In the past decade, TDP has gained momentum, but limitations in protein separation and coverage of large proteoforms (>30 kDa) are still present (19).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Brown KA, Melby JA, Roberts DS, Ge Y, Expert Rev. Proteomics 17, 719– 733 (2020). 33232185 PMC7864889 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationreasoningThis cellular and molecular specificity can help advance protein-level diagnostics and broader understanding of human biology.
“This cellular and molecular specificity can help advance the future of protein-level diagnostics and broader goals for understanding human biology.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningPrior datasets miss posttranscriptional and posttranslational processing and the way mRNA splicing combines with modifications to generate protein-level diversity.
“However, these datasets do not capture posttranscriptional and posttranslational processing or how mRNA splicing combines with modifications to create protein-level diversity.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductcitationA conservative 1% global false discovery rate was applied at the protein and proteoform levels.
“with a consistent proportion (34%) of them yielding a hit using a conservative 1% global false discovery rate (FDR) at the protein and proteoform levels (20)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] LeDuc RD, Mol. Cell. Proteomics 18, 796– 805 (2019). 30647073 PMC6442365 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe absence of biopsies in TX was a limitation, but transplant centers generally do not perform surveillance biopsies in liver transplant recipients with healthy graft function.
“The absence of biopsies in TX was a limitation; however, transplant centers do not generally perform surveillance biopsies in LTR with healthy graft function.”
Quote in the paperNot a substantial claim- Rests on an assumption: Transplant centers generally do not perform surveillance biopsies in liver transplant recipients with healthy graft function.
May combine two claims.
PremisecitationPF4 expression is reduced in humans and mice with acute liver injury and inhibits ischemia-reperfusion injury in liver transplantation mouse models.
“PF4 expression is reduced in humans and mice with acute liver injury and inhibits ischemia-reperfusion injury in LT mouse models (43, 44).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationThe number of AR subjects was small but reflects the approximately 20% prevalence of AR in liver transplant recipients.
“We note that the number of AR subjects is small but reflects the ~20% prevalence of AR in LTR (26, 38–40).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [26] Levitsky J, Clin. Gastroenterol. Hepatol. 15, 584– 593.e2 (2017). 27567694 PMC5326609 source
Not checked in the free run.
- cites [38] Ramji A, Liver Transpl. 8, 945– 951 (2002). 12360439 source
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- cites [39] Uemura T, Clin. Transplant. 22, 316– 323 (2008). 18190550 source
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- cites [40] Thurairajah PH, Transplantation 95, 955– 959 (2013). 23442806 source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPFN1 participates in actin organization and inhibits CD8+ cytotoxicity by reducing migration and degranulation.
“PFN1 is involved in actin organization, which inhibits CD8+ cytotoxicity by reducing migration and degranulation (45).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Schoppmeyer R, Eur. J. Immunol. 47, 1562– 1572 (2017). 28688208 source
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Study design and conductcitationAR and ADNR phenotypes were diagnosed by needle biopsy, and TX by clinical and laboratory criteria, as previously described.
“The AR and ADNR phenotypes were diagnosed by needle biopsy, and TX by clinical and laboratory criteria, as previously described (31–34).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [31] Toby TK, Am. J. Transplant. 17, 2458– 2467 (2017). 28510335 PMC5612406 source
Not checked in the free run.
- cites [32] Levitsky J, Am. J. Transplant. 20, 2173– 2183 (2020). 32356368 PMC7496674 source
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- cites [33] Levitsky J, Transplantation 10.1097/TP.0000000000003895 (2021). source
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- cites [34] Levitsky J, Am. J. Transplant ajt.16835 (2021).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
The balance between immune activation and immune quiescence that relates to acute rejection risk is difficult to determine in liver transplant recipients without objective markers.
“This key balance of IA versus IQ relating to AR risk is, however, difficult to determine without available objective markers in LT recipients (LTRs).”
The paper relies on this without support.
Transplant centers generally do not perform surveillance biopsies in liver transplant recipients with healthy graft function.
“however, transplant centers do not generally perform surveillance biopsies in LTR with healthy graft function.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The Blood Proteoform Atlas is a reference map of proteoforms in 21 cell types in human blood and bone marrow.
“A recent landmark study introduced the Blood Proteoform Atlas, a reference map of proteoforms in 21 cell types in human blood and bone marrow (133).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [133]
Proteoforms have higher cell type specificity than protein-level measurements.
“This platform has uncovered that proteoforms have higher cell type specificity than protein-level measurements, laying the groundwork for possible dissection of the different arms of the inflammatory response.”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [133]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
PF4 proteoform has conflicting counts of extra amino acids
MinorPFR18631 is described as having five extra amino acids, but later as having four extra amino acids relative to PFR18628, which is identified as the canonical isoform.
“platelet factor 4 (PF4) N-terminally truncated with five extra amino acids, PFR18631”
“This proteo form has four extra amino acids (FASA) on the N terminus compared with PFR18628, which maps to the canonical isoform”
PF4 cell-type count does not match the list
MinorThe sentence says PFR18631 was observed in six cell types but names only five: platelets, plasma, B cells, T cells, and HSCs.
“PFR18631, was observed in six cell types”
“(platelets, plasma, B cells, T cells, and HSCs)”
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Self-citationTop-Down Proteomics Enables Comparative Analysis of Brain Proteoforms Between Mouse Strains
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Self-citationPlatelet Factor 4 Attenuates Experimental Acute Liver Injury in Mice
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Unbiased spatial proteomics with single-cell resolution in tissues
Mund, A., Brunner, A.-D., & Mann, M. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.05.022 · Cited by 259 · see citing works
Connecting aging biology and inflammation in the omics era
Walker, K. A., Basisty, N., Wilson, D. M., & Ferrucci, L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158448 · Cited by 189 · see citing works
- Authors
- Melani, R. D., Gerbasi, V. R., Anderson, L. C., Sikora, J. W., Toby, T. K., Hutton, J. E., Butcher, D. S., Negrão, F., Seckler, H. S., Srzentić, K., Fornelli, L., Camarillo, J. M., LeDuc, R. D., Cesnik, A. J., Lundberg, E., Greer, J. B., Fellers, R. T., Robey, M. T., DeHart, C. J., Forte, E., Hendrickson, C. L., Abbatiello, S. E., Thomas, P. M., Kokaji, A. I., Levitsky, J., & Kelleher, N. L.
- Affiliations
- Northwestern University (US)
- Florida State University (US)
- Science for Life Laboratory (SE)
- Thermo Fisher Scientific (United States) (US)
- Stemcell Technologies (CA)
- Corresponding author
- Melani, Rafael D.
- Gerbasi, Vincent R.
- Anderson, Lissa C.
- Levitsky, Josh
- Kelleher, Neil L.
- ORCID
- Melani, Rafael D.
- Gerbasi, Vincent R.
- Anderson, Lissa C.
- Sikora, Jacek W.
- Toby, Timothy K.
- Hutton, Josiah E.
- Butcher, David S.
- Negrão, Fernanda
- Seckler, Henrique S.
- Srzentić, Kristina
- Fornelli, Luca
- Camarillo, Jeannie M.
- LeDuc, Richard D.
- Cesnik, Anthony J.
- Lundberg, Emma
- Greer, Joseph B.
- Fellers, Ryan T.
- Robey, Matthew T.
- DeHart, Caroline J.
- Forte, Eleonora
- Hendrickson, Christopher L.
- Abbatiello, Susan E.
- Thomas, Paul M.
- Levitsky, Josh
- Kelleher, Neil L.
- Venue
- Science
- Published
- 2022-01-28
- Volume
- 375
- Issue
- 6579
- Pages
- 411-418
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC9097315
- OpenAlex
- W4210380316
- Cited by
- 140
- References
- 76
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 33 · 2023: 36 · 2022: 23
- FWCI
- 10.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (UH3CA246635)
- National Institute of General Medical Sciences (P41GM108569, T32GM105538)
- National Institute of Allergy and Infectious Diseases (R21AI135827)
- U.S. National Library of Medicine (R21LM013097)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced Biosensing Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- proteoforms, human hematopoietic cells, blood proteome, bone marrow, alternative splicing, post-translational modification, liver transplantation, acute rejection, graft dysfunction, plasma proteome
- MeSH terms
- B-Lymphocytes, Blood Cells, Blood Proteins, Bone Marrow Cells, Humans, Leukocytes, Mononuclear, Plasma, Protein Processing, Post-Translational, T-Lymphocytes, Liver Transplantation, Alternative Splicing, Cell Lineage, Protein Isoforms, Proteome, Databases, Protein, Proteomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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