Patent Publication Number: US-11662352-B2

Title: Erythrocyte-derived extracellular vesicles and proteins associated with such vesicles as biomarkers for parkinson&#39;s disease

Description:
RELATED APPLICATIONS 
     This application is the U.S. National Stage of International Application No. PCT/CA2018/050150, filed Feb. 9, 2018, which designates the U.S., published in English, and claims the benefit of U.S. Provisional Application No. 62/457,350, filed Feb. 10, 2017. The entire teachings of the above applications are incorporated herein by reference. 
    
    
     BACKGROUND 
     Parkinson&#39;s disease (PD) is one of the most common neurodegenerative disorders affecting millions of people worldwide. Definite diagnosis for PD can only be made postmortem, for instance, by the characteristic accumulation of the protein alpha-synuclein into Lewy body inclusions observed within neurons. Currently, the diagnosis of PD is based on fitting observed symptoms and their severity into clinical rating scales such as the Unified Parkinson&#39;s Disease Rating Scale (UPDRS) or the Hoehn &amp; Yahr scale. Current clinical assessments are subjective, however, and would benefit from improved methods of clinically assessing PD, particularly at early stages of the disease when therapeutic options are likely to be most efficient. 
     SUMMARY 
     The present description relates to Parkinson&#39;s disease. More particularly, the present description relates to extracellular vesicles originating from erythrocytes, and protein biomarkers associated erythrocyte-derived extracellular vesicles, for use in clinically assessing Parkinson&#39;s disease in a subject. 
     The present description relates to the proteomic analysis of erythrocyte-derived extracellular vesicles (EEV) from healthy control subjects, subjects with mild Parkinson&#39;s disease, and subjects with moderate Parkinson&#39;s disease, as well as the identification of protein biomarkers for which expression within EEV was found to be significantly modified therebetween. Accordingly, the present description generally relates to methods of clinically assessing Parkinson&#39;s disease based on the detection and/or quantification of the expression level of one or more protein biomarker(s) within EEV. 
     In some aspects, the present description may relate to one or more of the following items:
         1. An in vitro method for clinically assessing Parkinson&#39;s disease, the method comprising obtaining a preparation of isolated erythrocyte-derived extracellular vesicles (EEV) from a blood sample of a subject having or suspected of having Parkinson&#39;s disease; and determining the expression level(s) of one or more protein biomarker(s) in the preparation of isolated EEV, wherein the one or more protein biomarker(s) comprises: (i) Alpha/beta hydrolase domain-containing protein 14B, if the subject has or is suspected of having mild or moderate Parkinson&#39;s disease; (ii) Alcohol dehydrogenase [NADP(+)], if the subject has or is suspected of having mild Parkinson&#39;s disease; (iii) ATP synthase subunit alpha, mitochondrial, if the subject has or is suspected of having moderate Parkinson&#39;s disease; or (iv) any combination of (i) to (iii), wherein the expression level of one or more of the protein biomarker(s) is indicative of, or correlates with, the subject&#39;s Parkinson&#39;s disease state.   2. An in vitro method for clinically assessing Parkinson&#39;s disease, the method comprising: obtaining a preparation of isolated erythrocyte-derived extracellular vesicles (EEV) from a blood sample of a subject having or suspected of having Parkinson&#39;s disease; and determining the expression level(s) of one or more protein biomarker(s) in the preparation of isolated EEV, wherein the expression level of one or more of the protein biomarker(s) is indicative of, or correlates with, the subject&#39;s Parkinson&#39;s disease state.   3. The method of item 2, wherein the one or more protein biomarker(s) comprises at least one of: (a) Axin interactor, dorsalization-associated protein; (b) Alpha/beta hydrolase domain-containing protein 14B; (c) Glutamine-dependent NAD(+) synthetase; (d) Dihydropteridine reductase; (e) Alcohol dehydrogenase [NADP(+)]; (f) CB1 cannabinoid receptor-interacting protein 1; (g) Ubiquitin carboxyl-terminal hydrolase 24; and (h) ATP synthase subunit alpha, mitochondrial.   4. The method of item 3, wherein the one or more protein biomarkers comprises at least two of (a) to (h).   5. The method of item 3, wherein the one or more protein biomarkers comprises at least three of (a) to (h).   6. The method of item 3, wherein the one or more protein biomarkers comprises at least four of (a) to (h).   7. The method of item 3, wherein the one or more protein biomarkers comprises at least five of (a) to (h).   8. The method of item 3, wherein the one or more protein biomarkers comprises at least six of (a) to (h).   9. The method of item 3, wherein the one or more protein biomarkers comprises at least seven of (a) to (h).   10. The method of any one of items 2 to 9, wherein the one or more protein biomarkers comprises (a).   11. The method of any one of items 2 to 10, wherein the one or more protein biomarkers comprises (b).   12. The method of any one of items 2 to 11, wherein the one or more protein biomarkers comprises (c).   13. The method of any one of items 2 to 12, wherein the one or more protein biomarkers comprises (d).   14. The method of any one of items 2 to 13, wherein the one or more protein biomarkers comprises (e).   15. The method of any one of items 2 to 14, wherein the one or more protein biomarkers comprises (f).   16. The method of any one of items 2 to 15, wherein the one or more protein biomarkers comprises (g).   17. The method of any one of items 2 to 16, wherein the one or more protein biomarkers comprises (h).   18. The method of any one of items 2 to 17, further comprising determining the expression level(s) of one or more of the EEV protein(s) listed in Table 4, wherein the one or more EEV protein(s) does not comprise (a) to (h).   19. The method of any one of items 2 to 18, further comprising normalizing the expression level(s) of the one or more protein biomarker(s) to one or more of the EEV protein(s) as defined in item 18.   20. The method of any one of items 1 to 19, wherein the preparation of isolated EEV is obtained after inducing the calcium-dependent production of EEV from activated erythrocytes in the blood sample of the subject.   21. The method of any one of items 1 to 20, wherein the preparation of isolated erythrocyte-derived extracellular vesicles (EEV) is obtained by separating the EEV by flow cytometry, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, size-exclusion chromatography, ultracentrifugation, magnetic activated cell sorting (MACS), nanoparticle tracking analysis, light scattering, electrophoretic light scattering, dynamic light scattering, electron microscopy, or any combination thereof.   22. The method of any one of items 1 to 21, wherein the EEV are CD235a+ extracellular vesicles.   23. The method of any one of items 1 to 22, wherein the EEV are TSG101+, Rabs+, CD9+, CD63+, CD81+, or any combination thereof.   24. The method of any one of items 1 to 23, wherein the EEV are between about 20 nm and about 1000 nm in diameter.   25. The method of any one of items 1 to 24, wherein said EEV are greater than about 100 nm in diameter.   26. The method of any one of items 1 to 25, further comprising removing hemoglobin from the preparation of isolated EEV prior to determining the expression level(s) of the one or more protein biomarker(s).   27. The method of any one of items 1 to 26, wherein determining the expression level(s) of one or more of the protein biomarker(s) in the preparation of isolated EEV comprises contacting the protein biomarker with an antibody directed against the protein biomarker.   28. The method of any one of items 1 to 27, wherein determining the expression level(s) of one or more of the protein biomarker(s) in the preparation of isolated EEV comprises mass spectrometry.   29. The method of item 28, wherein determining the expression level(s) of one or more of the protein biomarker(s) in the preparation of isolated EEV comprises nano liquid chromatography tandem mass spectrometry (nanoLC-MS/MS).   30. The method of any one of items 1 to 29, wherein clinically assessing Parkinson&#39;s disease comprises diagnosing Parkinson&#39;s disease.   31. The method of any one of items 1 to 30, wherein clinically assessing Parkinson&#39;s disease in the subject comprises staging Parkinson&#39;s disease.   32. The method of any one of items 1 to 31, wherein clinically assessing Parkinson&#39;s disease comprises monitoring the progression of Parkinson&#39;s disease.   33. The method of any one of items 1 to 32, wherein clinically assessing Parkinson&#39;s disease comprises monitoring the effectiveness of treatment of a Parkinson&#39;s disease subject.   34. The method of item 32 or 33, comprising determining the expression level(s) of one or more of the protein biomarker(s) in a preparation of isolated EEV from a further blood sample of the subject obtained at a later point of time.   35. A method for analyzing proteins of erythrocyte-derived extracellular vesicles (EEV), the method comprising: (i) isolating erythrocyte-derived extracellular vesicles (EEV) from a blood sample of a subject and forming an EEV preparation therefrom; (ii) extracting proteins from the EEV preparation; (iii) removing hemoglobin from the EEV preparation to obtain a hemoglobin-free EEV preparation; and (iv) detecting EEV proteins present in the hemoglobin-free EEV preparation.   36. The method of item 35, wherein: step (iii) comprises removing a hemoglobin-containing fraction of proteins from the EEV preparation to obtain a hemoglobin-depleted EEV preparation and a hemoglobin-rich fraction; and step (iv) comprises detecting EEV proteins present in the hemoglobin-free EEV preparation and EEV proteins present in the hemoglobin-rich fraction.   37. The method of item 35 or 36, wherein the EEV proteins detected comprise the protein biomarkers as defined in any one of items 3 to 17.   38. The method of any one of items 35 to 37, wherein the preparation of isolated EEV is obtained after inducing the calcium-dependent production of EEV from activated erythrocytes in the blood sample of the subject.   39. The method of any one of items 35 to 38, wherein the preparation of isolated erythrocyte-derived extracellular vesicles (EEV) is obtained as defined in item 21.   40. The method of any one of items 35 to 39, wherein the EEV are as defined in any one of items 21 to 24.   41. The method of any one of items 35 to 40, wherein the EEV proteins are detected as defined in any one of items 26 to 28.   42. Use of one or more erythrocyte-derived extracellular vesicle (EEV) protein biomarker(s) as defined in any one of items 3 to 17 for clinically assessing Parkinson&#39;s disease in a subject.   43. The use of item 42, wherein the clinical assessment is as defined in any one of items 30 to 33.   44. A method of treating a subject with Parkinson&#39;s disease, the method comprising: (i) clinically assessing the subject according to the method of any one of items 1 to 41; and (ii) beginning or modifying the subject&#39;s Parkinson&#39;s disease treatment based on the clinical assessment in (i).       

     General Definitions 
     Headings, and other identifiers, e.g., (a), (b), (i), (ii), etc., are presented merely for ease of reading the specification and claims. The use of headings or other identifiers in the specification or claims does not necessarily require the steps or elements be performed in alphabetical or numerical order or the order in which they are presented. 
     The use of the word “a” or “an”, when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one” but it is also consistent with the meaning of “one or more”, “at least one”, and “one or more than one”. 
     The term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In general, the terminology “about” is meant to designate a possible variation of up to 10%. Therefore, a variation of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10% of a value is included in the term “about”. Unless indicated otherwise, use of the term “about” before a range applies to both ends of the range. 
     As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, un-recited elements or method steps. 
     Other objects, advantages and features of the present description will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the appended drawings: 
         FIGS.  1 A- 1 F . Optimization of EV detection: controls for flow cytometry.  FIG.  1 A : To properly set the EV gate, fluorescent silica beads of 100 nm (Red), 500 nm (Blue) and 1000 nm (Yellow) were acquired on a flow cytometer Canto II modified with a FSC-PMT small particles option. The EV gate was used throughout the experiments.  FIG.  1 B : Serial dilutions (1, 2, 4 and 10) of erythrocyte-derived EV (EEV) to confirm the linearity of the quantification.  FIG.  1 C : FSC-PMT/SSC gates of platelet-free plasma (PFP) stained with annexin V and respective fluorochrome-conjugated antibodies directed against erythrocyte (CD235a+), endothelial (CD31+/CD41−)/platelets (CD41+) and leukocytes (CD14+CD45+, monocytes; CD15+CD45+, granulocytes)-derived EV. Controls for EV labeling.  FIG.  1 D : Treatment with the ion chelator EDTA inhibited the binding of annexin V to phosphatidylserine.  FIG.  1 E : Minimal background was observed using antibodies in absence of PFP. This background was subtracted from all subsequent EV quantifications.  FIG.  1 F : EV sensitivity to 0.5% Triton™ was assessed. Abbreviations: AnnV, annexin V; FSC PMT-H, forward scatter photomultiplier; PBS, phosphate buffered saline; PFP, platelet free plasma; SSC-H, side scatter. 
         FIGS.  2 A and  2 B . EEV: A biomarker of PD state.  FIG.  2 A  shows the correlations between the number of erythrocyte-derived extracellular vesicles (EEV; expressed as CD235a+ EV/total number of erythrocytes) and the Unified Parkinson&#39;s Disease Rating Scale (UPDRS) of subjects (n=20). Robust correlations between the number of EEV/total number of erythrocytes and UPDRS scores (PD, n=20), displayed a clear split between mild and moderate patients, supporting the potential of EEV as a biomarker for disease state. Additional information on five patients (identified as 1-5) derived from each correlation is provided (number of EEV/total number of erythrocytes and levodopa dose equivalent) to illustrate that levodopa dosing cannot account for differences in EEV counts. Note that patient no. 5, which falls outside the confidence boundary, is the only patient on a regimen of anti-inflammatory drugs to manage arthritis.  FIG.  2 B  shows the results of a similar analysis as in  FIG.  2 A , but performed on Huntington&#39;s disease subjects (n=42) using the Unified Huntington&#39;s Disease Rating Scale (UHDRS). The numbers of EEV are expressed as CD235a+ EV/total number of erythrocytes. No statistically significant correlations were found between the number of EEV/total number of erythrocytes and UHDRS scores. This argues in favor of EEV being a specific biomarker of PD. Distributions were determined using unpaired t-test with Welch&#39;s correction (PD) or one-way ANOVA (HD). Correlations were determined using Pearson&#39;s correlation, *p&lt;0.05. Abbreviations: CD235a, glycophorin A; CTRL, Controls; EEV, erythrocyte-derived extracellular vesicle; EV, extracellular vesicle; HD, Huntington&#39;s disease; LEDD, Levodopa equivalent daily dose; PD, Parkinson&#39;s disease; Pre-HD, Pre-manifest; UHDRS, Unified Huntington&#39;s Disease Rating Scale; UPDRS, Unified Parkinson&#39;s Disease Rating Scale. 
         FIG.  3   . Detection of normal and phosphorylated α-Syn in EEV.  FIG.  3 A : Representative scanning electron microscopy observations of resting and activated erythrocytes (treated with calcium ionophore A23187 to generate EEV) in both PD patients and healthy sex- and age-matched CTRL. Scale bar: 2 μm.  FIG.  3 B : Representative transmission electron microscopy images of immunogold labeling for α-Syn and α-Syn pS129 in activated erythrocytes and EEV (some examples delineated by dotted lines). Arrowheads point to positive immunolabeling for either α-Syn or α-Syn pS129. Scale bar: 100 nm.  FIG.  3 C : Quantification of α-Syn in EEV as detected by transmission electron microscopy and expressed as the percentage of EEVs positive for α-Syn/total number of EEV in healthy sex- and age-matched CTRL and PD patients (n=100 erythrocytes sampled in n=3 CTRL and n=3 PD).  FIG.  3 D : Quantification of α-Syn in EEV by ELISA assay in healthy sex- and age-matched CTRL, mild and moderate stage patients selected according to their H&amp;Y stage (n=4 erythrocytes per group; n=13 EEV per group) revealing the absence of measurable changes in α-Syn levels between PD and healthy sex- and age-matched CTRL. Statistical analyses were performed using a Mann-Whitney U test ( FIG.  3 C ) or a Kruskal-Wallis ANOVA ( FIG.  3 D ). Abbreviations: α-Syn, α-synuclein; α-Syn pS129, α-synuclein phosphorylated Serine 129; CTRL, Control; EEV, erythrocyte-derived extracellular vesicle; H&amp;Y, Hoehn and Yahr; PD, Parkinson&#39;s disease. 
         FIGS.  4 A- 4 D . Specific protein signature of EEV in PD patients.  FIG.  4 A : NanoLC-MS/MS Label-free analysis of EEV in PD patients and healthy age-matched CTRL (PD, n=4; CTRL, n=4) revealed a total of 818 proteins, with 8 of which the expression was significantly modified as a function of PD states.  FIG.  4 B : The 8 differentially expressed proteins are referenced according to the gene to which they are associated, and further separated into 3 groups in relation to their expression variations in comparison to CTRL (Group I), mild PD (Group II) or moderate PD (Group III).  FIG.  4 C : Normalized expression (intensity) of the proteins associated with the Group I genes AIDA, ABHD14B, and NADSYN1; the Group II genes QDPR, AKR1A1, and CNRIP1; and the Group III genes USP24 and ATP5A1.  FIG.  4 D : Heatmap establishing correlations between disease states and the abundance of the variable proteins. Cold (C) and hot (H) colors represent low and high correlation levels, respectively. The AU p value is indicated for each node. Protein modulation was determined by unpaired t-tests with Welch&#39;s correction using the criteria of a p value under 0.05 and a minimum of 2-fold change between groups, *p&lt;0.05, **p&lt;0.01. Abbreviations: AU, Approximately Unbiased; CTRL Control; PD, Parkinson&#39;s disease. 
         FIGS.  5 A- 5 C . Confirmation of EEV proteins selectively modified in PD patients by Volcano plots. The protein ratios (log 2(ratio)) of the three comparison ( FIG.  5 A : mild PD/CTRL,  FIG.  5 B : moderate PD/CTRL, and  FIG.  5 C : moderate PD/mild PD) were plotted over the corresponding Welch&#39;s test p value (−log 10(p-value)). The graphs display a V shape, as expected, and only the proteins falling outside the limits of a p value&lt;0.05 and absolute value of z-score&gt;1.96 (identified by black lines) were considered as variant proteins (arrows). Two variant proteins were excluded given that they were quantified using only one peptide. Abbreviations: CTRL: Control; PD, Parkinson&#39;s disease. 
     
    
    
     SEQUENCE LISTING 
     This application contains a Sequence Listing in computer readable form created Feb. 8, 2017 and modified on Feb. 8, 2018 having a size of about 40 kb. The computer readable form is incorporated herein by reference. 
     
       
         
           
               
               
               
             
               
                   
               
               
                 SEQ  
                   
                   
               
               
                 ID 
                   
                   
               
               
                 NO: 
                 Protein sequence of: 
                 Uniprot ID 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 Axin interactor, dorsalization-associated protein 
                 Q96BJ3 
               
               
                 2 
                 Alpha/beta hydrolase domain-containing protein 14B 
                 Q96IU4 
               
               
                 3 
                 Glutamine-dependent NAD(+) synthetase 
                 E9PNF5 
               
               
                 4 
                 Dihydropteridine reductase 
                 P09417 
               
               
                 5 
                 Alcohol dehydrogenase [NADP(+)] 
                 P14550 
               
               
                 6 
                 CB1 cannabinoid receptor-interacting protein 1 
                 B8ZZB8 
               
               
                 7 
                 Ubiquitin carboxyl-terminal hydrolase 24 
                 Q9UPU5 
               
               
                 8 
                 ATP synthase subunit alpha, mitochondrial 
                 K7EQH4 
               
               
                   
               
            
           
         
       
     
     DETAILED DESCRIPTION 
     The present description relates to the proteomic analysis of erythrocyte-derived extracellular vesicles (EEV) and the identification of protein biomarkers whose expression levels within EEV correlate with different Parkinson&#39;s disease (PD) states. 
     In one aspect, the present description relates to a method for clinically assessing Parkinson&#39;s disease in a human subject, based on the expression level of one or more protein biomarker(s) that may correlate with or be indicative of the subject&#39;s Parkinson&#39;s disease state. As used herein, the expression “clinically assessing” or “clinical assessment” in the context of PD refers to an evaluation of a subject&#39;s PD state, which may or may not occur in a clinical setting, and which may or may not be performed by a health care professional. For example, clinically assessing may comprise screening and/or diagnosing PD in a subject having or suspected of having PD, staging a subject&#39;s PD, monitoring the progression of PD in a subject, monitoring the effect of PD medication or treatment (e.g., over time), or any combination thereof. The use of the methods described herein with other methods for clinically assessing PD subjects is also envisaged. 
     In some aspects, the methods described herein may comprise obtaining a preparation of isolated erythrocyte-derived extracellular vesicles (EEV) from a blood sample of a subject having or suspected of having Parkinson&#39;s disease. As used herein, the expression “extracellular vesicles” (EV) refers to subcellular membrane vesicles found in the extracellular environment (e.g., bodily fluids) that originate from cells, and which range in size from about 20 nm to about 1000 nm. EV may comprise exosomes, microvesicles (MV), multivesicular endosomes (MVE), or vesicles produced by apoptotic bodies, or any combination thereof, as well as other types of extracellular vesicles. Whereas the majority of the circulating EV that are detected by flow cytofluorometric assays are likely to be MV, we do not completely exclude the potential contribution of larger exosomes or vesicles produced by apoptotic bodies. In some embodiments, the EV of the present description comprise vesicles between about 30, 40, 50, 60, 70, 80, 90, or 100 nm to about 500, 600, 700, 800, 900, or 1000 nm in size. In some embodiments, the EV of the present description comprise vesicles from 100 nm to 1000 nm in size. In some embodiments, the EV of the present description comprise vesicles between 150 nm to 1000 nm in size. All EV are composed of membrane proteins and lipids, as well as cytoplasmic components of the cell from which they originate, such as mRNA and miRNA, organelles or infectious particles (e.g., prions, virus). A variety of methods may be used to determine the origin of EV. For example, cell surface markers (e.g., with immunolabeling and/or flow cytometry techniques) may be used to identify, enrich/purify/isolate, and/or quantify EV according to their cell of origin. Examples of such markers include: CD235a+ (erythrocytes), CD31+/CD41− (endothelial cells), CD41+ (platelets), CD45+ (leukocytes), CD45+CD14+(monocytes), and CD45+CD15+ (granulocytes). Of particular interest for the present description are markers that are present in (or specific for) EEV that may be used to identify, enrich/purify/isolate, and/or quantify EEV from other types of EV. Examples of such EEV markers include endosome or membrane-bonding proteins such as TSG101 and Rabs (enriched in exosomes), tetraspanins such as CD9, CD63 and CD81 (enriched in exosomes), golgi and mitochondrial proteins (enriched in MVs and absent in exosomes) (Lotvall et al., 2014). In some embodiments, the EEVs of the present description may comprise one or more of the EEV protein(s) listed in Table 4. 
     As used herein, the expression “[marker]+EV” or “[marker]-positive” in relation to extracellular vesicles refers to the presence or detectability of that marker in an EV population of interest, regardless of whether that marker is actually detected (e.g., using an immunolabel). Conversely, the expression “[marker]−EV” or “[marker]- negative EV” refers to the absence or lack of detectability of that marker in an EV population of interest, regardless of whether that marker is actually detected (e.g., using an immunolabel). For example, the expression “CD235+EV” or “CD235a-positive EV” means EV that comprise the marker CD235a (Glycophorin A). 
     As used herein, the term “protein biomarker” refers to a molecular indicator that is a polypeptide or protein that is associated with a particular pathological or physiological state (e.g., PD disease state). For example, the expression “Parkinson&#39;s disease biomarker” or “PD biomarker” refers to a molecular indicator that is associated with the presence, stage, and/or progression of PD in a subject. Furthermore, the term “EEV protein biomarker” refers to a protein biomarker that is expressed in EEV, whose level of expression is associated with a particular pathological or physiological state (e.g., PD disease state). 
     In some embodiments, obtaining a preparation of isolated EEV from a blood sample of a subject (e.g., a subject having or suspected of having Parkinson&#39;s disease) may involve identifying, enriching/purifying/isolating, and/or quantifying EEV in a blood sample from the subject. In some embodiments, the blood samples may be processed to obtain platelet-free plasma (PFP), and the preparation of isolated EEV may be prepared from PFP. As used herein, the terms “enriched”, “purified”, “isolated” and the like, refer to either removing contaminants from a biological sample and/or increasing the concentration of an analyte of interest (e.g., EEV) in the sample, to an extent that is not found in nature. In some embodiments, identifying, enriching/purifying/isolating, and/or quantifying EEV may involve flow cytometry, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, size-exclusion chromatography, ultracentrifugation, magnetic activated cell sorting (MACS), nanoparticle tracking analysis, light scattering, electrophoretic light scattering, dynamic light scattering, electron microscopy or any combination thereof, or using other techniques that can separate vesicles based on their size and/or surface protein expression. Quantifying EEVs may also be performed by methods such as nanoparticle tracking (NTA), biochemical approaches and semi-quantitative electron microscopy approaches. In some embodiments, the methods described herein may further comprise quantifying the level of EEV in a blood sample from a subject. The quantification of EEV may be expressed as a relative value by normalizing the number of EEV (e.g., in terms of the total number of erythrocytes). 
     In some embodiments, preparations of isolated EEV described herein may comprise at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% (e.g., by weight or number) of EEV, and/or less than 30%, 25%, 20%, 15%, 10%, 5%, or 1% (e.g., by weight or number) of non-EEV. 
     In some embodiments, the methods described herein may comprise obtaining a blood sample from a subject that is less than 5 mL, less than 4 mL, less than 3 mL, less than 2 mL, less than 1 mL, less than 900 μL, less than 800 μL, less than 700 μL, less than 600 μL, less than 500 μL, less than 400 μL, less than 300 μL, less than 200 μL, less than 100 μL, less than 50 μL, less than 40 μL, less than 30 μL, less than 25 μL, less than 20 μL, or less than 10 μL. 
     In some embodiments, the methods described herein may comprise detecting or determining the expression level of an EEV protein biomarker that is differentially expressed in controls (e.g., non-PD subjects) and/or in different PD states (e.g., mild, moderate, or severe), for example based on the unified Parkinson&#39;s disease rating scale (UPDRS). As used herein, the expression “mild PD patients” are defined as patients characterized by a UPDRS score of lower than 37; “moderate PD patients” are defined as patients characterized by a UPDRS score of between 37 and 75, and “severe PD patients” are defined as patients characterized by a UPDRS score of greater than 75. In some embodiments, the EEV protein biomarkers described herein may be used, for example, to distinguish between mild, moderate and severe PD patients. In some embodiments, the EEV protein biomarkers described herein may be used to distinguish between patients characterized by UPDRS scores within different ranges from those mentioned above. As used herein, “control subjects” or “controls” refer to non-PD subjects (e.g., healthy subjects). 
     In some embodiments, the methods described herein comprise determining the expression level(s) of one or more protein biomarker(s) in a preparation of isolated EEV, wherein the protein biomarker(s) is/are one or more of the proteins defined in the Table below. 
     
       
         
           
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                 SEQ  
                 Related 
                   
                 Corresponding 
               
               
                   
                   
                 ID 
                 accession  
                 Related 
                 gene 
               
               
                 Groups 
                 Protein biomarker 
                 NO: 
                 no. 
                 UniProt ID 
                 name 
               
               
                   
               
             
            
               
                 I 
                 Axin interactor, dorsalization- 
                 1 
                 NP_073742.2 
                 Q96BJ3 
                 AIDA 
               
               
                 (Control) 
                 associated protein 
                   
                   
                   
                   
               
               
                   
                 Alpha/beta hydrolase domain- 
                 2 
                 NP_116139.1 
                 Q96IU4 
                 ABHD148 
               
               
                   
                 containing protein 14B 
                   
                   
                   
                   
               
               
                   
                 Glutamine-dependent NAD(+) 
                 3 
                 EAW74792.1 
                 E9PNF5 
                 NADSYN1 
               
               
                   
                 synthetase 
                   
                   
                   
                   
               
               
                 II 
                 Dihydropteridine reductase 
                 4 
                 NP_001293069.1 
                 QDPR 
                 QDPR 
               
               
                 (mild PD) 
                 Alcohol dehydrogenase [NADP(+)] 
                 5 
                 AAP36383.1 
                 P14550 
                 AKR1A1 
               
               
                   
                 CB1 cannabinoid receptor- 
                 6 
                 NP_056278.1 
                 B8ZZB8 
                 CNRIP1 
               
               
                   
                 interacting protein 1 
                   
                 NP_001104571.1 
                   
                   
               
               
                 III 
                 Ubiquitin carboxyl- 
                 7 
                 NP_056121.2 
                 Q9UPU5 
                 USP24 
               
               
                 (moderate 
                 terminal hydrolase 24 
                   
                   
                   
                   
               
               
                 PD) 
                 ATP synthase subunit alpha, 
                 8 
                 EAX01470.1 
                 K7EQH4 
                 ATP5A1 
               
               
                   
                 mitochondrial 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the protein biomarkers identified herein as belonging to Group I may be differentially expressed in the EEV of healthy or non-PD control subjects, as compared to those of mild and/or moderate PD subjects. In some embodiments, the protein biomarkers identified herein as belonging to Group II may be differentially expressed in the EEV of mild PD subjects, as compared to those of healthy or non-PD control subjects and/or moderate PD subjects. In some embodiments, the protein biomarkers identified herein as belonging to Group III may be differentially expressed in the EEV of moderate PD subjects, as compared to those of healthy or non-PD control subjects and/or mild PD subjects. 
     In some embodiments, the methods described herein may comprise determining the expression of one or more of the protein biomarkers described herein, based on the PD state which is to be clinically assessed. For example, different protein biomarkers or combinations of protein biomarkers may be selected based on, for example, the differential expression patterns reported herein (e.g., in Table 3.1 and in  FIG.  4 C ). In some embodiments, the methods described herein may comprise determining the expression of: (i) Alpha/beta hydrolase domain-containing protein 14B, if the subject has or is suspected of having mild or moderate Parkinson&#39;s disease; (ii) Alcohol dehydrogenase [NADP(+)], if the subject has or is suspected of having mild Parkinson&#39;s disease; (iii) ATP synthase subunit alpha, mitochondrial, if the subject has or is suspected of having moderate Parkinson&#39;s disease; or (iv) any combination of (i) to (iii). In some embodiments, the subject is determined to have mild or moderate PD when the expression level of alpha/beta hydrolase domain-containing protein 14B in the preparation of isolated EEV from a blood sample of the subject is lower than that corresponding to a control subject (i.e., not having PD). In some embodiments, the subject is determined to have mild PD when the expression level of alcohol dehydrogenase [NADP(+)] in the preparation of isolated EEV from a blood sample of the subject is higher than that corresponding to a control subject (i.e., not having PD). In some embodiments, the subject is determined to have moderate PD when the expression level of ATP synthase subunit alpha, mitochondrial in the preparation of isolated EEV from a blood sample of the subject is higher than that corresponding to a control subject (i.e., not having PD). In some embodiments, the terms “higher” or “lower” may refer to a difference in expression from the reference value of at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, or 3.5-fold. In some embodiments, methods described herein may comprise determining the expression level(s) of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all eight of the protein biomarker(s):
         (a) Axin interactor, dorsalization-associated protein (represented by SEQ ID NO: 1);   (b) Alpha/beta hydrolase domain-containing protein 14B (represented by SEQ ID NO: 2);   (c) Glutamine-dependent NAD(+) synthetase (represented by SEQ ID NO: 3);   (d) Dihydropteridine reductase (represented by SEQ ID NO: 4);   (e) Alcohol dehydrogenase [NADP(+)] (represented by SEQ ID NO: 5);   (f) CB1 cannabinoid receptor-interacting protein 1 (represented by SEQ ID NO: 6);   (g) Ubiquitin carboxyl-terminal hydrolase 24 (represented by SEQ ID NO: 7); and   (h) ATP synthase subunit alpha, mitochondrial (represented by SEQ ID NO: 8).       

     In some embodiments, the expression level of one or more of the protein biomarker(s) described herein may be determined by detecting and/or quantifying the presence of a polypeptide fragment of any one of the polypeptides of SEQ ID NOs: 1-8. Such fragments may be comprise or consist of at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, or more contiguous amino acids of any one of SEQ ID NOs: 1-8. In some embodiments, the polypeptides of any one of SEQ ID NOs: 1-8 may be present in the EEV (or a preparation of isolated EEV) as a fragment of SEQ ID NOs: 1-8. Detection of such fragments are considered within the scope of the present description. In some embodiments, a protein biomarker described herein may comprise one or more fragments of any one of SEQ ID NOs: 1-8, for example a fragment comprising or consisting of: residues 127-192 of SEQ ID NO: 1; residues 188-200 of SEQ ID NO: 2; residues 112-260 or residues 349-446 of SEQ ID NO: 3; residues 1-213 of SEQ ID NO: 4; residues 1-325 of SEQ ID NO: 5; residues 1-110 or residues 84-110 of SEQ ID NO: 6; residues 2570-2620 of SEQ ID NO: 7; or residues 51-161, residues 111-137, or residues 53-152 of SEQ ID NO: 8. 
     In some embodiments, methods described herein may comprise determining the expression level(s) of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all eight of the protein biomarker(s) encoded by the human genes AIDA, ABHD14B, NADSYN1, QDPR, AKR1A1, CNRIP1, USP24, and ATP5A1. 
     In some embodiments, methods described herein may comprise determining the expression level(s) of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all eight of the protein biomarker(s) defined by accession numbers: NP_073742.2, NP_116139.1, EAW74792.1, NP_001293069.1, AAP36383.1, NP_056278.1, NP_001104571.1, NP_056121.2, and EAX01470.1. 
     In some embodiments, protein biomarker (a) may be at least 70%, 75%, 80%, 85%, 90%, or 95% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, protein biomarker (b) may be at least 70%, 75%, 80%, 85%, 90%, or 95% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, protein biomarker (c) may be at least 70%, 75%, 80%, 85%, 90%, or 95% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, protein biomarker (d) may be at least 70%, 75%, 80%, 85%, 90%, or 95% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, protein biomarker (e) may be at least 70%, 75%, 80%, 85%, 90%, or 95% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, protein biomarker (f) may be at least 70%, 75%, 80%, 85%, 90%, or 95% identical to the amino acid sequence of SEQ ID NO: 6. In some embodiments, protein biomarker (g) may be at least 70%, 75%, 80%, 85%, 90%, or 95% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, protein biomarker (f) may be at least 70%, 75%, 80%, 85%, 90%, or 95% identical to the amino acid sequence of SEQ ID NO: 8. 
     In some embodiments, the methods described herein may comprise determining the expression levels of an EEV protein signature comprising any combination of the protein biomarkers (a) to (h). In some embodiments, the methods described herein may comprise determining the expression levels of at least one of protein biomarkers (a), (b), and (c) [Group I]; at least one of protein biomarkers (d), (e), and (f) [Group II]; and/or at least one of protein biomarkers (g) and (h) [Group III]. 
     In some embodiments, the methods described herein may further comprise comparing the expression level of the protein biomarker(s) so detected and comparing the expression level to a reference value corresponding to that of a control group, non-PD group, mild PD group, moderate PF group, or severe PD group. 
     In some embodiments, the EEV protein biomarkers described herein do not comprise alpha-synuclein; and/or the methods described herein do not comprise detecting and/or quantifying alpha-synuclein. 
     In some embodiments, the expression level(s) of one or more of the protein biomarker(s) in the preparation of isolated EEV may comprise contacting the protein biomarker with an antibody directed against the protein biomarker (e.g., an immunoassay). In some embodiments, the antibody specifically binds to the polypeptide of any one of SEQ ID NOs: 1-8. Antibodies against the proteins of SEQ ID NOs: 1-8 are commercially available, for example from Novus Biologicals (e.g., catalog numbers NBP1-88323, NBP2-26122, H00055191-M01, H00005860-M02, NBP2-02164, NBP1-86800, NB100-40830, and NBP2-38525, respectively). In some embodiments, antibodies described herein may bind to, or be raised against, a fragment of any one of SEQ ID NOs: 1-8, for example a fragment comprising or consisting of: residues 127-192 of SEQ ID NO: 1; residues 188-200 of SEQ ID NO: 2; residues 112-260 or residues 349-446 of SEQ ID NO: 3; residues 1-213 of SEQ ID NO: 4; residues 1-325 of SEQ ID NO: 5; residues 84-110 of SEQ ID NO: 6; residues 2570-2620 of SEQ ID NO: 7; or residues 53-152 of SEQ ID NO: 8. In some embodiments, antibodies described herein may bind to an epitope comprising or consisting of at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 contiguous residues of any one of SEQ ID NOs: 1-8. 
     As used herein, the term “antibody” may encompass any type of antibody, including but not limited to monoclonal antibodies, polyclonal antibodies, “antigen-binding fragments” (or portion), such as Fab, Fab′, F(ab′)2, Fd, Fv, Fc, etc., of intact antibodies that retain the ability to specifically bind to a given antigen (e.g., an EEV protein described herein), an isolated complementarity determining region (CDR), bispecific antibodies, heteroconjugate antibodies, mutants thereof, fusion proteins having an antibody, or antigen-binding fragment thereof, (e.g., a domain antibody), single chain (ScFv) and single domain antibodies (e.g., shark and camelid antibodies), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv, humanized antibodies, chimeric antibodies and any other modified configuration of the immunoglobulin molecule that includes an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. The antibodies may be murine, rat, human, or any other origin (including chimeric or humanized antibodies). 
     In some embodiments, the expression level(s) of one or more of the protein biomarker(s) in the preparation of isolated EEV may comprise mass spectrometry (e.g., nano liquid chromatography tandem mass spectrometry (nanoLC MS/MS)). 
     In some embodiments, the methods described herein may comprise combining the expression of one or more of the protein biomarker(s) in the preparation of isolated EEV with the quantity of EEV to increase the power of a biomarker described herein. 
     In some embodiments, the methods described herein may further comprise determining the expression level(s) of one or more of the EEV protein(s) listed in Table 4 (Proteins identified in the EEV proteome), wherein the one or more EEV protein(s) does not comprise (a) to (h). The expression level of one or more EEV proteins that are not differentially expressed between PD states may be useful for example as normalization parameters in conjunction with the one or more of the protein biomarkers (a) to (h). 
     In some embodiments, the methods described herein may comprise determining the expression level(s) of one or more of the EEV protein(s) defined by UniProt ID: P02549, P11277, P16157, P02730, P55072, P16452, P11171, P04040, Q13228, B4DT77, Q8WUM4, P35612, P68871, Q00610, P69905, B4DVE7, J3QLD9, P08758, P09525, 075955, P11142, P32119, P00491, P27105, P00918, P23634, C9JIF9, P00915, P63261, Q5VU58, P30041, E7EU23, Q00013, E7EV01, J3KPS3, Q08495, P23276, P69892, P60174, P62258, O75326, O75340, E7EV99, Q5VZU9, P53396, C9JOK6, P04406, P07738, B7Z319, Q86X55, P07195, P23526, Q32Q12, B7Z7A9, P11166, P22303, Q9NP58, P40925, P00352, F2Z2V0, K7EMC9, F5H7S3, A6NN80, P30043, H7BXD5, P04083, P62937, P37837, Q06830, 075131, P00390, E7EQB2, P07384, P02042, P30086, P35613, Q9H0U4, P63092, P48506, P06702, Q9UBV8, P17931, P28066, P07451, E7EQ12, P50895, P28074, G3V5Z7, P25786, G3V1D3, P49247, Q5T9B7, P25789, B4E022, J3QS39, H0Y7A7, P28070, Q9H4G4, Q9BY43, P48426, P28289, P07911, Q9GZP4, P78417, P25788, 014818, P08107, H0YD13, P61225, P05109, P23528, Q99808, P84077, P31946, C9JIS1, P53990, Q99497, F5H7U0, B7Z7E9, P62834, P04899, P25325, Q9NP79, P00492, Q16531, P22314, P00441, H7BY58, P10768, P09543, P06733, P26038, 075368, K7EQ48, P25787, P49721, F5H8J2, C9J9P4, P09211, B5MDF5, P07900, K7EQ02, Q13630, F5H0T1, P50502, P20618, P62805, P51148, H7C2G2, J3KQ18, H3BPK3, B4DIT7, 043633, B4DQH4, Q9UN37, 13L397, Q9Y5Z4, Q9UKV8, F5H442, H3BLV0, P02008, E7EPV7, P63104, P02724, U3KQE2, Q9NP59, Q5QPM9, C9J8U2, P61981, Q9UQ80, E5RJR5, Q9NRV9, Q9H444, P10599, Q5VSJ9, Q9UK41, Q9Y3I1, P61026, Q14974, P27797, P18669, P54725, P30613, P63000, P05164, F5GWY2, P48637, F5H5V4, G5E9R5, P46976, P28072, P26447, F5GXQ0, P08754, Q99436, P62942, U3KQK0, J3QKR3, P01116, P13489, Q08722, Q5T123, Q8WYQ7, 075695, P00167, Q9Y4D1, P11021, H7C1D4, P07737, M0R389, A6NJA2, P10644, Q9BS40, G5EA52, P53004, Q04656, H9KV70, O00299, F8WF69, G3V2F7, F8WDS9, P60891, K7ESE8, H0YNE3, P16930, F8VSD4, P07203, P62328, E5RIW3, M0R0Y2, P15374, P04921, H0YDI1, B4E220, C9JEN3, F5H2R5, Q53TN4, Q9NZD4, Q8NHG7, Q5JYX0, Q71RC9, E9PNW4, P09105, R4GN98, O75531, Q5T6W5, F5H4Q5, J3QK90, H3BV85, Q9NRX4, H3BS66, E7ESC6, P68402, Q9BRF8, P08246, E9PN50, E7EUC7, B8ZZB8, E9PCS3, P59666, O15400, P00338, P61970, E7EMV0, F5GY90, P61020, Q99828, B4DUA0, C9JTY3, P27348, H0YKZ7, P08238, J3KQP6, A6NMU3, P53985, F6USW4, O14964, P20020, P36959, Q9Y376, Q9Y6M5, Q8IZ83, Q99459, P06132, J3KNT0, P49189, H3BNT7, P05023, P34932, K7EMV3, Q81U68, E7ENZ3, Q5TZA2, Q9P203, Q7LBR1, U3KQ56, H0YJ11, Q9UDT6, P09960, Q5HY54, E9PJL5, G3V2U7, E9PQN4, Q9BSL1, Q04917, B7ZBP9, Q8NDC0, P68133, P69891, S4R3Y4, 13L3E4, Q16570, Q5VY30, E7END7, Q5VU59, P17066, Q04760, D6RD66, K7EM02, P14209, E9PIR7, K7EMQ9, P15531, H7BZT4, O00560, Q9BVM4, K7EKH5, P49773, H0YBY6, Q9Y624, B1AKQ8, K7EKN6, I3L0K2, A8MXY0, 014773, E9PNW0, Q5TDH0, Q96JM4, F5GWT9, F2Z3J2, J3QL74, E9PJC7, Q9H936, D6RD63, Q6B0K9, Q31611, H7BY04, Q9UL25, H7C3P7, P08311, E9PE37, G3V1N2, P00387, O75339, P14324, K7EKG2, P02549, P11277, P16157, P55072, P111714, P35579, Q8WUM4, P02730, P16452, P04040, A0A087WVQ6, P35612, P16157, Q14254, P20073, 075955, P53396, P06753, P49368, P236344, P11142, P60709, Q5T4S7, P78371, P28289, P50395, P27105, P68871, P02730, Q00013, J3KPS3, P00352, Q86VP6, P49327, Q13228, P00915, P50991, P50990, P32119, P50995, P69905, P00558, H7BXK9, P08758, P09525, P07900, P48643, P07384, P22314, P04406, Q08495, Q99832, P29144, P30041, E9PM69, P40227, P50570, E7EQB2, P31948, E7ESC6, E7EV99, P62258, P30613, A0A0G2JIW1, Q16531, P11021, F5H2F4, P07195, P45974, O43242, C9JOK6, P08133, Q13200, P23276, P34932, A0A0A0MSI0, Q9Y230, Q5XPI4, P68871, P60174, P00491, C9JIF9, H7BYY1, P35998, P17987, P09543, Q99460, Q9Y4E8, Q90009, P26038, P04083, P30043, P11166, P00918, P06733, Q5TDH0, B0QZ18, O75326, P05164, Q9Y265, P29401, I3L0N3, Q4VB86, P11277, P13716, P07738, P48506, Q99816, O14818, P23526, P61225, 000231, P11413, P00338, Q99808, A6NJA2, Q06323, or any combination thereof. 
     In some embodiments, the methods described herein may comprise determining the expression level(s) of one or more of the EEV protein(s) defined by protein accession number: NP_000017.1, NP_000022.3, NP_000028.3, NP_000034.1, NP_000036.2, NP_000043.4, NP_000058.1, NP_000110.2, NP_000128.1, NP_000134.2, NP_000149.3, NP_000166.2, NP_000169.1, NP_000175.1, NP_000185.1, NP_000230.1, NP_000241.1, NP_000260.1, NP_000261.2, NP_000276.2, NP_000280.1, NP_000282.1, NP_000289.1, NP_000311.2, NP_000333.1, NP_000338.3, NP_000356.1, NP_000365.3, NP_000366.1, NP_000382.3, NP_000389.1, NP_000393.4, NP_000410.2, NP_000411.1, NP_000421.1, NP_000445.1, NP_000471.1, NP_000507.1, NP_000508.1, NP_000509.1, NP_000510.1, NP_000549.1, NP_000550.2, NP_000572.2, NP_000623.2, NP_000628.2, NP_000656.1, NP_000678.1, NP_000680.2, NP_000687.3, NP_000691.1, NP_000692.2, NP_000703.2, NP_000704.1, NP_000792.1, NP_000843.1, NP_000886.1, NP_001001323.1, NP_001001396.1, NP_001001521.1, NP_001002021.2, NP_001002857.1, NP_001002858.1, NP_001002860.2, NP_001003938.1, NP_001003945.1, NP_001005360.1, NP_001005361.1, NP_001005362.1, NP_001005386.1, NP_001005753.1, NP_001007068.1, NP_001007069.1, NP_001007070.1, NP_001007071.1, NP_001008390.1, NP_001008800.1, NP_001009185.1, NP_001009186.1, NP_001009570.1, NP_001010935.1, NP_001010942.1, NP_001013275.1, NP_001013454.1, NP_001017963.2, NP_001019397.1, NP_001019398.1, NP_001019399.1, NP_001019820.1, NP_001020029.1, NP_001020276.1, NP_001020560.1, NP_001020561.1, NP_001026897.1, NP_001026997.1, NP_001027017.1, NP_001028196.1, NP_001028690.1, NP_001028691.1, NP_001028692.1, NP_001029197.1, NP_001029249.1, NP_001030611.1, NP_001034221.1, NP_001034271.1, NP_001034288.1, NP_001034455.1, NP_001034456.1, NP_001034679.2, NP_001034680.2, NP_001034708.1, NP_001034891.1, NP_001035517.1, NP_001035784.1, NP_001035810.1, NP_001035941.1, NP_001036816.1, NP_001036817.1, NP_001036818.1, NP_001055.1, NP_001070654.1, NP_001070956.1, NP_001070957.1, NP_001070958.1, NP_001071643.1, NP_001071645.1, NP_001073379.1, NP_001077086.1, NP_001077861.1, NP_001087.2, NP_001091.1, NP_001092.1, NP_001092006.1, NP_001092925.1, NP_001096137.1, NP_001096138.1, NP_001098985.1, NP_001099000.1, NP_001107606.1, NP_001107607.1, NP_001107608.1, NP_001107609.1, NP_001107610.1, NP_001107611.1, NP_001108628.1, NP_001112362.1, NP_001116370.1, NP_001116423.1, NP_001116849.1, NP_001116850.1, NP_001118.3, NP_001120855.1, NP_001121776.1, NP_001121777.1, NP_001121778.1, NP_001122060.3, NP_001122301.1, NP_001122302.1, NP_001122303.1, NP_001123291.1, NP_001123654.1, NP_001123655.1, NP_001123989.1, NP_001124197.1, NP_001124321.1, NP_001124322.1, NP_001124384.1, NP_001128527.1, NP_001128711.1, NP_001129171.1, NP_001129172.1, NP_001129173.1, NP_001129174.1, NP_001129293.1, NP_001129294.1, NP_001129333.1, NP_001129487.1, NP_001129511.1, NP_001135827.1, NP_001135828.1, NP_001135917.1, NP_001135918.1, NP_001136336.2, NP_001137359.1, NP_001137430.1, NP_001137457.1, NP_001138404.1, NP_001138436.1, NP_001138437.1, NP_001138438.1, NP_001138439.1, NP_001138440.1, NP_001138441.1, NP_001138442.1, NP_001138443.1, NP_001138868.1, NP_001138872.1, NP_001139280.1, NP_001139281.1, NP_001139411.1, NP_001139412.1, NP_001139501.1, NP_001139502.1, NP_001139508.2, NP_001139509.1, NP_001139748.1, NP_001139786.1, NP_001144.1, NP_001145.1, NP_001146.2, NP_001147.1, NP_001148.1, NP_001152759.1, NP_001153705.1, NP_001153706.1, NP_001154840.1, NP_001155059.1, NP_001155238.1, NP_001155901.1, NP_001156467.1, NP_001156852.1, NP_001157565.1, NP_001157566.1, NP_001157567.1, NP_001158095.1, NP_001158302.1, NP_001158886.1, NP_001158887.1, NP_001158888.1, NP_001159418.1, NP_001159477.1, NP_001159478.1, NP_001159491.1, NP_001159528.1, NP_001159529.1, NP_001159583.1, NP_001159584.1, NP_001159585.1, NP_001159586.1, NP_001159588.1, NP_001159756.1, NP_001159757.1, NP_001159897.1, NP_001159932.1, NP_001159933.1, NP_001159934.1, NP_001159968.1, NP_001160158.1, NP_001160159.1, NP_001160160.1, NP_001161694.1, NP_001161971.1, NP_001165131.1, NP_001165132.1, NP_001165901.1, NP_001165902.1, NP_001165906.1, NP_001167568.1, NP_001170775.1, NP_001171588.1, NP_001171589.1, NP_001171649.1, NP_001171650.1, NP_001171651.1, NP_001171675.1, NP_001171676.1, NP_001171677.1, NP_001171725.1, NP_001171983.1, NP_001171984.1, NP_001172006.1, NP_001172007.1, NP_001177645.1, NP_001177736.1, NP_001177931.1, NP_001177932.1, NP_001177966.1, NP_001177989.1, NP_001177990.1, NP_001180262.1, NP_001180446.1, NP_001180473.1, NP_001182016.1, NP_001182031.1, NP_001182032.1, NP_001182033.1, NP_001184044.1, NP_001185739.1, NP_001185771.1, NP_001185797.1, NP_001185798.1, NP_001185883.1, NP_001186040.1, NP_001186041.1, NP_001186054.1, NP_001186092.1, NP_001186701.1, NP_001186702.1, NP_001186703.1, NP_001186883.1, NP_001188412.1, NP_001189342.1, NP_001189343.1, NP_001189360.1, NP_001191331.1, NP_001191382.1, NP_001191439.1, NP_001192176.1, NP_001192177.1, NP_001192179.1, NP_001192180.1, NP_001193469.1, 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NP_002955.2, NP_002956.1, NP_003013.1, NP_003042.3, NP_003095.2, NP_003117.2, NP_003266.1, NP_003282.2, NP_003290.1, NP_003304.1, NP_003320.2, NP_003325.2, NP_003339.1, NP_003352.2, NP_003379.3, NP_003391.1, NP_003395.1, NP_003396.1, NP_003397.1, NP_003464.1, NP_003469.2, NP_003472.2, NP_003486.1, NP_003509.1, NP_003513.1, NP_003514.2, NP_003516.1, NP_003517.2, NP_003529.1, NP_003530.1, NP_003531.1, NP_003532.1, NP_003533.1, NP_003534.1, NP_003535.1, NP_003536.1, NP_003537.1, NP_003539.1, NP_003560.2, NP_003565.4, NP_003581.1, NP_003603.1, NP_003604.3, NP_003618.1, NP_003644.2, NP_003698.1, NP_003711.1, NP_003741.1, NP_003817.1, NP_003851.1, NP_003899.2, NP_003900.1, NP_003906.2, NP_003923.2, NP_003935.2, NP_004025.1, NP_004030.1, NP_004035.2, NP_004085.1, NP_004090.4, NP_004095.4, NP_004121.2, NP_004152.1, NP_004153.2, NP_004175.2, NP_004209.2, NP_004227.1, NP_004277.2, NP_004291.1, NP_004299.1, NP_004300.1, NP_004334.1, NP_004336.3, NP_004420.1, NP_004428.1, NP_004449.1, NP_004466.2, NP_004574.2, NP_004595.2, NP_004604.2, NP_004628.4, NP_004703.1, NP_004777.1, NP_004818.2, NP_004823.1, NP_004850.1, NP_004883.3, NP_004888.2, NP_004896.1, NP_004921.1, NP_004936.2, NP_004960.2, NP_004976.2, NP_004985.2, NP_005013.1, NP_005019.2, NP_005038.1, NP_005044.1, NP_005172.1, NP_005177.2, NP_005208.1, NP_005304.3, NP_005317.2, NP_005322.1, NP_005323.1, NP_005331.1, NP_005336.3, NP_005337.2, NP_005338.1, NP_005339.3, NP_005361.2, NP_005393.2, NP_005462.1, NP_005498.1, NP_005546.2, NP_005557.1, NP_005572.2, NP_005616.2, NP_005680.1, NP_005713.1, NP_005727.1, NP_005759.4, NP_005787.1, NP_005794.1, NP_005796.1, NP_005800.3, NP_005836.2, NP_005850.1, NP_005882.2, NP_005902.1, NP_005908.1, NP_005909.2, NP_005955.3, NP_005960.1, NP_005989.3, NP_005993.1, NP_006045.1, NP_006057.1, NP_006079.1, NP_006084.2, NP_006100.2, NP_006126.1, NP_006127.1, NP_006136.1, NP_006182.2, NP_006187.2, NP_006254.1, NP_006280.3, NP_006283.1, NP_006304.1, NP_006311.2, NP_006312.1, NP_006358.1, NP_006364.2, NP_006375.2, NP_006382.1, NP_006391.1, NP_006398.1, NP_006409.3, NP_006420.1, NP_006421.2, NP_006422.1, NP_006487.1, NP_006494.1, NP_006507.2, NP_006546.1, NP_006576.2, NP_006588.1, NP_006639.3, NP_006657.1, NP_006693.3, NP_006695.1, NP_006699.2, NP_006746.1, NP_006750.3, NP_006752.1, NP_006808.1, NP_006810.1, NP_006817.1, NP_006818.3, NP_006828.2, NP_006868.3, NP_008839.2, NP_008846.2, NP_008996.1, NP_009005.1, NP_009030.1, NP_009057.1, NP_009193.2, NP_009200.2, NP_015565.1, NP_031381.2, NP_033665.1, NP_036205.1, NP_036220.1, NP_036286.2, NP_036311.3, NP_036335.1, NP_036365.1, NP_036457.1, NP_036524.1, NP_036525.1, NP_036557.1, NP_036611.2, NP_037364.1, NP_037377.1, NP_037506.2, NP_054735.3, NP_054888.2, NP_054891.2, NP_055018.2, NP_055063.1, NP_055131.2, NP_055135.1, NP_055176.1, NP_055268.1, NP_055400.1, NP_055461.1, NP_055490.4, NP_055576.2, NP_055596.3, NP_055617.1, NP_055622.3, NP_055629.1, NP_055638.2, NP_055746.3, NP_055807.1, NP_055814.1, NP_055851.1, NP_055866.1, NP_055955.1, NP_056060.2, NP_056071.2, NP_056092.2, NP_056107.1, NP_056121.2, NP_056193.2, NP_056274.3, NP_056358.1, NP_056425.1, NP_056461.1, NP_056646.1, NP_056949.4, NP_057038.2, NP_057070.3, NP_057071.2, NP_057087.2, NP_057159.2, NP_057163.1, NP_057190.2, NP_057215.3, NP_057226.1, NP_057227.2, NP_057231.1, NP_057256.2, NP_057292.1, NP_057373.1, NP_057403.1, NP_057406.2, NP_057460.3, NP_057569.2, NP_057707.3, NP_057717.1, NP_058131.1, NP_058642.1, NP_059516.2, NP_059522.1, NP_059980.2, NP_060342.2, NP_060357.1, NP_060468.2, NP_060522.3, NP_060555.2, NP_060626.2, NP_060637.1, NP_060705.2, NP_060717.1, NP_060760.2, NP_060810.2, NP_060895.1, NP_060918.2, NP_061036.3, NP_061072.3, NP_061327.2, NP_061485.1, NP_061985.2, NP_062427.1, NP_064505.1, NP_064554.3, NP_064623.2, NP_064711.1, NP_065086.2, NP_065095.2, NP_065145.2, NP_065147.1, NP_065208.2, NP_065209.2, NP_065210.2, NP_065211.2, NP_065213.2, NP_065691.2, NP_065816.2, NP_066569.1, NP_066932.1, NP_066949.2, NP_066952.1, NP_066953.1, NP_067017.2, NP_068596.2, NP_068751.4, NP_068803.1, NP_071347.2, NP_071349.3, NP_071441.1, NP_071738.1, NP_071933.2, NP_073567.1, NP_073742.2, NP_073744.2, NP_075266.1, NP_075566.2, NP_077007.1, NP_077307.2, NP_078850.3, NP_078867.2, NP_078958.2, NP_078974.1, NP_079005.3, NP_079119.3, NP_109587.1, NP_109591.1, NP_110379.2, NP_112243.1, NP_113584.3, NP_113618.2, NP_113657.1, NP_113659.3, NP_115501.2, NP_115618.3, NP_115661.1, NP_115717.3, NP_115788.1, NP_115797.1, NP_116139.1, NP_116235.2, NP_116251.4, NP_149101.1, NP_149124.3, NP_203524.1, NP_426359.1, NP_463460.1, NP_536350.2, NP_536351.1, NP_536856.2, NP_563578.2, NP_569057.1, NP_570603.2, NP_619639.3, NP_620164.1, NP_620407.1, NP_631913.3, NP_647539.1, NP_653164.2, NP_653179.1, NP_653296.2, NP_659449.3, NP_660202.3, NP_663723.1, NP_663782.2, NP_665875.1, NP_665876.1, NP_683691.1, NP_683725.1, NP_683877.1, NP_687033.1, NP_689476.2, NP_689681.2, NP_689937.2, NP_690610.1, NP_690611.1, NP_694546.1, NP_694881.1, NP_695012.1, NP_697021.1, NP_699160.2, NP_703150.1, NP_705935.1, NP_733842.2, NP_775853.2, NP_775871.2, NP_776049.1, NP_777360.1, NP_777637.1, NP_778224.1, NP_780775.1, NP_787128.2, NP_789782.1, NP_848537.1, NP_859047.1, NP_859048.1, NP_859049.2, NP_870986.1, NP_878255.1, NP_898880.1, NP_919415.2, NP_919424.1, NP_937792.2, NP_937818.1, NP_937837.1, NP_938148.1, NP_938149.2, NP_940818.1, NP_940991.1, NP_940992.1, NP_940993.1, NP_942088.1, NP_942127.1, NP_942599.1, NP_945189.1, NP_954592.1, NP_954655.1, NP_955472.1, NP_958831.1, NP_958832.1, NP_958833.1, NP_958842.1, NP_976217.1, NP_976317.1, NP_976318.1, NP_976319.1, NP_976320.1, NP_976321.1, NP_976322.1, NP_976323.1, NP_982257.1, NP_996759.1, NP_997401.1, NP_997636.1, NP_997637.1, NP_998810.1, NP_998811.1, XP_005245019.1, XP_005245020.1, XP_005245818.1, XP_005245821.1, XP_005246799.1, XP_005247711.1, XP_005247712.1, XP_005248837.1, XP_005248935.1, XP_005248936.1, XP_005248937.1, XP_005248938.1, XP_005248939.1, XP_005249832.1, XP_005251108.2, XP_005251118.1, XP_005251120.1, 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XP_011538814.1, XP_011538815.1, XP_011538816.1, XP_011538817.1, XP_011540328.1, XP_011540329.1, XP_011541100.1, XP_011541173.1, XP_011542487.1, XP_011543594.1, XP_011543596.1, XP_011544016.1, XP_016855107.1, XP_016855556.1, XP_016855557.1, XP_016855558.1, XP_016855559.1, XP_016855560.1, XP_016855561.1, XP_016855863.1, XP_016855908.1, XP_016856078.1, XP_016856849.1, XP_016856850.1, XP_016857451.1, XP_016857452.1, XP_016857453.1, XP_016859432.1, XP_016859433.1, XP_016860119.1, XP_016860205.1, XP_016860206.1, XP_016861020.1, XP_016861021.1, XP_016862507.1, XP_016863624.1, XP_016864342.1, XP_016864523.1, XP_016864524.1, XP_016865852.1, XP_016866306.1, XP_016866307.1, XP_016866433.1, XP_016866833.1, XP_016867171.1, XP_016868009.1, XP_016868678.1, XP_016868682.1, XP_016868683.1, XP_016868684.1, XP_016868685.1, XP_016868686.1, XP_016868687.1, XP_016868735.1, XP_016869028.1, XP_016869029.1, XP_016869030.1, XP_016869031.1, XP_016869032.1, XP_016869033.1, XP_016869034.1, XP_016869035.1, XP_016869036.1, XP_016869037.1, XP_016869038.1, XP_016869039.1, XP_016869040.1, XP_016869047.1, XP_016869048.1, XP_016869049.1, XP_016869050.1, XP_016869051.1, XP_016869299.1, XP_016869300.1, XP_016869434.1, XP_016869469.1, XP_016869596.1, XP_016871328.1, XP_016871329.1, XP_016871330.1, XP_016871651.1, XP_016871652.1, XP_016871819.1, XP_016871820.1, XP_016872103.1, XP_016872104.1, XP_016872455.1, XP_016872709.1, XP_016873415.1, XP_016873595.1, XP_016873596.1, XP_016873887.1, XP_016873940.1, XP_016874003.1, XP_016874004.1, XP_016874335.1, XP_016874336.1, XP_016874847.1, XP_016874957.1, XP_016875508.1, XP_016876293.1, XP_016876959.1, XP_016877101.1, XP_016877103.1, XP_016877116.1, XP_016877117.1, XP_016877118.1, XP_016877200.1, XP_016877579.1, XP_016877580.1, XP_016879883.1, XP_016879884.1, XP_016880112.1, XP_016880169.1, XP_016880170.1, XP_016880171.1, XP_016880188.1, XP_016880189.1, XP_016880190.1, XP_016880354.1, XP_016880355.1, XP_016880356.1, XP_016880360.1, XP_016880361.1, XP_016880362.1, XP_016880363.1, XP_016880364.1, XP_016880365.1, XP_016880435.1, XP_016880436.1, XP_016880437.1, XP_016881168.1, XP_016881582.1, XP_016881587.1, XP_016881588.1, XP_016882418.1, XP_016882662.1, XP_016883197.1, XP_016883198.1, XP_016883528.1, XP_016884292.1, XP_016884293.1, XP_016884294.1, XP_016884295.1, XP_016885269.1, XP_016885270.1, or any combination thereof. 
     In some embodiments, the preparation of isolated EEV described herein may be obtained after inducing the production of EEV from activated erythrocytes in the blood sample of the subject. Erythrocytes may be activated to induce EEV production, for example, using a calcium ionophore (e.g., A23187), cold-storage, or ATP depletion (Prudent et al., 2015). 
     In some embodiments, the methods described herein may comprise a step of removing or depleting hemoglobin from a preparation of EEV prior to determining the level of expression of EEV proteins. Given the significant amounts of hemoglobin within erythrocytes that could mask the true nature of the protein signature in EEV, this step may improve the detection of non-hemoglobin EEV proteins. In some embodiments, hemoglobin-depleted and hemoglobin-rich fractions may be prepared in parallel and analyzed separated for expression of EEV proteins (e.g., in mass spectrometry-based proteomic detection techniques). 
     In some aspects, the methods described herein may further comprise comparing the level of an EEV protein biomarker to a suitable reference value indicative of the presence, stage and/or progression of Parkinson&#39;s disease, thereby clinically assessing Parkinson&#39;s disease in the subject. 
     As used herein, the expression “reference value” means a control value or range of values corresponding to a known level or range of an EEV protein biomarker associated with the presence, stage and/or progression of Parkinson&#39;s disease. In some embodiments, for example where the expression level of an EEV protein biomarker has previously been measured in a blood sample from a subject, the reference value may be a value corresponding to the same subject&#39;s previous reading (e.g., a baseline). The term “suitable” in the expression “suitable reference value” reflects the observations reported herein that the number of EEV (and/or the protein expressed therein) in blood samples from PD subjects may vary depending on, for example, factors which may also affect the EV and/or EEV levels. For example, it is reported herein that a subject&#39;s EEV levels may be affected by whether or not the subject is being treated for their PD symptoms, whether the subject has or previously had cancer, whether the subject has or previously had diabetes, or whether the subject is taking anti-inflammatory medication. 
     In some embodiments, the present description relates to a method for treating a subject with PD, the method comprising clinically assessing Parkinson&#39;s disease in the subject by a method described herein, and commencing, administering, and/or modifying PD treatment based on the clinical assessment. 
     The scope of the claims should not be limited by the particular embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole 
     EXAMPLES 
     Example 1—Methods 
     1.1 Participant Recruitment and Ethic Statement 
     Human blood was obtained from two cohorts of participants. The first cohort was composed of Parkinson&#39;s disease (PD) patients and healthy age- and sex-matched Controls, and the second cohort was composed of Huntington&#39;s disease (HD) patients and healthy age- and sex-matched Controls. The demographics for both cohorts are shown in Table 1. For the two cohorts, the Controls were recruited amongst the caregivers, spouses, family and friends of the patients. Institutional review boards approved this study (CHU de Québec-Université Laval, # A13-2-1096; CHUM, #14.228; Cambridge Central Regional Ethics Committee, REC #03/303 &amp; #08/H0306/26; and Cambridge University Hospitals Foundation Trust Research and Development department, R&amp;D # A085170 &amp; A091246) in accordance with the Declaration of Helsinki, and written informed consent was obtained from all participants. 
     In the case of PD patients, the clinical evaluation included measures on the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr (H&amp;Y) stage, the Mini Mental State Examination (MMSE), the Addenbrooke&#39;s Cognitive Examination (ACE), and the Beck Depression Inventory (BDI). In the case of the HD patients, we collected their scores on the Unified Huntington Disease Rating Scale (UPDRS), Total Functional capacity (TFC) and calculated values for burden of disease (BDS). All the clinical evaluations were conducted within 9 months of the blood drive. Participants were further asked to fill out a questionnaire related to health issues and medication and their full blood count performed on the day of blood sampling. 
     Of note, participants excluded from the present EEV-related analyses included those with diabetes and those suffering or having suffered from cancer, because we observed a significant PD-independent increase in EEV concentration in the platelet-free plasma of these participants. Furthermore, PFP samples with elevated free hemoglobin (&gt;45 000 ng/mL), potentially due to hemolysis at blood sampling, were also excluded from EEV-related analyses, which explains the discrepancies between the total number of participants initially recruited and those contained in each analysis. 
                     TABLE 1               Participant demographics                  Parkinson&#39;s disease (PD) cohort                                     PD Patients-Stages of disease                                                 Ctrl   Unknown   Mild   Moderate   Severe   P value               n   37   7   12   33   8           Age   66.8   69.8   66.7   71.1   75.0*   0.04                                                             Gender F (M)   18    (19)   1    (6)   6    (6)   16    (17)   0    (8)   0.05                 Disease severity                                                     Hoehn &amp; Yahr (n)           1 ± 0.3    (12)   2 ± 0.2    (33)   3 ± 0.5    (8)   &lt;0.0001       UPDRS (n)           38 ± 11    (6)   52 ± 19    (17)   73 ± 20    (6)   0.02       ACE (n)           96 ± 4    (6)   92 ± 7    (17)   84 ± 14    (6)   0.13       MMSE (n)           29 ± 2    (7)   29 ± 1    (19)   26 ± 3    (6)   0.01       BDI (n)           3 ± 2    (6)   4 ± 2    (17)   13 ± 7    (4)   0.03                 Comorbidities                                         Asthma   3   1   1   5   0   0.71       Hypertension   10   1   2   10   3   0.76       Diabetes   2   0   0   1   2   0.10       Cancer   5   0   3   4   1   0.64       Allergies   2   0   2   6   2   0.28       Depression   3   1   2   1   2   0.29       Hyper-   5   0   1   6   1   0.73       cholesterolemia                         Huntington&#39;s disease (HD) cohort                                     HD Patients-Stages of disease                                                         Ctrl   Pre-HD   Stage 1   Stage 2   Stage 3   Stage 4   Stage 5   P value               n   55   11   15   13   12   10   2           Age   55.0   37.5   53.1   54.2   58.3   58.1   55.5   0.02                                                                             Gender F (M)   31    (22)   6    (5)   5    (10)   4    (9)   8    (4)   7    (3)   1    (1)   0.26                 Disease severity                                                                         UHDRS (n)       2.7    (11)   15.7    (14)   34.5    (11)   42.9    (12)   55.9    (10)   67.5    (2)   &lt;0.001                                                                             TFC (n)   13    (16)   13    (11)   12.5    (15)   7.8    (13)   4.3    (12)   1.6    (10)   0   (2)   &lt;0.001                                                                         CAG (n)   28.3    (3)   41.1    (10)   42.3    (13)   42.6    (12)   43.7    (7)   44.3    (7)       &lt;0.001                                                                     BDS (n)       206    (10)   337    (13)   356    (12)   442    (7)   465    (7)       &lt;0.001                 Comorbidities                                                 Asthma   0   0   1   0   0   0   0   0.65       Hypertension   4   1   2   1   1   2   0   0.92       Diabetes   3   1   1   1   1   1   0   0.99       Cancer   0   0   0   0   0   0   0           Allergies   3   0   2   2   0   0   0   0.33       Depression   8   1   1   3   6   4   1   0.0497       Hyper-   8   1   1   0   0   1   0   0.32       cholesterolemia               Table 1: Participant clinical information. (PD cohort) Disease severity levels in relation to the H&amp;Y scale (score): Mild (1-1.5); Moderate (2-2.5); Severe (3-3.5).       *p &lt; 0.05 vs. CTRL. Statistical analyses were performed using a Welch ANOVA followed by Dunnett&#39;s multiple comparison test. Disease severity was evaluated within 6 months of blood sampling. Comorbidities were determined from medical information reported by the participant or caregiver. Cancer refers to participant having suffered from cancer in the past. (HD cohort) Disease severity levels in relation to the TFC scale: Stage 1 (11-13); Stage 2 (7-10); Stage 3 (3-6); Stage 4 (1-2); Stage 5 (0). Disease severity was evaluated within 6 months of blood sampling. Comorbidities were determined from medical information reported by the participant or caregiver. Abbreviations: ACE, Addenbrooke&#39;s cognitive examination; BDI, Beck depression inventory; BDS, Burden of Disease Score; CAG, Trinucleotide repeat; MMSE, Mini-Mental State Examination; UHDRS, Unified Huntington&#39;s Disease Rating Scale; TFC, Total Function Capacity.            
1.2 Preparation of Platelet-Free Plasma (PFP) and Extracellular Vesicle (EV) Labeling
 
     Citrated blood was centrifuged twice for 15 minutes at 2500 g at room temperature. Platelet-free plasma (PFP) was harvested and stored at −80° C. within 2 hours of collection following guidelines suggested by Lacroix and colleagues (Lacroix et al., 2012). 
     For all experiments, diluted annexin-V buffer (BD Pharmingen, Mississauga, ON, Canada) and phosphate buffered saline (PBS) were filtered on 0.22 μm pore size membranes. To quantify the EV according to their cell of origin, the following surface markers were used: CD235a+(erythrocytes) (5 μL), CD31+/CD41−(endothelial cells) (1 μL), CD41+(platelets) (5 μL), CD45+(leukocytes) (3 μL), CD45+CD14+(monocytes) (10 μL), and CD45+CD15+(granulocytes) (2 μL), with or without annexin-V staining (5 μL). PFP (5 μL) was incubated with Phenylalanyl-prolyl-arginyl Chloromethyl Ketone (PPACK) (Calbiochem, Etobicoke, ON, Canada) for 5 minutes, followed by a 30-minute incubation with antibodies and annexin-V in a final PBS volume of 100 μL, all at room temperature. Finally, the samples were diluted to a final volume of 2 mL prior to FACS analysis. The following antibodies were purchased at BD Pharmingen and used throughout the experiments: FITC-conjugated mouse anti-human CD235a (clone GA-R2 (HIR2), 1/20), PE-conjugated mouse anti-human CD31 (clone WM59, 1/100), V450-conjugated mouse anti-human CD41a (clone HIP8, 1/20), APC mouse anti-human CD14 (clone M5E2, 1/10), PE-conjugated mouse anti-human CD15 (clone H198, 1/50), V450-conjugated mouse anti-human CD45 (clone H130, 1/33), V450- and PerCP-Cy™5.5-conjugated annexin-V (1/33 and 1/10, respectively). 
     1.3 Flow Cytometry Quantification 
     For EV quantification, we used a FACS Canto II Special Order Research Product equipped with a forward scatter (FSC) coupled to a photomultiplier tube (FSC-PMT). Flow cytometer performance tracking was carried out daily using the BD cytometer setup and tracking beads (BD Biosciences, San Jose, Calif., USA). The size of the EV was determined using fluorescent silicone beads of 100, 500 and 1000 nm. Controls and optimization of the detection method are presented in  FIGS.  1 A- 1 F . The settings for the EV detection were determined as described previously (Rousseau et al., 2015) using a threshold of 200 for SSC. Between PD and HD analyses, the blue laser had to be replaced for maintenance issues and therefore laser settings were reassessed. For FSC-PMT, the assigned voltage was 363 (PD) and 160 (HD) Volts. For SSC, the assigned voltage was 407 (PD) and 300 (HD) Volts. All other parameters were set between 450 and 500 Volts. The acquisition of EV was performed at low speed with an approximate rate of 10 μL/min. To determine background noise level, antibody mixes were incubated in absence of PFP sample and unlabeled PFP was used as a negative control. 
     1.4 Statistical Analyses 
     All statistical analyses pertaining to Examples 2.1 and 2.2 were performed using “The Statistics and Machine Learning Toolbox” provided by MathWorks™ under the MATLAB™ platform. The version used was MATLAB®R2015a. The analysis included the scatter plot, the classical least-squares linear regression model, the R-squared and p values, as well as Pearson&#39;s goodness-of-fit model. Interval cut-off values were determined using a loop program developed in MATLAB™. Model diagnostics, including residual behaviour and homoscedastivity, were also obtained with the same Toolbox. 
     1.5 Production and Purification of EEV 
     Blood was collected in heparin tubes and centrifuged for 10 minutes at 282 g at room temperature. Blood cells were washed first in PBS-2% FBS, then with 0.9% sodium chloride solution and centrifuged for 10 minutes at 750 g. To avoid leukocyte and/or platelet contamination, the buffy coat and the upper fraction of erythrocytes were removed. To preserve erythrocytes, two volumes of glycerolyte 57 solution (57% glycerol, 142 mM sodium lactate, 1 mM KCl, 25 mM sodium phosphate pH 6.8) were added to the pellet and stored at −80° C. 
     For the production of EEV, red bloods cells were thawed and EV production was induced as previously described (Minetti et al., 2004). Briefly, the erythrocyte pellet was activated with 3 volumes of calcium ionophore solution (150 mM NaCl; 10 mM Tris-HCl; 1 mM CaCl 2 ; 5 μM ionophore A23187 (Sigma, St Louis, Mo.)) for 30 minutes at 37° C. The activation was stopped by the addition of 5 mM EDTA. Remaining erythrocytes were pelleted at 15 000 g for 20 minutes. The EEV were centrifuged at 20 000 g for 90 minutes and washed once in PBS. The EEV pellet was resuspended in PBS and frozen at −80° C. until further analyses. 
     1.6 C-Reactive Protein, Free Hemoglobin and α-Synuclein Quantification 
     The concentrations of C-reactive protein (CRP) and free hemoglobin were determined in the PFP of all donors using the RayBio™ Human CRP ELISA Kit (RayBiotech, Norcross, Ga., USA) and the Hemoglobin Human ELISA kit (Abcam, Toronto, ON, Canada). To quantify α-synuclein (α-Syn) in erythrocytes and EEV, we used the human α-Syn ELISA kit (ThermoFisher Scientific, Waltham, Mass., USA). Absorbance values were measured at 450 nm using a multi-detection microplate reader (Synergy HT; BioTek; Winooski, Vt., USA). All ELISA tests were performed according to the manufacturer&#39;s instructions. 
     1.7 Scanning Electron Microscopy 
     Preparations of erythrocytes (5 μL) were fixed in 2% paraformaldehyde and 2.5% glutaraldehyde in PBS buffer at least 24 hours before standard dehydration. Samples were washed 3 times for 10 minutes with sodium cacodylate buffer (0.1 M, pH 7.3) and fixed with 1% osmium tetroxide in sodium cacodylate buffer for 90 minutes. Subsequently, samples were washed and processed in 50%, 70%, 90% and 100% ethanol for dehydration (10 minutes/step). Finally, samples were soaked in two subsequent baths of 100% ethanol, for 40 minutes and 10 minutes, air-dried overnight and coated with palladium. Observations were completed using a JEOL 6360LV scanning electron microscope (JEOL, Peabody, Mass., USA). 
     1.8 Transmission Electron Microscopy 
     Preparations of EEV (30 μL) and activated erythrocytes (5 μL) were fixed in 2% paraformaldehyde at least 24 hours before being dehydrated and sealed in LR white resin. Slices of LR white resin were placed on a Formvar/carbon-coated grid and processed for immunolabeling. The tissues mounted on grids were blocked in 0.5% BSA-c (Aurion, Wageningen, The Netherlands) in HBSS and incubated for 120 minutes with rabbit anti-α-Syn antibody (Abcam, Toronto, ON, Canada) or rabbit anti-α-Syn (phospho S129) antibody (Abcam, Toronto, ON, Canada), both diluted at 1:250 in HBSS and washed several times with distilled water. Finally, the grids were incubated for 60 minutes with an anti-rabbit IgG conjugated to 6 nm gold particles (EMS, Hatfield, Pa., USA) diluted at 1:200 and washed several times with distilled water to ultimately be fixed in 2.5% glutaraldehyde (EMS, Hatfield, Pa., USA) in HBSS for 15 minutes. For this last step, the grids were treated with 3% uranyl acetate-0.075 M oxalate (pH 7.0) (EMS, Hatfield, Pa., USA) for 1 minute, which was followed by several washes in distilled water. Observations were completed with a TECNAI Spirit G2 transmission electron microscope at 80 kV (FEI, Hillsboro, Oreg., USA). 
     1.9 Mass Spectrometry Analysis and Label Free Protein Quantification 
     For proteomic analyses, EEV from 4 individuals per group (Control, mild PD and moderate PD) were prepared as described above. For each individual, 25 μg of protein sample, according to Bradford protein assay, were migrated onto an electrophoresis gel 4-12% Bis-Tris to separate hemoglobin from higher proteins. Following gel staining using Sypro Ruby (Thermo Fischer Scientific), the 12 kDa band corresponding to the hemoglobin size was cut out and the remaining part of the gel further fractioned into 7 slices, exposed to trypsin digestion and peptide extraction on a MassPrep™ liquid handling robot (Waters, Milford, USA) according to the manufacturer&#39;s specifications and to the protocol of Shevchenko et al., 1996, with the modifications suggested by Havlis et al., 2003. The extracted peptides from the 7 slices of the same individual were pooled and analyzed by nanoLC-MS/MS. The excised hemoglobin gel slices were also analyzed in the same conditions. One μg of each individual sample was injected on a Dionex UltiMate™ 3000 nanoRSLC system (Thermo Scientific) equipped with a nanoviper Acclaim Pepmap100™, C18, 3 μm, 75 μm×50 cm column (Thermo Scientific) connected to the nanoelectrospray source of an Orbitrap Fusion™ mass spectrometer (Thermo Scientific). The peptides were eluted at 300 nL/min using an acetonitrile gradient of 90 minutes and the mass spectrometer was operating in Data Dependent Acquisition mode. Peptide masses were measured in MS spectra detected in the orbitrap at 120K resolution. MSMS fragmentation spectra of peptides were generated by Higher energy Collisional Dissociation (HCD) and detected in the ion trap. Spectra were searched against a human protein database (Uniprot Complete Proteome, taxonomy  Homo sapiens —83512 sequences) using Andromeda™ search engine included in MaxQuant™ software version 1.5.5.1 (Cox et al., 2008). MaxQuant™ was also used to validate proteins and peptides at 1% False Discovery Rate using a target/decoy database search and to perform Label Free Quantification of the identified proteins using the ‘match between runs’ option. 
     1.10 Further Statistical Analyses 
     For  FIGS.  3 C and  3 D , data were first tested for normality using the D&#39;Agostino &amp; Pearson normality test. Comparisons between groups were obtained by Mann-Whitney U test or Kruskal-Wallis ANOVA and performed using Prism 6.0 (GraphPad Software, LaJolla, Calif.). For analyses displayed in  FIG.  4 C , the ‘Intensity values’ contained in the output ‘proteingroup.txt’ file of MaxQuant™ were used to quantify each identified protein in each individual sample. The values were normalized by the median of each column (all intensity values of proteins for one sample). The missing values were imputed with a noise value corresponding to the 1-percentile of each sample column. For each comparison between two groups (Control, mild PD or moderate PD), proteins with too many imputed values where considered not quantifiable (a minimum of three not-imputed values in one of the 2 groups are required). A protein ratio was calculated between the two groups using the average of intensity values in each group. Finally, a statistical Welch&#39;s test was performed between the two groups. The protein ratios were transformed into log 2(ratio) then centered by calculation of a z-score (z-score=(x−μ/σ). A protein was considered as variant if it fulfilled the following criteria: minimum of 2 peptides quantified, Welch&#39;s test p value&lt;0.05 and absolute value of z-score&gt;1.96 (corresponding to values outside of the 95% confidence interval). The Gene Ontology enrichment analysis on the identified proteins ( FIG.  4 D ) was performed on the Cytoscape™ platform (v. 3.4.0) using the BinGO™ software version 3.0.3 (Maere et al., 20005) against all human genes with GO annotation (Uniprot-GOA generated 2015Jun. 2022). Enrichment was calculated by hypergeometric test and Bonferroni Family-Wise Error Rate (FWER) was used to correct for multiple testing. The data for the resulting 8 proteins was standardized, hierarchically clustered and visualized as a heatmap by using the statistical framework R (R Core Team, 2016). The robustness of the nodes was evaluated by computing Approximately Unbiased (AU) p values using the R package pvclust (10000 bootstraps, average method and correlation-based dissimilarity matrix) (Suzuki et al., 2006). 
     Example 2—Results 
     The cohorts studied here included Parkinson&#39;s disease (PD) (n=60) and Huntington&#39;s disease (HD) patients (n=63) of all stages (see Example 1.1), as well as their respective age- and sex-matched healthy controls (n=37; n=55, respectively). The demographics for both cohorts are shown in Table 1. Full blood counts (erythrocytes, lymphocytes, platelets, leukocytes, monocytes, neutrophils) and C-reactive protein (indicative of an inflammatory response) quantification were obtained for all participants, but they did not reveal any significant differences between groups (data not shown). Similarly, the hematocrit, the mean corpuscular hemoglobin, as well as the mean corpuscular volume values were similar between PD and control groups (data not shown). 
     2.1 PD Patients Exhibit a Disease-Specific Increase in Erythrocyte-Derived EV 
     Platelet-free plasma (PFP) and extracellular vesicles (EV) were labeled and quantified according to their cell of origin for all participants, as described in Examples 1.2 and 1.3. Results are summarized in Table 2A (PD patients and controls) and Table 2B (HD patients and controls). 
     As shown in Table 2A, no significant differences between PD patient and control samples were observed in the number of EV originating from platelets, endothelial cells, monocytes, granulocytes, and leukocytes. Similarly, as shown in Table 2B, no significant differences between HD patient and control samples were observed in the concentrations of EV originating from these same cell types. 
     Interestingly, a significant increase in erythrocyte-derived EV in patients with PD was observed, as compared to the control group (see values highlighted in black in Table 2A). This increase in erythrocyte-derived EV in patients with PD was disease-specific, as the same effect was not observed in erythrocyte-derived EV in patients with HD (Table 2B). 
     
       
         
           
               
             
               
                 TABLE 2A 
               
             
            
               
                   
               
               
                 Quantification of extracellular vesicles (EV) derived from 
               
               
                 different cell types of PD patients and controls 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 CTRL 
                 PD 
                 P  
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Cell type 
                 Markers 
                 Units 
                 n 
                 Mean 
                 SEM 
                 n 
                 Mean 
                 SEM 
                 value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Platelets 
                 CD41+PS− 
                 ×10 3 /μL 
                 37 
                 7.88 
                 1.68 
                 59 
                 10.3 
                 1.33 
                 0.27 
               
               
                   
                 CD41+PS+  
                   
                 37 
                 15.2 
                 3.20 
                 59 
                 17.9 
                 2.53 
                 0.51 
               
               
                   
                 CD41+CD31+  
                   
                 37 
                 1.51 
                 0.69 
                 59 
                 1.99 
                 0.54 
                 0.59 
               
               
                   
                 CD41+total 
                   
                 37 
                 23.1 
                 4.62 
                 59 
                 28.2 
                 3.66 
                 0.38 
               
               
                   
                 EV  
                   
                 35 
                 0.106 
                 0.021 
                 57 
                 0.125 
                 0.016 
                 0.49 
               
               
                   
                 CD41+/platelet 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Endothelial  
                 CD31+CD41−PS− 
                 ×10 3 /μL 
                 37 
                 15.8 
                 8.04 
                 59 
                 11.7 
                 6.37 
                 0.75 
               
               
                 cells 
                 CD31+CD41−PS+  
                   
                 37 
                 0.91 
                 0.13 
                 59 
                 0.92 
                 0.10 
                 0.96 
               
               
                   
                 CD31+CD41−total 
                   
                 37 
                 16.7 
                 8.03 
                 59 
                 12.6 
                 6.36 
                 0.75 
               
               
                 Monocytes 
                 CD45−CD14−PS− 
                 ×10 3 /μL 
                 37 
                 1.70 
                 0.30 
                 59 
                 1.62 
                 0.24 
                 0.85 
               
               
                   
                 CD45−CD14+PS+  
                   
                 37 
                 1.20 
                 4.00 
                 59 
                 5.84 
                 3.17 
                 0.50 
               
               
                   
                 CD45+CD14+PS− 
                   
                 37 
                 0.16 
                 0.04 
                 59 
                 0.14 
                 0.03 
                 0.74 
               
               
                   
                 CD45+CD14+PS+  
                   
                 37 
                 0.60 
                 0.79 
                 59 
                 1.47 
                 0.63 
                 0.59 
               
               
                   
                 CD14+total 
                   
                 37 
                 3.66 
                 4.88 
                 59 
                 9.06 
                 3.87 
                 0.60 
               
               
                   
                 EV  
                   
                 35 
                 7.08 
                 1.99 
                 57 
                 9.16 
                 1.56 
                 0.41 
               
               
                   
                 CD14+/monocyte 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Granulocytes 
                 CD45−CD15+PS− 
                 ×10 3 /μL 
                 37 
                 12.3 
                 7.96 
                 59 
                 16.7 
                 6.30 
                 0.92 
               
               
                   
                 CD45−CD15+P5+  
                   
                 37 
                 2.21 
                 0.77 
                 59 
                 1.39 
                 0.61 
                 0.47 
               
               
                   
                 CD45+CD15+PS− 
                   
                 37 
                 0.55 
                 0.36 
                 59 
                 1.15 
                 0.29 
                 0.20 
               
               
                   
                 CD45+CD15+PS+  
                   
                 37 
                 1.01 
                 0.30 
                 59 
                 1.25 
                 0.24 
                 0.56 
               
               
                   
                 CD15+total 
                   
                 37 
                 16.0 
                 8.83 
                 59 
                 20.6 
                 6.99 
                 0.91 
               
               
                   
                 EV  
                   
                 35 
                 3.70 
                 0.64 
                 57 
                 3.16 
                 0.50 
                 0.53 
               
               
                   
                 CD15+/granulocyte 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Leukocytes 
                 CD45+total 
                 ×10 3 /μL 
                 37 
                 10.4 
                 2.21 
                 59 
                 13.8 
                 1.75 
                 0.26 
               
               
                 Erythrocytes 
                 CD235a+PS− 
                 ×10 3 /μL 
                 36 
                 18.2 
                 46.5 
                 59 
                 32.0 
                 36.3 
                 0.04 
               
               
                   
                 CD235a+PS+  
                   
                 36 
                 0.22 
                 0.07 
                 59 
                 0.29 
                 0.05 
                 0.70 
               
               
                   
                 CD235a+total 
                   
                 36 
                 18.4 
                 47.0 
                 59 
                 32.3 
                 36.7 
                 0.04 
               
               
                   
                 EV  
                   
                 34 
                 0.0039 
                 0.011 
                 57 
                 0.0069 
                 0.008 
                 0.04 
               
               
                   
                 CD235a+/erythrocyte 
               
               
                   
               
               
                 Abbreviations: CD235a, glycophorin A; EV, extracellular vesicle; PD, Parkinson&#39;s disease; PS, phosphatidylserine. 
               
            
           
         
       
     
                     TABLE 2B                  Quantification of extracellular vesicles (EV) derived from different cell types of HD patients and controls                                         Cell            CTRL   HD pre-manifest   HD   P                                                                  types   Markers   Units   n   Mean   SEM   n   Mean   SEM   n   Mean   SEM   value                                                                         Platelets   CD41+PS−   ×10 3 /μL   54   9.2   2.2   10   4.3   1.3   50   6.1   1.0   0.78           CD41+PS+        54   19.3   4.8   10   7.1   2.0   50   12.4   2.4   0.74           CD41+total       54   28.4   6.9   10   11.4   3.2   50   18.6   3.4   0.70           EV        53   0.12   0.03   10   0.05   0.02   48   0.08   0.01   0.34           CD41+/platelet                                                   Endothelial   CD31+CD41−PS−   ×10 3 /μL   54   1.4   0.3   10   0.6   0.2   50   1.2   0.2   0.31       cells   CD31+CD41−PS+        54   0.68   0.16   10   0.25   0.06   50   0.46   0.09   0.59           CD31+CD41−total       54   2.1   0.4   10   0.8   0.2   50   1.7   0.3   0.26       Monocytes   CD45−CD14+PS−   ×10 3 /μL   54   3.4   1.1   10   1.6   0.2   51   1.6   0.1   0.91           CD45−CD14+PS+        54   1.8   0.3   10   0.8   0.3   51   1.5   0.2   0.14           CD45+CD14+PS−       54   0.18   0.07   10   0.069   0.016   51   0.056   0.008   0.34           CD45+CD14+PS+        54   0.62   0.12   10   0.24   0.06   51   0.55   0.14   0.12           CD14+total       54   6.0   1.3   10   2.6   0.4   51   3.7   0.4   0.08           EV        53   12.3   2.5   10   5.7   0.6   48   8.0   1.0   0.13           CD14+/monocyte                                                   Granulocytes   CD45−CD15+PS−   ×10 3 /μL   54   1.2   0.1   10   1.2   0.3   51   1.5   0.2   0.33           CD45−CD15+PS+        54   0.12   0.04   10   0.18   0.08   51   0.22   0.11   0.33           CD45+CD15+PS−       54   0.20   0.05   10   0.07   0.02   51   0.15   0.04   0.64           CD45+CD15+PS+        54   0.25   0.05   10   0.13   0.06   51   0.20   0.04   0.39           CD15+total       54   1.7   0.2   10   1.6   0.4   51   0.20   0.3   0.67           EV        53   0.41   0.04   10   0.42   0.13   48   0.50   0.08   0.75           CD15+/                                                       granulocyte                                                   Leukocytes   CD45+total   ×10 3 /μL   54   33.4   2.7   10   31.6   5.3   51   31.7   2.4   0.88       Erythrocytes   CD235a+PS−   ×10 3 /μL   54   15.2   2.0   10   10.3   3.5   51   14.1   1.4   0.16           CD235a+PS+        54   1.1   0.2   10   0.4   0.2   51   1.1   0.1   0.04           CD235a+total       54   16.4   2.0   10   10.7   3.5   51   15.3   1.5   0.09           EV        54   0.0035   0.0005   10   0.0023   0.0008   50   0.0033   0.0003   0.11           CD235a+/                                                       erythrocyte               Abbreviations: CD235a, glycophorin A; EV, extracellular vesicle; HD, Huntington&#39;s disease; PS, phosphatidylserine.            
2.2 Increase in Erythrocyte-Derived EV in PD Patient Samples Correlates with PD Progression and PD Treatment
 
     To evaluate its suitability as a potential biomarker for monitoring PD progression, we examined correlations between the number of erythrocyte-derived EV (EEV) and the Unified Parkinson&#39;s Disease Rating Scale (UPDRS) PD staging system, because of its greater sensitivity and the recent publications validating this approach (Martinez-Martin et al., 2015). Strikingly, statistical linear regression analysis revealed strong correlations between the number of erythrocyte-derived EV and PD stage/progression. As shown in  FIG.  2 A , strong correlations (correlations exceeding 0.8) were observed between the number of erythrocyte-derived EV (expressed as CD135a+EV/total number of erythrocytes) and patient UPDRS score, and thus PD stages. The R 2  values obtained demonstrated that in both “mild” and “moderate” PD patient groups, at least 87% of the variation in the total number of EEV/erythrocytes is due to the variation of the UPDRS. Moreover, the results are significant with respect to the p values obtained for each fit, since they fall below the 5% confidence level. Hence, the statistical tests on EEV counts uncovered a clear cut-off point between mild and moderate PD patients, which could not be accounted for by daily levodopa doses administered to the patient ( FIG.  2 A , see details of the 5 patients pinpointed). 
     The above correlations observed with respect to the number of EEV in PD patients was found to be disease-specific, since a similar analysis performed in HD patients failed to reveal the same strong correlations (see  FIG.  2 B ). In the HD cohort, the total number of EEV between pre-manifest and manifest HD was similar to their age- and sex-matched healthy Controls. In contrast to PD, correlation analyses failed to reveal an association between the number of EEV and HD stage using the United Huntington&#39;s Disease Rating Scale (UHDRS) score ( FIG.  2 B ). Based on this, all our subsequent analyses focused only on the PD cohort. It is should be re-emphasized that total blood counts did not indicate any significant differences in the number of endothelial cell-, platelet-, monocyte- and granulocyte-derived EV in the platelet-free plasma (PFP) in PD (Table 2A) and HD patients (Table 2B), when compared to their respective control cohorts. 
     We have thus identified at least two distinct groups of PD patients with highly significant correlations to the number of EV derived from erythrocytes, which relates to PD stage and/or PD treatment ( FIG.  2 A ). Strikingly, these correlations appear to be specific to PD, as similar correlations were not observed in the cohort of HD patients (of varying degrees of severity) in which we performed identical analyses ( FIG.  2 B ). 
     2.3 α-Syn is not Differentially Expressed in Normal Vs. Diseased PD Conditions 
     Having established that EEV counts correlate with disease state in PD, we aimed to assess whether α-Syn—which is not only the main component of Lewy bodies but is highly expressed in most blood cells—was differentially expressed in normal vs. diseased conditions. For this, we opted to use scanning electron microscopy, but this did not reveal any morphological changes between resting and activated erythrocytes in either condition ( FIG.  3 A ). We further used transmission electron microscopy to quantify the number of EEV containing α-Syn and phosphorylated (serine 129) forms of the protein but again no significant differences between PD patients and age- and sex-matched healthy Controls ( FIGS.  3 B and  3 C ) were observed. Quantified α-Syn levels in EEV from PD patients and Controls using commercial ELISA kits corroborated these results ( FIG.  3 D ). 
     2.4 Analysis of the EEV Proteome Revealed 8 Differentially Expressed Proteins 
     Since our combined quantifications (ELISA and transmission electron microscopy) suggested that α-Syn levels could not be used as a blood marker of disease, we sought to obtain the specific protein signature of EEV from mild and moderate PD patients (with respect to the UPDRS scores) and their age-matched Controls. Given the significant amounts of hemoglobin within erythrocytes that could mask the true nature of the protein signature in EEV, we performed a label free quantitative proteomic analysis by nanoLC/MSMS (Wither et al., 2016) using two distinct approaches: with and without hemoglobin. 
     By removing the hemoglobin, we identified a total of 818 proteins in comparison with 356 when we did not perform this methodological step (refer to Table 4 for complete list of proteins), which clearly, provides a much more thorough evaluation of the protein content of EEV. Additionally, a Gene Ontology enrichment analysis on the ‘Cellular Component’ ontology performed on the two sets of identified proteins in comparison with the whole human proteome, revealed that our samples are enriched with elements associated to ‘vesicles’ and ‘hemoglobin complex’ which show the efficiency of our EEV production and purification protocol (data not shown). 
     Out of the 818 proteins identified in the proteome of EEV, 8 had their expression significantly modified according to the different stages of PD ( FIGS.  4 A and  4 B ). Hierarchical clustering, coupled to a heatmap ( FIG.  4 D ), allowed us to group individuals according to stages of disease (Control, mild PD and moderate PD) and provided compelling evidence that the 8 proteins identified could also be grouped into three categories. Proteins of group I were highly and predominantly expressed in Controls, proteins of group II were highly and predominantly expressed in mild PD patients, and proteins belonging to group Ill were highly and predominantly expressed in moderate PD patients ( FIGS.  4 B and  4 C ; Table 3). This data set was further confirmed by volcano plots ( FIG.  5   ). Of note, two proteins of group I are associated with the regulation system of the cell (ABHD14B, NADSYN1) and one protein significantly expressed in moderate PD patients (ATP5A1) is involved in the regulation of mitochondrial ATP. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 EEV proteins differentially expressed  
               
               
                 according to different stages of PD 
               
            
           
           
               
               
               
               
            
               
                   
                 Groups 
                 Protein 
                 Gene 
               
               
                   
                   
               
               
                   
                 I 
                 Axin interactor, dorsalization- 
                 AIDA 
               
               
                   
                 (Control) 
                 associated protein 
                 ABHD148 
               
               
                   
                   
                 Alpha/beta hydrolase domain- 
                   
               
               
                   
                   
                 containing protein 14B 
                   
               
               
                   
                   
                 Glutamine-dependent  
                 NADSYN1 
               
               
                   
                   
                 NAD(+) synthetase 
                   
               
               
                   
                 II 
                 Dihydropteridine reductase 
                 QDPR 
               
               
                   
                 (mild PD) 
                 Alcohol dehydrogenase [NADP(+)] 
                 AKR1A1 
               
               
                   
                   
                 CB1 cannabinoid receptor- 
                 CNRIP1 
               
               
                   
                   
                 interacting protein 1 
                   
               
               
                   
                 III 
                 Ubiquitin carboxyl-terminal  
                 USP24 
               
               
                   
                 (moderate 
                 hydrolase 24 
                   
               
               
                   
                 PD) 
                 ATP synthase subunit 
                 ATP5A1 
               
               
                   
                   
                 alpha, mitochondrial 
               
               
                   
                   
               
            
           
         
       
     
     Fold changes and the results of statistical analyses of the proteins of Table 3 are shown in Table 3.1, in which the proteins are listed in order of their “fold” difference for each group comparison. For example, a “fold” of 1.931 indicates that the AKR1A1 protein was detected in the isolated EEV preparations almost two times higher in the mild group, as compared to the control group. 
     
       
         
           
               
             
               
                 TABLE 3.1 
               
             
            
               
                   
               
               
                 Fold changes and statistics of EEV proteins of Table 3 
               
            
           
           
               
               
               
               
               
            
               
                 Protein 
                 Gene 
                 Welch&#39;s test 
                 Fold change 
                 Z-score 
               
               
                   
               
            
           
           
               
            
               
                 Mild (Group II) v. Controls (Group I) 
               
            
           
           
               
               
               
               
               
            
               
                 Alcohol dehydrogenase [NADP(+)] 
                 AKR1A1 
                 0.019 
                 1.931 
                 2.25 
               
               
                 Alpha/beta hydrolase domain- 
                 ABHD148 
                 0.016 
                 0.274 
                 −3.57 
               
               
                 containing protein 14B 
                   
                   
                   
                   
               
            
           
           
               
            
               
                 Moderate (Group III) v. Controls (Group I) 
               
            
           
           
               
               
               
               
               
            
               
                 ATP synthase subunit  
                 ATP5A1 
                 0.028 
                 3.906 
                 3.25 
               
               
                 alpha, mitochondrial 
                   
                   
                   
                   
               
               
                 Glutamine-dependent  
                 NADSYN1 
                 0.009 
                 0.391 
                 −2.31 
               
               
                 NAD(+) synthetase 
                   
                   
                   
                   
               
               
                 Axin interactor, dorsalization- 
                 AIDA 
                 0.046 
                 0.379 
                 −2.38 
               
               
                 associated protein 
                   
                   
                   
                   
               
               
                 Alpha/beta hydrolase domain- 
                 ABHD148 
                 0.017 
                 0.282 
                 −3.09 
               
               
                 containing protein 14B 
                   
                   
                   
                   
               
            
           
           
               
            
               
                 Moderate (Group III) v. Mild (Group II) 
               
            
           
           
               
               
               
               
               
            
               
                 ATP synthase subunit  
                 ATP5A1 
                 0.027 
                 3.629 
                 2.77 
               
               
                 alpha, mitochondrial 
                   
                   
                   
                   
               
               
                 Ubiquitin carboxyl- 
                 USP24 
                 0.036 
                 2.971 
                 2.29 
               
               
                 terminal hydrolase 24 
                   
                   
                   
                   
               
               
                 CB1 cannabinoid receptor- 
                 CNRIP1 
                 0.014 
                 0.352 
                 −2.80 
               
               
                 interacting protein 1 
                   
                   
                   
                   
               
               
                 Alcohol dehydrogenase [NADP(+)] 
                 AKR1A1 
                 0.002 
                 0.342 
                 −2.87 
               
               
                 Dihydropteridine reductase 
                 QDPR 
                 0.040 
                 0.341 
                 −2.88 
               
               
                   
               
               
                 Proteins were considered as significantly differentially expressed if they respected two conditions: Z-score &gt;1.96 or &lt;−1.96, and Welch&#39;s test p-value &lt;0.05. 
               
            
           
         
       
     
     As seen in Table 3.1 and in  FIG.  4 C , the ABHD14B protein (alpha/beta hydrolase domain-containing protein 14B) was detected over 3.5-fold lower both in the mild v. controls and in the moderate v. controls groups, suggesting that this EEV protein may be a useful biomarker for clinically assessing symptomatic PD subjects. The results in Table 3.1 and in  FIG.  4 C  suggest that the AKR1A1 protein (alcohol dehydrogenase [NADP(+)]) may be a useful biomarker for clinically assessing mild PD subjects, as this EEV protein was detected almost 2-fold higher in mild v. control PD subjects, but was not differentially expressed in moderate v. control PD subjects. Finally, the results in Table 3.1 and in  FIG.  4 C  suggest that the ATP5A1 protein may be a useful biomarker for clinically assessing moderate PD subjects, since this protein was detected over 3.6-fold higher in both moderate v. controls and in moderate v. mild PD subjects. 
     Example 3—Discussion 
     We have identified biomarkers correlating to different states of PD based on the quantification of EV shed from erythrocytes and UPDRS scores. In particular, we have shown a strong correlation between the number of EEV and the clinical expression/stages of PD. Finding this level of correlation in a 60-patient sample size in such a heterogeneous disorder highlights the robustness of the biomarkers identified herein. 
     Although staging of PD is often done using the H &amp; Y clinical scale, we sought to use the UPDRS given its greater sensitivity and the recent publications validating this approach (Martinez-Martin et al., 2015). Using these scores, we found that mild PD patients—with a UPDRS score lower than 37—are characterized by an increased number of EV during the mild disease stage (correlations=0.886); and that the same pattern repeated itself with patients who had UPDRS scores between 37 and 75 (correlations=0.873). When comparing individual patients from both correlation curves, the dose of levodopa taken daily did not seem to account for the differences, as there was no correlation between the levodopa dose and the number of EEV. 
     Finally, we herein report an improved method to perform proteomic analysis of EEV in blood samples by removing hemoglobin, a large protein that can easily mask other ones within a protein signature. Indeed, the high dynamic range of protein concentrations in erythrocytes and therefore in EEV, due to the high abundance of hemoglobin, decreases the capacity of the mass spectrometer to detect signals corresponding to low abundance proteins. Analyzing the hemoglobin separately from the other proteins of other molecular weights allowed us to go deeper in the EEV proteome by identifying 129% more proteins than in the initial analysis. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Proteins identified in the EEV proteome. 
               
               
                 Lists of the proteins identified by LC-MS/MS analysis using Andromeda ™/MaxQuant ™ search engine in the Uniprot 
               
               
                 Complete Proteome  Homo sapiens  database for the non-hemoglobin-depleted sample (356 proteins) (A), or when 
               
               
                 the hemoglobin-depleted and hemoglobin-containing fractions were analyzed separately (818 proteins) (B). The lists 
               
               
                 were filtered at 1% False Discovery Rate using a target/decoy database search. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Razor + 
               
               
                   
                   
                 Gene  
                 unique 
               
               
                 Protein ID 
                 Protein names 
                 names 
                 peptides 
               
               
                   
               
            
           
           
               
            
               
                 (A). UNIPROT COMPLETE PROTEOME  HOMO SAPIENS   
               
               
                 DATABASE FOR THE NON-DEPLETED SAMPLE 
               
            
           
           
               
               
               
               
            
               
                 P02549 
                 Spectrin alpha chain, erythrocytic 1 
                 SPTA1 
                 136 
               
               
                 P11277 
                 Spectrin beta chain, erythrocytic 
                 SPTB 
                 123 
               
               
                 P16157 
                 Ankyrin-1 
                 ANK1 
                 70 
               
               
                 P02730 
                 Band 3 anion transport protein 
                 SLC4A1 
                 38 
               
               
                 P55072 
                 Transitional endoplasmic reticulum ATPase 
                 VCP 
                 33 
               
               
                 P16452 
                 Erythrocyte membrane protein band 4.2 
                 EPB42 
                 33 
               
               
                 P11171 
                 Protein 4.1 
                 EPB41 
                 33 
               
               
                 P04040 
                 Catalase 
                 CAT 
                 32 
               
               
                 Q13228 
                 Selenium-binding protein 1 
                 SELENBP1 
                 29 
               
               
                 B4DT77 
                 Annexin; Annexin A7 
                 ANXA7 
                 27 
               
               
                 Q8WUM4 
                 Programmed cell death 6-interacting protein 
                 PDCD6IP 
                 27 
               
               
                 P35612 
                 Beta-adducin 
                 ADD2 
                 26 
               
               
                 P68871 
                 Hemoglobin subunit beta; LW-hemorphin-7; Spinorphin 
                 HBB 
                 25 
               
               
                 Q00610 
                 Clathrin heavy chain 1 
                 CLTC 
                 25 
               
               
                 P69905 
                 Hemoglobin subunit alpha 
                 HBA1 
                 22 
               
               
                 B4DVE7 
                 Annexin All 
                 ANXa11 
                 20 
               
               
                 J3QLD9 
                 Flotillin-2 
                 FLOT2 
                 20 
               
               
                 P08758 
                 Annexin A5; Annexin 
                 ANXA5 
                 19 
               
               
                 P09525 
                 Annexin A4; Annexin 
                 ANXA4 
                 18 
               
               
                 O75955; 
                 Flotillin-1 
                 FL0T1 
                 18 
               
               
                 P11142 
                 Heat shock cognate 71 kDa protein 
                 HSPA8 
                 18 
               
               
                 P32119 
                 Peroxiredoxin-2 
                 PRDX2 
                 17 
               
               
                 P00491 
                 Purine nucleoside phosphorylase 
                 PNP 
                 17 
               
               
                 P27105 
                 Erythrocyte band 7 integral membrane protein 
                 STOM 
                 17 
               
               
                 P00918 
                 Carbonic anhydrase 2 
                 CA2 
                 17 
               
               
                 P23634 
                 Plasma membrane calcium-transporting ATPase 4 
                 ATP2B4 
                 17 
               
               
                 C9JIF9 
                 Acylamino-acid-releasing enzyme 
                 APEH 
                 17 
               
               
                 P00915 
                 Carbonic anhydrase 1 
                 CA1 
                 16 
               
               
                 P63261 
                 Actin, cytoplasmic 2 
                 ACTG1 
                 16 
               
               
                 Q5VU58 
                 Tropomyosin alpha-3 chain 
                 TPM3 
                 16 
               
               
                 P30041 
                 Peroxiredoxin-6 
                 PRDX6 
                 16 
               
               
                 E7EU23 
                 Rab GDP dissociation inhibitor beta 
                 GDI2 
                 16 
               
               
                 Q00013 
                 55 kDa erythrocyte membrane protein 
                 MPP1 
                 16 
               
               
                 E7EV01 
                 Calpain-5 
                 CAPN5 
                 16 
               
               
                 J3KPS3 
                 Fructose-bisphosphate aldolase A 
                 ALDOA 
                 15 
               
               
                 Q08495 
                 Dematin 
                 DMTN 
                 15 
               
               
                 P23276 
                 Kell blood group glycoprotein 
                 KEL 
                 15 
               
               
                 P69892 
                 Hemoglobin subunit gamma-2 
                 HBG2 
                 14 
               
               
                 P60174 
                 Triosephosphate isomerase 
                 TPI1 
                 14 
               
               
                 P62258 
                 14-3-3 protein epsilon 
                 YWHAE 
                 14 
               
               
                 O75326 
                 Semaphorin-7A 
                 SEMA7A 
                 14 
               
               
                 O75340 
                 Programmed cell death protein 6 
                 PDCD6 
                 13 
               
               
                 E7EV99 
                 Alpha-adducin 
                 ADD1 
                 13 
               
               
                 Q5VZU9 
                 Tripeptidyl-peptidase 2 
                 TPP2 
                 13 
               
               
                 P53396 
                 ATP-citrate synthase 
                 ACLY 
                 13 
               
               
                 C9J0K6 
                 Sorcin 
                 SRI 
                 12 
               
               
                 P04406 
                 Glyceraldehyde-3-phosphate dehydrogenase 
                 GAPDH 
                 12 
               
               
                 P07738 
                 Bisphosphoglycerate mutase 
                 BPGM 
                 12 
               
               
                 B7Z3I9 
                 Delta-aminolevulinic acid dehydratase 
                 ALAD 
                 12 
               
               
                 Q86X55 
                 Histone-arginine methyltransferase CARM1 
                 CARM1 
                 12 
               
               
                 P07195 
                 L-lactate dehydrogenase B chain; L-lactate dehydrogenase 
                 LDHB 
                 12 
               
               
                 P23526 
                 Adenosylhomocysteinase 
                 AHCY 
                 12 
               
               
                 Q32Q12 
                 Nucleoside diphosphate kinase 
                 NME1-NME2 
                 12 
               
               
                 B7Z7A9 
                 Phosphoglycerate kinase 1 
                 PGK1 
                 11 
               
               
                 P11166 
                 Solute carrier family 2, facilitated glucose transporter member 1 
                 SLC2A1 
                 11 
               
               
                 P22303 
                 Acetylcholinesterase 
                 ACHE 
                 11 
               
               
                 Q9NP58 
                 ATP-binding cassette sub-family B member 6, mitochondrial 
                 ABCB6 
                 11 
               
               
                 P40925 
                 Malate dehydrogenase, cytoplasmic; Malate dehydrogenase 
                 MDH1 
                 11 
               
               
                 P00352 
                 Retinal dehydrogenase 1 
                 ALDH1A1 
                 11 
               
               
                 F2Z2V0 
                 Copine-1 
                 CPNE1 
                 11 
               
               
                 K7EMC9 
                 WW domain-binding protein 2 
                 WBP2 
                 10 
               
               
                 F5H7S3 
                 Tropomyosin alpha-1 chain 
                 TPM1 
                 10 
               
               
                 A6NN80 
                 Annexin A6; Annexin 
                 ANXA6 
                 10 
               
               
                 P30043 
                 Flavin reductase (NADPH) 
                 BLVRB 
                 9 
               
               
                 H7BXD5 
                 Grancalcin 
                 GCA 
                 9 
               
               
                 P04083 
                 Annexin A1; Annexin 
                 ANXA1 
                 9 
               
               
                 P62937 
                 Peptidyl-prolyl cis-trans isomerase 
                 PPIA 
                 9 
               
               
                 P37837 
                 Transaldolase 
                 TALDO1 
                 9 
               
               
                 Q06830 
                 Peroxiredoxin-1 
                 PRDX1 
                 9 
               
               
                 O75131 
                 Copine-3 
                 CPNE3 
                 9 
               
               
                 P00390 
                 Glutathione reductase, mitochondrial 
                 GSR 
                 9 
               
               
                 E7EQB2 
                 Lactotransferrin 
                 LTF 
                 9 
               
               
                 P07384 
                 Calpain-1 catalytic subunit 
                 CAPN1 
                 9 
               
               
                 P02042 
                 Hemoglobin subunit delta 
                 HBD 
                 8 
               
               
                 P30086 
                 Phosphatidylethanolamine-binding protein 1;  
                 PEBP1 
                 8 
               
               
                   
                 Hippocampal cholinergic neurostimulating peptide 
                   
                   
               
               
                 P35613 
                 Basigin 
                 BSG 
                 8 
               
               
                 Q9H0U4 
                 Ras-related protein Rab-1B; Putative  
                 RAB1B;  
                 8 
               
               
                   
                 Ras-related protein Rab-1C 
                 RAB1C 
                   
               
               
                 P63092 
                 Guanine nucleotide-binding protein G(s) subunit alpha isoforms 
                 GNAS 
                 8 
               
               
                 P48506 
                 Glutamate-cysteine ligase catalytic subunit 
                 GCLC 
                 8 
               
               
                 P06702 
                 Protein S100-A9 
                 S100A9 
                 7 
               
               
                 Q9UBV8 
                 Peflin 
                 PEF1 
                 7 
               
               
                 P17931 
                 Galectin-3;Galectin 
                 LGALS3 
                 7 
               
               
                 P28066 
                 Proteasome subunit alpha type-5 
                 PSMA5 
                 7 
               
               
                 P07451 
                 Carbonic anhydrase 3 
                 CA3 
                 7 
               
               
                 E7EQ12 
                 Calpastatin 
                 CAST 
                 7 
               
               
                 P50895 
                 Basal cell adhesion molecule 
                 BCAM 
                 7 
               
               
                 P28074 
                 Proteasome subunit beta type-5 
                 PSMB5 
                 7 
               
               
                 G3V5Z7 
                 Proteasome subunit alpha type; Proteasome subunit alpha type-6 
                 PSMA6 
                 7 
               
               
                 P25786 
                 Proteasome subunit alpha type-1 
                 PSMA1 
                 7 
               
               
                 G3V1D3 
                 Dipeptidyl peptidase 3 
                 DPP3 
                 7 
               
               
                 P49247 
                 Ribose-5-phosphate isomerase 
                 RPIA 
                 7 
               
               
                 Q5T9B7 
                 Adenylate kinase isoenzyme 1 
                 AK1 
                 7 
               
               
                 P25789 
                 Proteasome subunit alpha type-4; Proteasome subunit beta type 
                 PSMA4 
                 7 
               
               
                 B4E022 
                 Transketolase 
                 TKT 
                 7 
               
               
                 J3Q539 
                 Ubiquitin-605 ribosomal protein L40; Ubiquitin;605 ribosomal  
                 UBB; RPS27A; 
                 6 
               
               
                   
                 protein L40; Ubiquitin-40S ribosomal protein S27a; 
                 UBC; UBA52; 
                   
               
               
                   
                 Ubiquitin; 40S ribosomal protein S27a; Polyubiquitin-B; 
                 UBBP4 
                   
               
               
                   
                 Ubiquitin; Polyubiquitin-C; Ubiquitin 
                   
                   
               
               
                 H0Y7A7 
                 Calmodulin 
                 CALM2 
                 6 
               
               
                 P28070 
                 Proteasome subunit beta type-4 
                 PSMB4 
                 6 
               
               
                 Q9H4G4 
                 Golgi-associated plant pathogenesis-related protein 1 
                 GLIPR2 
                 6 
               
               
                 Q9BY43 
                 Charged multivesicular body protein 4a 
                 CHMP4A 
                 6 
               
               
                 P48426 
                 Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha 
                 PIP4K2A 
                 6 
               
               
                 P28289 
                 Tropomodulin-1 
                 TMOD1 
                 6 
               
               
                 P07911 
                 Uromodulin; Uromodulin, secreted form 
                 UMOD 
                 6 
               
               
                 Q9GZP4 
                 PITH domain-containing protein 1 
                 PITHD1 
                 6 
               
               
                 P78417 
                 Glutathione 5-transferase omega-1 
                 GSTO1 
                 6 
               
               
                 P25788 
                 Proteasome subunit alpha type-3 
                 PSMA3 
                 6 
               
               
                 O14818 
                 Proteasome subunit alpha type-7; 
                 PSMA7; 
                 6 
               
               
                   
                 Proteasome subunit alpha type-7-like 
                 PSMA8 
                   
               
               
                 P08107 
                 Heat shock 70 kDa protein 1A/1B 
                 HSPA1A 
                 6 
               
               
                 H0YD13 
                 CD44 antigen 
                 CD44 
                 6 
               
               
                 P61225 
                 Ras-related protein Rap-2b; Ras-related protein Rap-2c;  
                 RAP2B; RAP2A; 
                 6 
               
               
                   
                 Ras-related protein Rap-2a 
                 RAP2C 
                   
               
               
                 P05109 
                 Protein S100-A8; Protein S100-A8, N-terminally processed 
                 S100A8 
                 6 
               
               
                 P23528 
                 Cofilin-1 
                 CFL1 
                 6 
               
               
                 Q99808 
                 Equilibrative nucleoside transporter 1 
                 SLC29A1 
                 6 
               
               
                 P84077 
                 ADP-ribosylation factor 1; ADP-ribosylation factor 3; 
                 ARF1; ARF3; 
                 6 
               
               
                   
                 ADP-ribosylation factor 5; ADP-ribosylation factor 4 
                 ARF5; ARF4 
                   
               
               
                 P31946 
                 14-3-3 protein beta/alpha; 14-3-3 protein beta/alpha,  
                 YWHAB 
                 6 
               
               
                   
                 N-terminally processed 
                   
                   
               
               
                 C9JIS1 
                 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2; 
                 GNB2; 
                 6 
               
               
                   
                 Guanine nucleotide-binding protein subunit beta-4 
                 GNB4 
                   
               
               
                 P53990 
                 IST1 homolog 
                 IST1 
                 6 
               
               
                 Q99497 
                 Protein DJ-1 
                 PARK7 
                 6 
               
               
                 F5H7U0 
                 6-phosphogluconate dehydrogenase, decarboxylating 
                 PGD 
                 6 
               
               
                 B7Z7E9 
                 Aspartate aminotransferase, cytoplasmic 
                 GOT1 
                 6 
               
               
                 P62834 
                 Ras-related protein Rap-1A; Ras-related protein Rap-1b;  
                 RAP1A; 
                   
               
               
                   
                 Ras-related protein Rap-1b-like protein 
                 RAP1B 
                 6 
               
               
                 P04899 
                 Guanine nucleotide-binding protein G(i) subunit alpha-2 
                 GNAI2 
                 6 
               
               
                 P25325 
                 3-mercaptopyruvate sulfurtransferase; Sulfurtransferase 
                 MPST 
                 6 
               
               
                 Q9NP79 
                 Vacuolar protein sorting-associated protein VTA1 homolog 
                 VTA1 
                 6 
               
               
                 P00492 
                 Hypoxanthine-guanine phosphoribosyltransferase 
                 HPRT1 
                 6 
               
               
                 Q16531 
                 DNA damage-binding protein 1 
                 DDB1 
                 6 
               
               
                 P22314 
                 Ubiquitin-like modifier-activating enzyme 1 
                 UBA1 
                 6 
               
               
                 P00441 
                 Superoxide dismutase [Cu-Z] 
                 SOD1 
                 5 
               
               
                 H7BY58 
                 Protein-L-isoaspartate O-methyltransferase;  
                 PCMT1 
                 5 
               
               
                   
                 Protein-L-isoaspartate(D-aspartate)  
                   
                   
               
               
                   
                 O-methyltransferase 
                   
                   
               
               
                 P10768 
                 S-formylglutathione hydrolase 
                 ESD 
                 5 
               
               
                 P09543 
                 2,3-cyclic-nucleotide 3-phosphodiesterase 
                 CNP 
                 5 
               
               
                 P06733 
                 Alpha-enolase; Enolase 
                 ENO1 
                 5 
               
               
                 P26038 
                 Moesin 
                 MSN 
                 5 
               
               
                 O75368 
                 SH3 domain-binding glutamic acid-rich-like protein 
                 SH3BGRL 
                 5 
               
               
                 K7EQ48 
                 Glucose-6-phosphate isomerase 
                 GPI 
                 5 
               
               
                 P25787 
                 Proteasome subunit alpha type-2 
                 PSMA2 
                 5 
               
               
                 P49721 
                 Proteasome subunit beta type-2 
                 PSMB2 
                 5 
               
               
                 F5H8J2 
                 Protein disulfide-isomerase 
                 P4HB 
                 5 
               
               
                 C9J9P4 
                 Phospholipid scramblase 1 
                 PLSCR1 
                 5 
               
               
                 P09211 
                 Glutathione S-transferase P 
                 GSTP1 
                 5 
               
               
                 B5MDF5 
                 GTP-binding nuclear protein Ran 
                 RAN 
                 5 
               
               
                 P07900 
                 Heat shock protein HSP 90-alpha 
                 HSP90AA1 
                 5 
               
               
                 K7EQ02 
                 DAZ-associated protein 1 
                 DAZAP1 
                 5 
               
               
                 Q13630 
                 GDP-L-fucose synthase 
                 TSTA3 
                 5 
               
               
                 F5H0T1 
                 Stress-induced-phosphoprotein 1 
                 STIP1 
                 5 
               
               
                 P50502 
                 Hsc70-interacting protein; Putative protein FAM10A5; 
                 ST13;  
                 5 
               
               
                   
                 Putative protein FAM10A4  
                 ST13P5; 
                   
               
               
                   
                   
                 ST13P4 
                   
               
               
                 P20618 
                 Proteasome subunit beta type-1 
                 PSMB1 
                 5 
               
               
                 P62805 
                 Histone H4 
                 HIST1H4A 
                 5 
               
               
                 P51148 
                 Ras-related protein Rab-50 
                 RAB5C 
                 5 
               
               
                 H7C2G2 
                 Ecto-ADP-ribosyltransferase 4 
                 ART4 
                 5 
               
               
                 J3KQ18 
                 D-dopachrome decarboxylase;  
                 DDT;  
                 5 
               
               
                   
                 D-dopachrome decarboxylase-like protein 
                 DDTL 
                   
               
               
                 H3BPK3 
                 Hydroxyacylglutathione hydrolase, mitochondrial 
                 HAGH 
                 5 
               
               
                 B4DIT7 
                 Protein-glutamine gamma-glutamyltransferase 2 
                 TGM2 
                 5 
               
               
                 O43633 
                 Charged multivesicular body protein 2a 
                 CHMP2A 
                 5 
               
               
                 B4DQH4 
                 T-complex protein 1 subunit theta 
                 CCT8 
                 5 
               
               
                 Q9UN37 
                 Vacuolar protein sorting-associated protein 4A 
                 VPS4A 
                 5 
               
               
                 I3L397 
                 Eukaryotic translation initiation factor 5A-1; 
                 EIF5A; 
                 5 
               
               
                   
                 Eukaryotic translation initiation factor 5A-1-like 
                 EIF5AL1 
                   
               
               
                 Q9Y5Z4 
                 Heme-binding protein 2 
                 HEBP2 
                 5 
               
               
                 Q9UKV8 
                 Protein argonaute-2 
                 AGO2 
                 5 
               
               
                 F5H442 
                 Tumor susceptibility gene 101 protein 
                 TSG101 
                 5 
               
               
                 H3BLV0 
                 Complement decay-accelerating factor 
                 CD55 
                 5 
               
               
                 P02008 
                 Hemoglobin subunit zeta 
                 HBZ 
                 5 
               
               
                 E7EPV7 
                 Alpha-synuclein 
                 SNCA 
                 4 
               
               
                 P63104 
                 14-3-3 protein zeta/delta 
                 YWHAZ 
                 4 
               
               
                 P02724 
                 Glycophorin-A 
                 GYPA; 
                 4 
               
               
                   
                   
                 GPErik 
                   
               
               
                 U3KQE2 
                 Calpain small subunit 1 
                 CAPNS1 
                 4 
               
               
                 Q9NP59 
                 Solute carrier family 40 member 1 
                 SLC40A1 
                 4 
               
               
                 Q5QPM9 
                 Proteasome inhibitor PI31 subunit 
                 PSMF1 
                 4 
               
               
                 C9J8U2 
                 Nicotinate phosphoribosyltransferase 
                 NAPRT 
                 4 
               
               
                 P61981 
                 14-3-3 protein gamma; 14-3-3 protein gamma, N-terminally processed 
                 YWHAG 
                 4 
               
               
                 Q9UQ80 
                 Proliferation-associated protein 2G4 
                 PA2G4 
                 4 
               
               
                 E5RJR5 
                 S-phase kinase-associated protein 1 
                 SKP1 
                 4 
               
               
                 Q9NRV9 
                 Heme-binding protein 1 
                 HEBP1 
                 4 
               
               
                 Q9H444 
                 Charged multivesicular body protein 4b 
                 CHMP4B 
                 4 
               
               
                 P10599 
                 Thioredoxin 
                 TXN 
                 4 
               
               
                 Q5VSJ9 
                 Blood group Rh(CE) polypeptide; Blood group Rh(D) polypeptide 
                 RHCE; RHD 
                 4 
               
               
                 Q9UK41 
                 Vacuolar protein sorting-associated protein 28 homolog 
                 VPS28 
                 4 
               
               
                 Q9Y3I1 
                 F-box only protein 7 
                 FBXO7 
                 4 
               
               
                 P61026 
                 Ras-related protein Rab-10 
                 RAB10 
                 4 
               
               
                 Q14974 
                 lmportin subunit beta-1 
                 KPNB1 
                 4 
               
               
                 P27797 
                 Calreticulin 
                 CALR 
                 4 
               
               
                 P18669 
                 Phosphoglycerate mutase 1; 
                 PGAM1; 
                 4 
               
               
                   
                 Probable phosphoglycerate mutase 4 
                 PGAM4 
                   
               
               
                 P54725 
                 UV excision repair protein RAD23 homolog A 
                 RAD23A 
                 4 
               
               
                 P30613 
                 Pyruvate kinase PKLR 
                 PKLR 
                 4 
               
               
                 P63000 
                 Ras-related C3 botulinum toxin substrate 1; 
                 RAC1; 
                 4 
               
               
                   
                 Ras-related C3 botulinum toxin substrate 3; 
                 RAC3; 
                   
               
               
                   
                 Ras-related C3 botulinum toxin substrate 2 
                 RAC2 
                   
               
               
                 P05164 
                 Myeloperoxidase 
                 MPO 
                 4 
               
               
                 F5GWY2 
                 Bifunctional purine biosynthesis protein PURH; 
                 ATIC 
                 4 
               
               
                   
                 Phosphoribosylaminoimidazolecarboxamide 
                   
                   
               
               
                   
                 formyltransferase; IMP cyclohydrolase 
                   
                   
               
               
                 P48637 
                 Glutathione synthetase 
                 GSS 
                 4 
               
               
                 F5H5V4 
                 26S proteasome non-ATPase regulatory subunit 9 
                 PSMD9 
                 4 
               
               
                 G5E9R5 
                 Low molecular weight phosphotyrosine protein phosphatase 
                 ACP1 
                 3 
               
               
                 P46976 
                 Glycogenin-1 
                 GYG1 
                 3 
               
               
                 P28072 
                 Proteasome subunit beta type-6 
                 PSMB6 
                 3 
               
               
                 P26447 
                 Protein S100-A4 
                 S100A4 
                 3 
               
               
                 F5GXQ0 
                 BRO1 domain-containing protein BROX 
                 BROX 
                 3 
               
               
                 P08754 
                 Guanine nucleotide-binding protein G(k) subunit alpha 
                 GNAI3 
                 3 
               
               
                 Q99436 
                 Proteasome subunit beta type-7 
                 PSMB7 
                 3 
               
               
                 P62942 
                 Peptidyl-prolyl cis-trans isomerase 
                 FKBP1A 
                 3 
               
               
                 U3KQK0 
                 Histone H2B 
                 HIST1H2B 
                 3 
               
               
                 J3QKR3 
                 Proteasome subunit beta type-3 
                 PSMB3 
                 3 
               
               
                 P01116 
                 GTPase KRas; GTPase KRas, N-terminally processed; 
                 KRAS; 
                 3 
               
               
                   
                 GTPase HRas; GTPaseH Ras,  
                 HRAS;  
                   
               
               
                   
                 N-terminally processed; GTPase NRas 
                 NRAS 
                   
               
               
                 P13489 
                 Ribonuclease inhibitor 
                 RNH1 
                 3 
               
               
                 Q08722 
                 Leukocyte surface antigen CD47 
                 CD47 
                 3 
               
               
                 Q5T123 
                 SH3 domain-binding glutamic acid-rich-like protein 3 
                 SH3BGRL3 
                 3 
               
               
                 Q8WYQ7 
                 Galectin; Galectin-9 
                 LGALS9 
                 3 
               
               
                 O75695 
                 Protein XRP2 
                 RP2 
                 3 
               
               
                 P00167 
                 Cytochrome b5 
                 CYB5A 
                 3 
               
               
                 Q9Y4D1 
                 Disheveled-associated activator of morphogenesis 1 
                 DAAM1 
                 3 
               
               
                 P11021 
                 78 kDa glucose-regulated protein 
                 HSPA5 
                 3 
               
               
                 H7C1D4 
                 Translin 
                 TSN 
                 3 
               
               
                 P07737 
                 Profilin-1 
                 PFN1 
                 3 
               
               
                 M0R389 
                 Platelet-activating factor acetylhydrolase IB subunit gamma 
                 PAFAH1B3 
                 3 
               
               
                 A6NJA2 
                 Ubiquitin carboxyl-terminal hydrolase 14 
                 USP14 
                 3 
               
               
                 P10644 
                 cAMP-dependent protein kinase type l-alpha regulatory subunit 
                 PRKAR1A 
                 3 
               
               
                 Q9BS40 
                 Latexin 
                 LXN 
                 3 
               
               
                 G5EA52 
                 Protein disulfide-isomerase A3 
                 PDIA3 
                 3 
               
               
                 P53004 
                 Biliverdin reductase A 
                 BLVRA 
                 3 
               
               
                 Q04656 
                 Copper-transporting ATPase 1 
                 ATP7A 
                 3 
               
               
                 H9KV70 
                 Neutrophil gelatinase-associated lipocalin 
                 LCN2 
                 3 
               
               
                 O00299 
                 Chloride intracellular channel protein 1 
                 CLIC1 
                 3 
               
               
                 F8WF69 
                 Clathrin light chain A 
                 CLTA 
                 3 
               
               
                 G3V2F7 
                 Ubiquitin-conjugating enzyme E2 variant 1; 
                 UBE2V1; 
                 3 
               
               
                   
                 Ubiquitin-conjugating enzyme E2 variant 2 
                 UBE2V2 
                   
               
               
                 F8WDS9 
                 LanC-like protein 1 
                 LANCL1 
                 3 
               
               
                 P60891 
                 Ribose-phosphate pyrophosphokinase 1 
                 PRPS1 
                 3 
               
               
                 K7ESE8 
                 Bleomycin hydrolase 
                 BLMH 
                 3 
               
               
                 H0YNE3 
                 Proteasome activator complex subunit 1 
                 PSME1 
                 3 
               
               
                 P16930 
                 Fumarylacetoacetase 
                 FAH 
                 3 
               
               
                 F8VSD4 
                 Ubiquitin-conjugating enzyme E2 N 
                 UBE2N 
                 3 
               
               
                 P07203 
                 Glutathione peroxidase 1 
                 GPX1 
                 3 
               
               
                 P62328 
                 Thymosin beta-4; Hematopoietic system regulatory peptide  
                 TMSB4X; 
                 3 
               
               
                   
                   
                 TMSB4XP4 
                   
               
               
                 E5RIW3 
                 Tubulin-specific chaperone A 
                 TBCA 
                 3 
               
               
                 M0R0Y2 
                 Alpha-soluble NSF attachment protein 
                 NAPA 
                 3 
               
               
                 P15374 
                 Ubiquitin carboxyl-terminal hydrolase isozyme L3 
                 UCHL3 
                 3 
               
               
                 P04921 
                 Glycophorin-C 
                 GYPC 
                 2 
               
               
                 H0YDI1 
                 Lymphocyte function-associated antigen 3 
                 CD58 
                 2 
               
               
                 B4E220 
                 Aquaporin-1 
                 AQP1 
                 2 
               
               
                 C9JEN3 
                 Protein lifeguard 3 
                 TMBIM1 
                 2 
               
               
                 F5H2R5 
                 Rho GDP-dissociation inhibitor 2 
                 ARHGDIB 
                 2 
               
               
                 Q53TN4 
                 Cytochrome b reductase 1 
                 CYBRD1 
                 2 
               
               
                 Q9NZD4 
                 Alpha-hemoglobin-stabilizing protein 
                 AHSP 
                 2 
               
               
                 Q8NHG7 
                 Small VCP/p97-interacting protein 
                 SVIP 
                 2 
               
               
                 Q5JYX0 
                 Cell division control protein 42 homolog 
                 CDC42 
                 2 
               
               
                 Q71RC9 
                 Small integral membrane protein 5 
                 SMIM5 
                 2 
               
               
                 E9PNW4 
                 CD59 glycoprotein 
                 CD59 
                 2 
               
               
                 P09105 
                 Hemoglobin subunit theta-1 
                 HBQ1 
                 2 
               
               
                 R4GN98 
                 Protein S100; Protein S100-A6 
                 S100A6 
                 2 
               
               
                 O75531  
                 Barrier-to-autointegration factor; Barrier-to-autointegration  
                 BANF1 
                 2 
               
               
                   
                 factor, N-terminally processed 
                   
                   
               
               
                 Q5T6W5 
                 Heterogeneous nuclear ribonucleoprotein K 
                 HNRNPK 
                 2 
               
               
                 F5H4Q5 
                 Vacuolar protein sorting-associated protein 37C 
                 VPS37C 
                 2 
               
               
                 J3QK90 
                 NSFL1 cofactor p47 
                 NSFL1C 
                 2 
               
               
                 H3BV85 
                 BolA-like protein 2 
                 BOLA2B; 
                 2 
               
               
                   
                   
                 BOLA2 
                   
               
               
                 Q9NRX4 
                 14 kDa phosphohistidine phosphatase 
                 PHPT1 
                 2 
               
               
                 H3B566 
                 Small integral membrane protein 1 
                 SMIM1 
                 2 
               
               
                 E7ESC6 
                 Exportin-7 
                 XPO7 
                 2 
               
               
                 P68402 
                 Platelet-activating factor acetylhydrolase IB subunit beta 
                 PAFAH1B2 
                 2 
               
               
                 Q9BRF8 
                 Serine/threonine-protein phosphatase CPPED1 
                 CPPED1 
                 2 
               
               
                 P08246 
                 Neutrophil elastase 
                 ELANE 
                 2 
               
               
                 E9PN50 
                 26S protease regulatory subunit 6A 
                 PSMC3 
                 2 
               
               
                 E7EUC7 
                 UTP--glucose-1-phosphate uridylyltransferase 
                 UGP2 
                 2 
               
               
                 B8ZZB8 
                 CB1 cannabinoid receptor-interacting protein 1 
                 CNRIP1 
                 2 
               
               
                 E9PCS3 
                 26S proteasome non-ATPase regulatory subunit 2 
                 PSMD2 
                 2 
               
               
                 P59666 
                 Neutrophil defensin 3; HP 3-56; Neutrophil defensin 2;  
                 DEFA3; 
                 2 
               
               
                   
                 Neutrophil defensin 1; HP 1-56;  
                 DEFA1 
                   
               
               
                   
                 Neutrophil defensin 2 
                   
                   
               
               
                 O15400 
                 Syntaxin-7 
                 STX7 
                 2 
               
               
                 P00338 
                 L-lactate dehydrogenase A chain 
                 LDHA 
                 2 
               
               
                 P61970 
                 Nuclear transport factor 2 
                 NUTF2 
                 2 
               
               
                 E7EMV0 
                 Protein diaphanous homolog 1 
                 DIAPH1 
                 2 
               
               
                 F5GY90 
                 Porphobilinogen deaminase 
                 HMBS 
                 2 
               
               
                 P61020 
                 Ras-related protein Rab-5B 
                 RAB5B 
                 2 
               
               
                 Q99828 
                 Calcium and integrin-binding protein 1 
                 CIB1 
                 2 
               
               
                 B4DUA0 
                 Plastin-2 
                 LCP1 
                 2 
               
               
                 C9JTY3 
                 Protein TFG 
                 TFG 
                 2 
               
               
                 P27348 
                 14-3-3 protein theta 
                 YWHAQ 
                 2 
               
               
                 H0YKZ7 
                 Annexin; Annexin A2; Putative annexin 
                 ANXA2; 
                 2 
               
               
                   
                 A2-like protein 
                 ANXA2P2 
                   
               
               
                 P08238 
                 Heat shock protein HSP 90-beta 
                 HSP90AB1 
                 2 
               
               
                 J3KQP6 
                 Ras-related protein Rab-11B; Ras-related protein Rab-11A 
                 RAB11A; 
                 2 
               
               
                   
                   
                 RAB11B 
                   
               
               
                 A6NMU3 
                 Signal transducing adapter molecule 1 
                 STAM 
                 2 
               
               
                 P53985 
                 Monocarboxylate transporter 1 
                 SLC16A1 
                 2 
               
               
                 F6USW4 
                 F-actin-capping protein subunit beta 
                 CAPZB 
                 2 
               
               
                 O14964 
                 Hepatocyte growth factor-regulated tyrosine kinase substrate 
                 HGS 
                 2 
               
               
                 P20020 
                 Plasma membrane calcium-transporting ATPase 1; 
                 ATP2B1 
                 2 
               
               
                   
                 Calcium-transporting ATPase 
                   
                   
               
               
                 P36959 
                 GMP reductase 1 
                 GMPR 
                 2 
               
               
                 Q9Y376 
                 Calcium-binding protein 39 
                 CAB39 
                 2 
               
               
                 Q9Y6M5 
                 Zinc transporter 1 
                 SLC30A1 
                 2 
               
               
                 Q8IZ83 
                 Aldehyde dehydrogenase family 16 member A1 
                 ALDH16A1 
                 2 
               
               
                 Q99459 
                 Cell division cycle 5-like protein 
                 CDC5L 
                 2 
               
               
                 P06132 
                 Uroporphyrinogen decarboxylase 
                 UROD 
                 2 
               
               
                 J3KNT0 
                 Fascin 
                 FSCN1 
                 2 
               
               
                 P49189 
                 4-trimethylaminobutyraldehyde dehydrogenase 
                 ALDH9A1 
                 2 
               
               
                 H3BNT7 
                 26S proteasome non-ATPase regulatory subunit 7 
                 PSMD7 
                 2 
               
               
                 P05023 
                 Sodium/potassium-transporting ATPase subunit alpha-1;  
                 ATP1A1;  
                 2 
               
               
                   
                 Sodium/potassium-transporting ATPase subunit alpha-3; 
                 ATP1A2; 
                   
               
               
                   
                 Sodium/potassium-transporting ATPase subunit alpha-2; 
                 ATP1A3; 
                   
               
               
                   
                 Sodium/potassium-transporting ATPase subunit alpha-4;  
                 ATP1A4; 
                   
               
               
                   
                 Potassium-transporting ATPase alpha chain 1; 
                 ATP4A; 
                   
               
               
                   
                 Potassium-transporting ATPase alpha chain 2 
                 ATP12A 
                   
               
               
                 P34932 
                 Heat shock 70 kDa protein 4 
                 HSPA4 
                 2 
               
               
                 K7EMV3 
                 Histone H3 
                 H3F3B 
                 2 
               
               
                 Q8IU68 
                 Transmembrane channel-like protein 8 
                 TMC8 
                 2 
               
               
                 E7ENZ3 
                 T-complex protein 1 subunit epsilon 
                 CCT5 
                 2 
               
               
                 Q5TZA2 
                 Rootletin 
                 CROCC 
                 2 
               
               
                 Q9P203 
                 BTB/POZ domain-containing protein 7 
                 BTBD7 
                 2 
               
               
                 Q7LBR1 
                 Charged multivesicular body protein lb 
                 CHMP1B 
                 2 
               
               
                 U3KQ56 
                 Glyoxylate reductase/hydroxypyruvate reductase 
                 GRHPR 
                 2 
               
               
                 H0YJ11 
                 Alpha-actinin-1; Alpha-actinin-2; 
                 ACTN1; 
                 2 
               
               
                   
                 Alpha-actinin-4 
                 ACTN4; 
                   
               
               
                   
                   
                 ACTN2 
                   
               
               
                 Q9UDT6 
                 CAP-Gly domain-containing linker protein 2 
                 CLIP2 
                 2 
               
               
                 P09960 
                 Leukotriene A-4 hydrolase 
                 LTA4H 
                 2 
               
               
                 Q5HY54 
                 Filamin-A 
                 FLNA 
                 2 
               
               
                 E9PJL5 
                 Uncharacterized protein C12orf55; 
                 C12orf55;  
                 2 
               
               
                   
                 Putative uncharacterized protein C12orf63 
                 C12orf63 
                   
               
               
                 G3V2U7 
                 Acylphosphatase; Acylphosphatase-1 
                 FBN3; ACYP1 
                 2 
               
               
                 E9PQN4 
                 Complement receptor type 1 
                 CR1 
                 2 
               
               
                 Q9BSL1 
                 Ubiquitin-associated domain-containing protein 1 
                 UBAC1 
                 2 
               
               
                 Q04917 
                 14-3-3 protein eta 
                 YWHAH 
                 2 
               
               
                 B7ZBP9 
                 Serine/threonine-protein phosphatase 2A activator 
                 PPP2R4; 
                 2 
               
               
                   
                   
                 DKFZp781M17165 
                   
               
               
                 Q8NDC0 
                 MAPK-interacting and spindle-stabilizing protein-like 
                 MAPK1IP1L 
                 1 
               
               
                 P68133 
                 Actin, alpha skeletal muscle; 
                 ACTA1; 
                 1 
               
               
                   
                 Actin, alpha cardiac muscle 1; 
                 ACTC1; 
                   
               
               
                   
                 Actin, gamma-enteric smooth muscle; 
                 ACTG2; 
                   
               
               
                   
                 Actin, aortic smooth muscle 
                 ACTA2 
                   
               
               
                 P69891 
                 Hemoglobin subunit gamma-1 
                 HBG1 
                 1 
               
               
                 S4R3Y4 
                 Protein AMBP; Alpha-1-microglobulin; 
                 AMBP 
                   
               
               
                   
                 Inter-alpha-trypsin inhibitor light chain;  
                   
                 1 
               
               
                   
                 Trypstatin 
                   
                   
               
               
                 I3L3E4 
                 Charged multivesicular body protein 6 
                 CHMP6 
                 1 
               
               
                 Q16570 
                 Atypical chemokine receptor 1 
                 ACKR1 
                 1 
               
               
                 Q5VY30 
                 Retinol-binding protein 4; Plasma retinol-binding protein(1-182); 
                 RBP4 
                   
               
               
                   
                 Plasma retinol-binding protein(1-181); 
                   
                 1 
               
               
                   
                 Plasma retinol-binding protein(1-179); 
                   
                   
               
               
                   
                 Plasma retinol-binding protein(1-176) 
                   
                   
               
               
                 E7END7 
                 Ras-related protein Rab-1A 
                 RAB1A 
                 1 
               
               
                 Q5VU59 
                   
                 TPM3 
                 1 
               
               
                 P17066 
                 Heat shock 70 kDa protein 6; Putative heat shock 70 kDa protein 7 
                 HSPA6; 
                 1 
               
               
                   
                   
                 HSPA7 
                   
               
               
                 Q04760 
                 Lactoylglutathione lyase 
                 GLO1 
                 1 
               
               
                 D6RD66 
                 WD repeat-containina protein 1 
                 WDR1 
                 1 
               
               
                 K7EM02 
                 Katanin p60 ATPase-containing subunit A-like 2 
                 KATNAL2 
                 1 
               
               
                 P14209 
                 CD99antigen 
                 CD99 
                 1 
               
               
                 E9PIR7 
                 Thioredoxin reductase 1, cytoplasmic 
                 GML; 
                 1 
               
               
                   
                   
                 TXNRD1 
                   
               
               
                 K7EMQ9 
                   
                 EIF3K 
                 1 
               
               
                 P15531 
                 Nucleoside diphosphate kinase A 
                 NME1 
                 1 
               
               
                 H7BZT4 
                 Small ubiquitin-related modifier 4; 
                 SUMO2; 
                 1 
               
               
                   
                 Small ubiquitin-related modifier 2; 
                 SUMO3; 
                   
               
               
                   
                 Small ubiquitin-related modifier 3 
                 SUMO4 
                   
               
               
                 O00560 
                 Syntenin-1 
                 SDCBP 
                 1 
               
               
                 Q9BVM4 
                 Gamma-glutamylaminecyclotransferase 
                 GGACT 
                 1 
               
               
                 K7EKH5 
                 Fructose-bisphosphate aldolase C 
                 ALDOC 
                 1 
               
               
                 P49773 
                 Histidine triad nucleotide-binding protein 1 
                 HINT1 
                 1 
               
               
                 H0YBY6 
                 Disks large-associated protein 2 
                 DLGAP2 
                 1 
               
               
                 Q9Y624 
                 Junctional adhesion molecule A 
                 F11R 
                 1 
               
               
                 B1AKQ8 
                 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1; 
                 GNB1; 
                 1 
               
               
                   
                 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 
                 GNB3 
                   
               
               
                 K7EKN6 
                 Urea transporter 1 
                 SLC14A1 
                 1 
               
               
                 I3L0K2 
                 Thioredoxin domain-containing protein 17 
                 TXNDC17 
                 1 
               
               
                 A8MXY0 
                 Syntaxin-4 
                 STX4 
                 1 
               
               
                 O14773 
                 Tripeptidyl-peptidase 1 
                 TPP1 
                 1 
               
               
                 E9PNW0 
                 Nucleosomeassembly protein 1-like 1; 
                 NAP1L4;  
                 1 
               
               
                   
                 Nucleosome assemblyprotein 1-like 4 
                 NAP1L1 
                   
               
               
                 Q5TDH0 
                 Protein DDI1 homolog 2 
                 DDI2 
                 1 
               
               
                 Q96JM4 
                 Leucine-rich repeat and IQ domain-containing protein 1 
                 LRRIQ1 
                 1 
               
               
                 F5GWT9 
                 Phosphoribosylformylglycinamidine synthase 
                 PFAS 
                 1 
               
               
                 F2Z3J2 
                 26S proteasome non-ATPase regulatory subunit 5 
                 PSMD5 
                 1 
               
               
                 J3QL74 
                 Zinc finger and BTB domain-containing protein 14  
                 ZBTB14 
                 1 
               
               
                 E9PJC7 
                 CD82 antigen  
                 CD82 
                 1 
               
               
                 Q9H936 
                 Mitochondrial glutamate carrier 1  
                 SLC25A22 
                 1 
               
               
                 D6RD63 
                 COP9 signalosomecomplex subunit 4 
                 COPS4 
                 1 
               
               
                 Q6B0K9 
                 Hemoglobin subunit mu 
                 HBM 
                 1 
               
               
                 Q31611 
                 HLA class I histocompatibility antigen, alpha chain G  
                 HLA-G 
                 1 
               
               
                 H7BY04 
                 Laminin subunit gamma-3 
                 LAMC3 
                 1 
               
               
                 Q9UL25 
                 Ras-related protein Rab-21  
                 RAB21 
                 1 
               
               
                 H7C3P7 
                 Ras-related protein Ral-A  
                 RALA 
                 1 
               
               
                 P08311 
                 Cathepsin G  
                 CTSG 
                 1 
               
               
                 E9PE37 
                 Ras-related protein Rab-2A;Ras-related protein Rab-2B  
                 RAB2B; 
                 1 
               
               
                   
                   
                 RAB2A 
                   
               
               
                 G3V1N2 
                   
                 HBA2  
                 1 
               
               
                 P00387 
                 NADH-cytochrome b5 reductase 3; 
                 CYB5R3 
                 1 
               
               
                   
                 NADH-cytochromeb5 reductase 3 membrane-bound form; 
                   
                   
               
               
                   
                 NADH-cytochrome b5 reductase 3 soluble form 
                   
                   
               
               
                 O75339 
                 Cartilage intermediate layer protein 1; 
                 CILP 
                 1 
               
               
                   
                 Cartilage intermediate layer protein 1 C1; 
                   
                   
               
               
                   
                 Cartilage intermediate layer protein 1 C2 
                   
                   
               
               
                 P14324 
                 Farnesyl pyrophosphate synthase 
                 FDPS 
                 1 
               
               
                 K7EKG2 
                 Thioredoxin-like protein 1 
                 TXNL1 
                 1 
               
            
           
           
               
            
               
                 (B). UNIPROT COMPLETE PROTEOME  HOMO SAPIENS   
               
               
                 DATABASE WHEN THE HEMOGLOBIN WAS ANALYZED SEPARATELY 
               
            
           
           
               
               
               
               
            
               
                 P02549 
                 Spectrin alpha chain, erythrocytic 1 
                 SPTA1 
                 197 
               
               
                 P11277 
                 Spectrin betachain, erythrocytic 
                 SPTB  
                 177 
               
               
                 P16157 
                 Ankyrin-1 
                 ANK1 
                 94 
               
               
                 P55072 
                 Transitional endoplasmic reticulum ATPase 
                 VCP 
                 53 
               
               
                 P111714 
                 Protein 4.1 
                 EPB41 
                 52 
               
               
                 P35579 
                 Myosin-9 
                 MYH9 
                 44 
               
               
                 Q8WUM4 
                 Programmed cell death 6-interacting protein 
                 PDCD6IP 
                 43 
               
               
                 P02730 
                 Band 3 anion transport protein 
                 SLC4A1 
                 43 
               
               
                 P16452 
                 Erythrocyte membrane protein band 4.2 
                 EPB42 
                 42 
               
               
                 P04040 
                 Catalase 
                 CAT 
                 40 
               
               
                 A0A087WVQ6 
                 Clathrin heavy chain; Clathrin heavy chain 1 
                 CLTC 
                 38 
               
               
                 P35612 
                 Beta-adducin 
                 ADD2 
                 37 
               
               
                 P16157 
                 Ankyrin-1 
                 ANK1 
                 36 
               
               
                 Q14254 
                 Flotillin-2 
                 FLOT2 
                 33 
               
               
                 P20073 
                 Annexin A7 
                 ANXA7 
                 31 
               
               
                 O75955 
                 Flotillin-1 
                 FLOT1 
                 30 
               
               
                 P53396 
                 ATP-citrate synthase 
                 ACLY 
                 30 
               
               
                 P06753 
                   
                 TPM3 
                 29 
               
               
                 P49368 
                 T-complex protein 1 subunit gamma 
                 CCT3 
                 29 
               
               
                 P236344 
                 Plasma membrane calcium-transporting ATPase 4 
                 ATP2B4 
                 28 
               
               
                 P11142 
                 Heat shock cognate 71 kDa protein 
                 HSPA8 
                 28 
               
               
                 P60709 
                 Actin, cytoplasmic 1; Actin, cytoplasmic 1, N-terminally processed 
                 ACTB 
                 28 
               
               
                 Q5T4S7 
                 E3 ubiquitin-protein ligase UBR4 
                 UBR4 
                 27 
               
               
                 P78371 
                 T-complex protein 1 subunit beta 
                 CCT2 
                 26 
               
               
                 P28289 
                 Tropomodulin-1 
                 TMOD1 
                 26 
               
               
                 P50395 
                 Rab GDP dissociation inhibitor beta 
                 GDI2 
                 25 
               
               
                 P27105 
                 Erythrocyte band 7 integral membrane protein 
                 STOM 
                 25 
               
               
                 P68871 
                 Hemoglobin subunit beta; LW-hemorphin-7; Spinorphin 
                 HBB 
                 25 
               
               
                 P02730 
                 Band 3 anion transport protein 
                 SLC4A1 
                 25 
               
               
                 Q00013 
                 55 kDa erythrocyte membrane protein 
                 MPP1 
                 24 
               
               
                 J3KPS3 
                 Fructose-bisphosphate aldolase; Fructose-bisphosphate aldolase A 
                 ALDOA 
                 24 
               
               
                 P00352 
                 Retinal dehydrogenase 1 
                 ALDH1A1 
                 24 
               
               
                 Q86VP6 
                 Cullin-associated NEDD8-dissociated protein 1 
                 CAND1 
                 24 
               
               
                 P49327 
                 Fatty acid synthase 
                 FASN 
                 24 
               
               
                 Q13228 
                 Selenium-binding protein 1 
                 SELENBP1 
                 22 
               
               
                 P00915 
                 Carbonic anhydrase 1 
                 CA1 
                 22 
               
               
                 P50991 
                 T-complex protein 1 subunit delta 
                 CCT4 
                 22 
               
               
                 P50990 
                 T-complex protein 1 subunit theta 
                 CCT8 
                 22 
               
               
                 P32119 
                 Peroxiredoxin-2 
                 PRDX2 
                 21 
               
               
                 P50995 
                 Annexin A11 
                 ANXA11 
                 21 
               
               
                 P69905 
                 Hemoglobin subunit alpha 
                 HBA1 
                 21 
               
               
                 P00558 
                 Phosphoglycerate kinase 1 
                 PGK1 
                 20 
               
               
                 H7BXK9 
                 ATP-binding cassette sub-family B member 6, mitochondrial 
                 ABCB6 
                 20 
               
               
                 P08758 
                 Annexin A5; Annexin 
                 ANXA5 
                 20 
               
               
                 P09525 
                 Annexin A4; Annexin 
                 ANXA4 
                 20 
               
               
                 P07900 
                 Heat shock protein HSP 90-alpha 
                 HSP90AA1 
                 20 
               
               
                 P48643 
                 T-complex protein 1 subunit epsilon 
                 CCT5 
                 20 
               
               
                 P07384 
                 Calpain-1 catalytic subunit 
                 CAPN1 
                 20 
               
               
                 P22314 
                 Ubiquitin-like modifier-activating enzyme 1 
                 UBA1 
                 19 
               
               
                 P04406 
                 Glyceraldehyde-3-phosphate dehydrogenase 
                 GAPDH 
                 19 
               
               
                 Q08495 
                 Dematin 
                 DMTN 
                 19 
               
               
                 Q99832 
                 T-complex protein 1 subunit eta 
                 CCT7 
                 19 
               
               
                 P29144 
                 Tripeptidyl-peptidase 2 
                 TPP2 
                 19 
               
               
                 P30041 
                 Peroxiredoxin-6 
                 PRDX6 
                 18 
               
               
                 E9PM69 
                 26S protease regulatory subunit 6A 
                 PSMC3 
                 18 
               
               
                 P40227 
                 T-complex protein 1 subunit zeta 
                 CCT6A 
                 18 
               
               
                 P50570 
                 Dynamin-2 
                 DNM2 
                 18 
               
               
                 E7EQB2 
                 Lactotransferrin; Lactoferricin-H; Kaliocin-1; 
                 LTF 
                 18 
               
               
                   
                 Lactoferroxin-A; Lactoferroxin-B; Lactoferroxin-C 
                   
                   
               
               
                 P31948 
                 Stress-induced-phosphoprotein 1 
                 STIP1 
                 18 
               
               
                 E7ESC6 
                 Exportin-7 
                 XPO7 
                 18 
               
               
                 E7EV99 
                 Alpha-adducin 
                 ADD1 
                 17 
               
               
                 P62258 
                 14-3-3 protein epsilon 
                 YWHAE 
                 17 
               
               
                 P30613 
                 Pyruvate kinase PKLR 
                 PKLR 
                 17 
               
               
                 A0A0G2JIW1 
                 Heat shock 70 kDa protein 1B; 
                 HSPA1B; 
                 17 
               
               
                   
                 Heat shock 70 kDa protein 1A 
                 HSPA1A 
                   
               
               
                 Q16531 
                 DNA damage-binding protein 1 
                 DDB1 
                 17 
               
               
                 P11021 
                 78 kDa glucose-regulated protein 
                 HSPA5 
                 17 
               
               
                 F5H2F4 
                 C-1-tetrahydrofolate synthase, cytoplasmic; 
                 MTHFD1 
                 17 
               
               
                   
                 Methylenetetrahydrofolate dehydrogenase 
                   
                   
               
               
                 P07195 
                 L-lactate dehydrogenase B chain; L-lactate dehydrogenase 
                 LDHB 
                 16 
               
               
                 P45974 
                 Ubiquitin carboxyl-terminal hydrolase 5 
                 USPS 
                 16 
               
               
                 O43242 
                 26S proteasome non-ATPase regulatory subunit 3 
                 PSMD3 
                 16 
               
               
                 C9J0K6 
                 Sorcin 
                 SRI 
                 16 
               
               
                 P08133 
                 Annexin A6; Annexin 
                 ANXA6 
                 16 
               
               
                 Q13200 
                 26S proteasome non-ATPase regulatory subunit 2 
                 PSMD2 
                 16 
               
               
                 P23276 
                 Kell blood group glycoprotein 
                 KEL 
                 16 
               
               
                 P34932 
                 Heat shock 70 kDa protein 4 
                 HSPA4 
                 16 
               
               
                 A0A0A0MSI0 
                 Peroxiredoxin-1 
                 PRDX1 
                 16 
               
               
                 Q9Y230 
                 RuvB-like 2 
                 RUVBL2 
                 16 
               
               
                 Q5XPI4 
                 E3 ubiquitin-protein ligase RNF123 
                 RNF123 
                 16 
               
               
                 P68871 
                 Hemoglobin subunit beta; LW-hemorphin-7; Spinorphin 
                 HBB 
                 15 
               
               
                 P60174 
                 Triosephosphate isomerase 
                 TPI1 
                 15 
               
               
                 P00491 
                 Purine nucleoside phosphorylase 
                 PNP 
                 15 
               
               
                 C9JIF9 
                 Acylamino-acid-releasing enzyme 
                 APEH 
                 15 
               
               
                 H7BYY1 
                 Tropomyosin alpha-1 chain 
                 TPM1 
                 15 
               
               
                 P35998 
                 26S protease regulatory subunit 7 
                 PSMC2 
                 15 
               
               
                 P17987 
                 T-complex protein 1 subunit alpha 
                 TCP1 
                 15 
               
               
                 P09543 
                 2,3-cyclic-nucleotide 3-phosphodiesterase 
                 CNP 
                 15 
               
               
                 Q99460 
                 26S proteasome non-ATPase regulatory subunit 1 
                 PSMD1  
                 15 
               
               
                 Q9Y4E8 
                 Ubiquitin carboxyl-terminal hydrolase 15 
                 USP15 
                 15 
               
               
                 Q9C0C9 
                 E2/E3 hybrid ubiquitin-protein ligase UBE20 
                 UBE2O 
                 15 
               
               
                 P26038 
                 Moesin 
                 MSN 
                 15 
               
               
                 P04083 
                 Annexin A1; Annexin 
                 ANXA1 
                 14 
               
               
                 P30043 
                 Flavin reductase (NADPH) 
                 BLVRB 
                 14 
               
               
                 P11166 
                 Solute carrier family 2, facilitated glucose transporter member 1 
                 SLC2A1 
                 14 
               
               
                 P00918 
                 Carbonic anhydrase 2 
                 CA2 
                 14 
               
               
                 P06733 
                 Alpha-enolase 
                 ENO1 
                 14 
               
               
                 Q5TDH0 
                 Protein DDI1 homolog 2 
                 DDI2 
                 14 
               
               
                 B0QZ18 
                 Copine-1 
                 CPNE1 
                 14 
               
               
                 O75326 
                 Semaphorin-7A 
                 SEMA7A 
                 14 
               
               
                 P05164 
                 Myeloperoxidase 
                 MPO 
                 14 
               
               
                 Q9Y265 
                 RuvB-like 1 
                 RUVBL1 
                 14 
               
               
                 P29401 
                 Transketolase 
                 TKT 
                 14 
               
               
                 I3L0N3 
                 Vesicle-fusing ATPase 
                 NSF 
                 14 
               
               
                 Q4VB86 
                 Protein 4.1 
                 EPB41 
                 14 
               
               
                 P11277 
                 Spectrin beta chain, erythrocytic 
                 SPTB 
                 14 
               
               
                 P13716 
                 Delta-aminolevulinic acid dehydratase 
                 ALAD 
                 13 
               
               
                 P07738 
                 Bisphosphoglycerate mutase 
                 BPGM 
                 13 
               
               
                 P48506 
                 Glutamate--cysteine ligase catalytic subunit 
                 GCLC 
                 13 
               
               
                 Q99816 
                 Tumor susceptibility gene 101 protein 
                 TSG101 
                 13 
               
               
                 O14818 
                 Proteasome subunit alpha type-7 
                 PSMA7  
                 13 
               
               
                 P23526 
                 Adenosylhomocysteinase 
                 AHCY 
                 13 
               
               
                 P61225 
                 Ras-related protein Rap-2b 
                 RAP2B 
                 13 
               
               
                 O00231 
                 26S proteasome non-ATPase regulatory subunit 11 
                 PSMD11 
                 13 
               
               
                 P11413 
                 Glucose-6-phosphate 1-dehydrogenase 
                 G6PD 
                 13 
               
               
                 P00338 
                 L-lactate dehydrogenase A chain 
                 LDHA 
                 12 
               
               
                 Q99808 
                 Equilibrative nucleoside transporter 1 
                 SLC29A1 
                 12 
               
               
                 A6NJA2 
                 Ubiquitin carboxyl-terminal hydrolase;  
                 USP14 
                 12 
               
               
                   
                 Ubiquitin carboxyl-terminal hydrolase 14 
                   
                   
               
               
                 Q06323 
                 Proteasome activator complex subunit 1 
                 PSME1 
                 12 
               
               
                 P28074 
                 Proteasome subunit beta type-5 
                 PSMB5 
                 12 
               
               
                 B3KQV6 
                 Serine/threonine-protein phosphatase 2A 65  
                 PPP2R1A  
                 12 
               
               
                   
                 kDa regulatory subunit A alpha isoform 
                   
                   
               
               
                 Q14974 
                 lmportin subunit beta-1 
                 KPNB1 
                 12 
               
               
                 P25786 
                 Proteasome subunit alpha type-1; Proteasome subunit alpha type 
                 PSMA1 
                 12 
               
               
                 Q86X55 
                 Histone-arginine methyltransferase CARM1 
                 CARM1 
                 12 
               
               
                 A6NG10 
                 WW domain-binding protein 2 
                 WBP2 
                 12 
               
               
                 P63092 
                 Guanine nucleotide-binding protein G(s) subunit alpha 
                 GNAS 
                 12 
               
               
                 P31939 
                 Bifunctional purine biosynthesis protein PURH; 
                 ATIC 
                 12 
               
               
                   
                 Phosphoribosylaminoimidazolecarboxamide 
                   
                   
               
               
                   
                 formyltransferase; IMP cyclohydrolase 
                   
                   
               
               
                 P52209 
                 6-phosphogluconate dehydrogenase, decarboxylating 
                 PGD 
                 12 
               
               
                 A0A087X0C8 
                 Calpain-5 
                 CAPN5 
                 12 
               
               
                 F8W9S7 
                 GTPase-activating protein and VPS9 domain-containing protein 1 
                 GAPVD1 
                 12 
               
               
                 P60842 
                 Eukaryotic initiation factor 4A-I 
                 EIF4A1 
                 12 
               
               
                 P69905 
                 Hemoglobin subunit alpha 
                 HBA1 
                 11 
               
               
                 Q6XQN6 
                 Nicotinate phosphoribosyltransferase 
                 NAPRT 
                 11 
               
               
                 P48637 
                 Glutathione synthetase 
                 GSS 
                 11 
               
               
                 H7BZ94 
                 Protein disulfide-isomerase 
                 P4HB 
                 11 
               
               
                 P21980 
                 Protein-glutamine gamma-glutamyltransferase 2 
                 TGM2 
                 11 
               
               
                 P50895 
                 Basal cell adhesion molecule 
                 BCAM 
                 11 
               
               
                 A0A087X2I1 
                 26S protease regulatory subunit 10B 
                 PSMC6  
                 11 
               
               
                 G3V1D3 
                 Dipeptidyl peptidase 3 
                 DPP3 
                 11 
               
               
                 P05023 
                 Sodium/potassium-transporting ATPase subunit alpha-1;  
                 ATP1A1; 
                 11 
               
               
                   
                 Sodium/potassium-transporting ATPase subunit alpha-3 
                 ATP1A3 
                   
               
               
                 P40925 
                 Malate dehydrogenase, cytoplasmic; Malate dehydrogenase 
                 MDH1 
                 11 
               
               
                 Q9UKV8 
                 Protein argonaute-2 
                 AGO2 
                 11 
               
               
                 P30566 
                 Adenylosuccinate lyase 
                 ADSL 
                 11 
               
               
                 P20618 
                 Proteasome subunit beta type-1 
                 PSMB1 
                 11 
               
               
                 P17858 
                 ATP-dependent 6-phosphofructokinase, liver type 
                 PFKL 
                 11 
               
               
                 A0A087X253 
                 AP-2 complex subunit beta 
                 AP2B1 
                 11 
               
               
                 O95782 
                 AP-2 complex subunit alpha-1 
                 AP2A1 
                 11 
               
               
                 O00232 
                 26S proteasome non-ATPase regulatory subunit 12 
                 PSMD12  
                 11 
               
               
                 Q9BSL1 
                 Ubiquitin-associated domain-containing protein 1 
                 UBAC1 
                 11 
               
               
                 A0A087WUL0 
                 Bifunctional ATP-dependent dihydroxyacetone kinase/ 
                 TKFC; 
                 11 
               
               
                   
                 FAD-AMP lyase (cyclizing); ATP-dependent 
                 DAK  
                   
               
               
                   
                 dihydroxyacetone kinase; FAD-AMP lyase (cyclizing) 
                   
                   
               
               
                 P69891 
                 Hemoglobin subunit gamma-1 
                 HBG1 
                 11 
               
               
                 A0A087WZE4 
                 Spectrin alpha chain, erythrocytic 1 
                 SPTA1 
                 11 
               
               
                 P48426 
                 Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha 
                 PIP4K2A 
                 10 
               
               
                 P10644 
                 cAMP-dependent protein kinase type l-alpha regulatory subunit 
                 PRKAR1A  
                 10 
               
               
                 Q9BWD1 
                 Acetyl-CoA acetyltransferase, cytosolic 
                 ACAT2 
                 10 
               
               
                 P62191 
                 26S protease regulatory subunit 4 
                 PSMC1 
                 10 
               
               
                 E9PBS1 
                 Multifunctional protein ADE2; 
                 PAICS 
                 10 
               
               
                   
                 Phosphoribosylaminoimidazole-succinocarboxamide synthase; 
                   
                   
               
               
                   
                 Phosphoribosylaminoimidazole carboxylase 
                   
                   
               
               
                 M0R0Y2 
                 Alpha-soluble NSF attachment protein 
                 NAPA  
                 10 
               
               
                 P78417 
                 Glutathione 5-transferase omega-1 
                 GSTO1 
                 10 
               
               
                 P25789 
                 Proteasome subunit alpha type-4; 
                 PSMA4 
                 10 
               
               
                   
                 Proteasome subunit alpha type;  
                   
                   
               
               
                   
                 Proteasome subunit betat ype 
                   
                   
               
               
                 Q9H0U4 
                 Ras-related protein Rab-1B; 
                 RAB1B; 
                 10 
               
               
                   
                 Putative Ras-related protein Rab-1C 
                 RAB1C 
                   
               
               
                 Q16401 
                 26S proteasome non-ATPase regulatory subunit 5 
                 PSMD5 
                 10 
               
               
                 P30101 
                 Protein disulfide-isomerase A3 
                 PDIA3 
                 10 
               
               
                 D6RAX7 
                 COP9signalosome complex subunit 4 
                 COPS4  
                 10 
               
               
                 O75340 
                 Programmedcell death protein 6 
                 PDCD6  
                 10 
               
               
                 Q96P70 
                 Importin-9 
                 IPO9 
                 10 
               
               
                 P38606 
                 V-type proton ATPase catalytic subunit A 
                 ATP6V1A 
                 10 
               
               
                 A0A0G2JH68 
                 Protein diaphanous homolog 1 
                 DIAPH1 
                 10 
               
               
                 Q5T9B7 
                 Adenylate kinase isoenzyme 1 
                 AK1 
                 10 
               
               
                 O14980 
                 Exportin-1 
                 XPO1 
                 10 
               
               
                 P43686 
                 26S protease regulatory subunit 6B 
                 PSMC4 
                 10 
               
               
                 H0YH81 
                 ATP synthase subunit beta; ATP synthase subunit beta, mitochondrial 
                 ATP5B 
                 10 
               
               
                 Q04656 
                 Copper-transporting ATPase 1 
                 ATP7A 
                 10 
               
               
                 P16452 
                 Erythrocyte membrane protein band 4.2 
                 EPB42 
                 10 
               
               
                 Q9BY43 
                 Charged multivesicular body protein 4a 
                 CHMP4A 
                 9 
               
               
                 P51148 
                 Ras-related protein Rab-5C 
                 RAB5C 
                 9 
               
               
                 Q9NRV9 
                 Heme-binding protein 1 
                 HEBP1 
                 9 
               
               
                 Q9UNZ2 
                 NSFL1 cofactor p47 
                 NSFL1C 
                 9 
               
               
                 Q16851 
                 UTP--glucose-1-phosphate uridylyltransferase 
                 UGP2 
                 9 
               
               
                 P28066 
                 Proteasome subunit alpha type-5 
                 PSMA5  
                 9 
               
               
                 A0A0C4DGQ5 
                 Calpain small subunit 1 
                 CAPNS1 
                 9 
               
               
                 A0A087X1Z3 
                 Proteasome activator complex subunit 2 
                 PSME2 
                 9 
               
               
                 Q01518 
                 Adenylyl cyclase-associated protein 1 
                 CAP1 
                 9 
               
               
                 B1AKQ8 
                 Guaninenucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 
                 GNB1  
                 9 
               
               
                 O75131 
                 Copine-3 
                 CPNE3 
                 9 
               
               
                 P54725 
                 UV excision repair protein RAD23 homolog A 
                 RAD23A 
                 9 
               
               
                 P11215 
                 Integrin alpha-M 
                 ITGAM 
                 9 
               
               
                 Q93008 
                 Probable ubiquitin carboxyl-terminal hydrolase FAF-X 
                 USP9X  
                 9 
               
               
                 Q96G03 
                 Phosphoglucomutase-2 
                 PGM2 
                 9 
               
               
                 P49721 
                 Proteasome subunit beta type-2 
                 PSMB2 
                 9 
               
               
                 Q15008 
                 26S proteasome non-ATPase regulatory subunit 6 
                 PSMD6  
                 9 
               
               
                 Q9UNQ0 
                 ATP-binding cassette sub-family G member 2 
                 ABCG2 
                 9 
               
               
                 P22303 
                 Acetylcholinesterase; Carboxylic ester hydrolase 
                 ACHE 
                 9 
               
               
                 G3V5Z7 
                 Proteasome subunit alpha type; Proteasome subunit alpha type-6 
                 PSMA6 
                 9 
               
               
                 O15439 
                 Multidrug resistance-associated protein 4 
                 ABCC4 
                 9 
               
               
                 P37837 
                 Transaldolase 
                 TALDO1 
                 9 
               
               
                 O14744 
                 Protein arginine N-methyltransferase 5 
                 PRMT5 
                 9 
               
               
                 P02042 
                 Hemoglobin subunit delta 
                 HBD 
                 9 
               
               
                 P25788 
                 Proteasomesubunit alpha type-3 
                 PSMA3  
                 8 
               
               
                 J3QS39 
                 Ubiquitin-60S ribosomal protein L40; Ubiquitin;  
                 UBB;  
                 8 
               
               
                   
                 60S ribosomal protein L40; Ubiquitin-40S ribosomal protein S27a; 
                 RPS27A; 
                   
               
               
                   
                 Ubiquitin; 40S ribosomal protein S27a; Polyubiquitin-B; 
                 UBC; 
                   
               
               
                   
                 Ubiquitin; Polyubiquitin-C; Ubiquitin 
                 UBA52; 
                   
               
               
                   
                   
                 UBBP4 
                   
               
               
                 O94919 
                 Endonucleasedomain-containing 1 protein 
                 ENDOD1  
                 8 
               
               
                 P31946 
                 14-3-3 protein beta/alpha 
                 YWHAB 
                 8 
               
               
                 P60891 
                 Ribose-phosphate pyrophosphokinase 1; 
                 PRPS1; 
                 8 
               
               
                   
                 Ribose-phosphate pyrophosphokinase 2; 
                 PRPS2;  
                   
               
               
                   
                 Ribose-phosphate pyrophosphokinase 3 
                 PRPS1L1 
                   
               
               
                 P62195 
                 26S protease regulatory subunit 8 
                 PSMC5 
                 8 
               
               
                 A0A024RA52 
                 Proteasome subunit alpha type;  
                 PSMA2 
                 8 
               
               
                   
                 Proteasome subunit alpha type-2 
                   
                   
               
               
                 P04899 
                 Guanine nucleotide-binding protein G(i) subunit alpha-2 
                 GNAI2 
                 8 
               
               
                 Q13561 
                 Dynactin subunit 2 
                 DCTN2 
                 8 
               
               
                 P53004 
                 Biliverdin reductase A 
                 BLVRA 
                 8 
               
               
                 P00387 
                 NADH-cytochrome b5 reductase 3 
                 CYB5R3 
                 8 
               
               
                 P16152 
                 Carbonyl reductase [NADPH] 1 
                 CBR1 
                 8 
               
               
                 P06744 
                 Glucose-6-phosphate isomerase 
                 GPI 
                 8 
               
               
                 Q99733 
                 Nucleosomeassembly protein 1-like 4 
                 NAP1L4  
                 8 
               
               
                 P04792 
                 Heat shock protein beta-1 
                 HSPB1 
                 8 
               
               
                 P17612 
                 cAMP-dependent protein kinase catalytic subunit alpha; 
                 PRKACA;  
                 8 
               
               
                   
                 cAMP-dependent protein kinase catalytic subunit beta 
                 KIN27; 
                   
               
               
                   
                   
                 PRKACB 
                   
               
               
                 P20340 
                 Ras-related protein Rab-6A 
                 RAB6A 
                 8 
               
               
                 P13796 
                 Plastin-2 
                 LCP1 
                 8 
               
               
                 P52907 
                 F-actin-capping protein subunit alpha-1 
                 CAPZA1 
                 8 
               
               
                 Q14697 
                 Neutral alpha-glucosidase AB 
                 GANAB 
                 8 
               
               
                 P08514 
                 Integrin alpha-IIb; 
                 ITGA2B 
                 8 
               
               
                   
                 Integrin alpha-IIb heavy chain;  
                   
                   
               
               
                   
                 Integrin alpha-IIb light chain, form 1;  
                   
                   
               
               
                   
                 Integrin alpha-IIb light chain, form 2 
                   
                   
               
               
                 P26641 
                 Elongation factor 1-gamma 
                 EEF1G 
                 8 
               
               
                 Q9UQ80 
                 Proliferation-associated protein 2G4 
                 PA2G4 
                 8 
               
               
                 Q9Y4D1 
                 Disheveled-associated activator of morphogenesis 1 
                 DAAM1 
                 8 
               
               
                 P11166 
                 Solute carrier family 2, facilitated glucose transporter member 1 
                 SLC2A1 
                 8 
               
               
                 P63261 
                 Actin, cytoplasmic 2; Actin, cytoplasmic 2, N-terminally processed; 
                 ACTG1; 
                 8 
               
               
                   
                 Actin, cytoplasmic 1; Actin, cytoplasmic 1, N-terminally processed; 
                 ACTB; 
                   
               
               
                   
                 Actin, gamma-enteric smooth muscle; Actin, alpha skeletal muscle; 
                 ACTG2; 
                   
               
               
                   
                 Actin, alpha cardiac muscle 1; Actin, aortic smooth muscle  
                 ACTA1; 
                   
               
               
                   
                   
                 ACTC1; 
                   
               
               
                   
                   
                 ACTA2 
                   
               
               
                 P02008 
                 Hemoglobin subunit zeta 
                 HBZ  
                 8 
               
               
                 P20073 
                 Annexin A7  
                 ANXA7  
                 8 
               
               
                 P35613 
                 Basigin 
                 BSG 
                 7 
               
               
                 P49720 
                 Proteasome subunit beta type-3 
                 PSMB3 
                 7 
               
               
                 P17931 
                 Galectin-3; Galectin 
                 LGALS3 
                 7 
               
               
                 P63104 
                 14-3-3 protein zeta/delta 
                 YWHAZ 
                 7 
               
               
                 Q9H444 
                 Charged multivesicular body protein 4b 
                 CHMP4B 
                 7 
               
               
                 O43396 
                 Thioredoxin-like protein 1 
                 TXNL1 
                 7 
               
               
                 P50502 
                 Hsc70-interacting protein; Putative protein FAM10A4; 
                 ST13; 
                 7 
               
               
                   
                 Putative protein FAM10A5 
                 ST13P4; 
                   
               
               
                   
                   
                 ST13P5 
                   
               
               
                 E7EQ12 
                 Calpastatin 
                 CAST 
                 7 
               
               
                 P49189 
                 4-trimethylaminobutyraldehyde dehydrogenase 
                 ALDH9A1 
                 7 
               
               
                 Q9Y3I1 
                 F-box only protein 7 
                 FBXO7 
                 7 
               
               
                 P07954 
                 Fumaratehydratase, mitochondrial 
                 FH  
                 7 
               
               
                 F6S8N6 
                 Protein-L-isoaspartate O-methyltransferase; 
                 PCMT1  
                 7 
               
               
                   
                 Protein-L-isoaspartate(D-aspartate) O-methyltransferase 
                   
                   
               
               
                 P49247 
                 Ribose-5-phosphateisomerase 
                 RPIA  
                 7 
               
               
                 P62834 
                 Ras-related protein Rap-1A 
                 RAP1A 
                 7 
               
               
                 A0A087WUQ6 
                 Glutathione peroxidase; Glutathione peroxidase 1 
                 GPX1 
                 7 
               
               
                 O60256 
                 Phosphoribosyl pyrophosphate synthase-associated protein 2 
                 PRPSAP2 
                 7 
               
               
                 Q00796 
                 Sorbitol dehydrogenase 
                 SORD 
                 7 
               
               
                 O00299 
                 Chloride intracellular channel protein 1 
                 CLIC1 
                 7 
               
               
                 Q99497 
                 Protein deglycase DJ-1 
                 PARK7 
                 7 
               
               
                 P17174 
                 Aspartate aminotransferase, cytoplasmic 
                 GOT1 
                 7 
               
               
                 H7BXD5 
                 Grancalcin 
                 GCA 
                 7 
               
               
                 E9PGT1 
                 Translin 
                 TSN 
                 7 
               
               
                 C9J7K9 
                 Phospholipid scramblase 1 
                 PLSCR1 
                 7 
               
               
                 Q13618 
                 Cullin-3 
                 CUL3 
                 7 
               
               
                 O75695 
                 Protein XRP2 
                 RP2 
                 7 
               
               
                 P09960 
                 Leukotriene A-4 hydrolase 
                 LTA4H 
                 7 
               
               
                 E9PLK3 
                 Puromycin-sensitive aminopeptidase 
                 NPEPPS 
                 7 
               
               
                 P00492 
                 Hypoxanthine-guanine phosphoribosyltransferase 
                 HPRT1 
                 7 
               
               
                 F5H4B6 
                 Aldehyde dehydrogenase family 16 member A1 
                 ALDH16A1  
                 7 
               
               
                 D6RA82 
                 Annexin; Annexin A3 
                 ANXA3 
                 7 
               
               
                 P61106 
                 Ras-related protein Rab-14 
                 RAB14 
                 7 
               
               
                 Q16775 
                 Hydroxyacylglutathione hydrolase, mitochondrial 
                 HAGH 
                 7 
               
               
                 P07355 
                 Annexin A2; Annexin; Putative annexin A2-like protein 
                 ANXA2; 
                 7 
               
               
                   
                   
                 ANXA2P2 
                   
               
               
                 A0A087VVX08 
                 Gamma-adducin 
                 ADD3 
                 7 
               
               
                 P08238 
                 Heat shockprotein HSP 90-beta 
                 HSP90AB1  
                 7 
               
               
                 Q8IZY2 
                 ATP-binding cassette sub-family A member 7 
                 ABCA7 
                 7 
               
               
                 P14780 
                 Matrix metalloproteinase-9 
                 MMP9 
                 7 
               
               
                 P12955 
                 Xaa-Prodipeptidase 
                 PEPD  
                 7 
               
               
                 P68371 
                 Tubulin beta-4B chain; Tubulin beta-4A chain;  
                 TUBB4B; 
                 7 
               
               
                   
                 Tubulin beta chain 
                 TUB B4A; 
                   
               
               
                   
                   
                 TUBB 
                   
               
               
                 O15067 
                 Phosphoribosylformylglycinamidine synthase 
                 PFAS 
                 7 
               
               
                 P35241 
                 Radixin 
                 RDX 
                 7 
               
               
                 O60488 
                 Long-chain-fatty-acid--CoA ligase 4 
                 ACSL4 
                 7 
               
               
                 A0A0C4DGX4 
                 Cullin-1 
                 CUL1 
                 7 
               
               
                 P50148 
                 Guanine nucleotide-binding protein G(q) subunit alpha 
                 GNAQ 
                 7 
               
               
                 Q15907 
                 Ras-related protein Rab-11B; Ras-related protein Rab-11A 
                 RAB11B; 
                 7 
               
               
                   
                   
                 RAB11A 
                   
               
               
                 P30086 
                 Phosphatidylethanolamine-bindingprotein 1; 
                 PEBP1  
                 6 
               
               
                   
                 Hippocampal cholinergic neurostimulating peptide 
                   
                   
               
               
                 P55036 
                 26S proteasome non-ATPaseregulatory subunit 4 
                 PSMD4  
                 6 
               
               
                 P28070 
                 Proteasome subunit beta type-4 
                 PSMB4 
                 6 
               
               
                 Q9UNS2 
                 COP9 signalosome complex subunit 3 
                 COPS3  
                 6 
               
               
                 P08754 
                 Guanine nucleotide-binding protein G(k) subunit alpha 
                 GNAI3 
                 6 
               
               
                 P61006 
                 Ras-related protein Rab-8A 
                 RAB8A 
                 6 
               
               
                 P61019 
                 Ras-related protein Rab-2A 
                 RAB2A 
                 6 
               
               
                 H0Y8C6 
                 Importin-5 
                 IPO5 
                 6 
               
               
                 Q00577 
                 Transcriptional activator protein Pur-alpha 
                 PURA 
                 6 
               
               
                 P52565 
                 Rho GDP-dissociation inhibitor 1 
                 ARHGDIA 
                 6 
               
               
                 Q9Y5Z4 
                 Heme-bindingprotein 2 
                 HEBP2  
                 6 
               
               
                 J3KNF4 
                 Copper chaperone for superoxide dismutase;  
                 CCS  
                 6 
               
               
                   
                 Superoxide dismutase [Cu-Zn] 
                   
                   
               
               
                 A0A087VVXS7 
                 ATPase ASNA1 
                 ASNA1  
                 6 
               
               
                 P05089 
                 Arginase-1 
                 ARG1 
                 6 
               
               
                 095336 
                 6-phosphogluconolactonase 
                 PGLS 
                 6 
               
               
                 Q92508 
                 Piezo-type mechanosensitive ion channel component 1 
                 PIEZO1 
                 6 
               
               
                 P84077 
                 ADP-ribosylation factor 1; ADP-ribosylation factor 3 
                 ARF1; 
                 6 
               
               
                   
                   
                 ARF3 
                   
               
               
                 P21281 
                 V-type proton ATPase subunit B, brain isoform; 
                 ATP6V1B2; 
                 6 
               
               
                   
                 V-type proton ATPase subunit B, kidney isoform 
                 ATP6V1B1 
                   
               
               
                 P04259 
                 Keratin, type II cytoskeletal 6B 
                 KRT6B 
                 6 
               
               
                 Q92905 
                 COP9 signalosome complex subunit 5 
                 COPS5  
                 6 
               
               
                 P61163 
                 Alpha-centractin 
                 ACTR1A 
                 6 
               
               
                 O95373 
                 Importin-7 
                 1PO7 
                 6 
               
               
                 C9JD73 
                 Protein phosphatase 1 regulatory subunit 7 
                 PPP1R7 
                 6 
               
               
                 Q99536 
                 Synaptic vesicle membraneprotein VAT-1 homolog 
                 VAT1  
                 6 
               
               
                 Q86UX7 
                 Fermitin family homolog 3 
                 FERMT3 
                 6 
               
               
                 C9JFE4 
                 COP9 signalosome complex subunit 1 
                 GPS1  
                 6 
               
               
                 P36959 
                 GMP reductase 1 
                 GMPR 
                 6 
               
               
                 B5MDF5 
                 GTP-binding nuclear protein Ran 
                 RAN 
                 6 
               
               
                 F5GY90 
                 Porphobilinogen deaminase 
                 HMBS 
                 6 
               
               
                 E7EX90 
                 Dynactin subunit 1 
                 DCTN1 
                 6 
               
               
                 H0Y512 
                 Adipocyte plasmamembrane-associated protein 
                 APMAP  
                 6 
               
               
                 Q32Q12 
                 Nucleoside diphosphate kinase; 
                 NME1-NME2; 
                 6 
               
               
                   
                 Nucleoside diphosphate kinase B; 
                 NME2; 
                   
               
               
                   
                 Putative nucleoside diphosphate kinase 
                 NME1; 
                   
               
               
                   
                   
                 NME2P1 
                   
               
               
                 P13807 
                 Glycogen [starch] synthase, muscle 
                 GYS1  
                 6 
               
               
                 K7ES02 
                 Bleomycin hydrolase 
                 BLMH 
                 6 
               
               
                 P17213 
                 Bactericidal permeability-increasing protein 
                 BPI 
                 6 
               
               
                 Q9UNM6 
                 26S proteasome non-ATPase regulatory subunit 13 
                 PSMD13  
                 6 
               
               
                 J3KQ32 
                 Obg-like ATPase 1 
                 OLA1 
                 6 
               
               
                 Q9Y490 
                 Talin-1 
                 TLN1 
                 6 
               
               
                 H0YD13 
                 CD44 antigen 
                 CD44 
                 6 
               
               
                 P18669 
                 Phosphoglycerate mutase 1; 
                 PGAM1; 
                 6 
               
               
                   
                 Phosphoglycerate mutase 2; 
                 PGAM2; 
                   
               
               
                   
                 Probable phosphoglycerate mutase 4 
                 PGAM4 
                   
               
               
                 P23528 
                 Cofilin-1 
                 CFL1 
                 6 
               
               
                 Q5SR44 
                 Complement receptor type 1 
                 CR1 
                 6 
               
               
                 Q99436 
                 Proteasome subunit beta type-7 
                 PSMB7 
                 6 
               
               
                 P47756 
                 F-actin-capping protein subunit beta 
                 CAPZB 
                 6 
               
               
                 P30740 
                 Leukocyte elastase inhibitor 
                 SERPINB1 
                 6 
               
               
                 A0A024R571 
                 EH domain-containing protein 1 
                 EHD1  
                 6 
               
               
                 P30043 
                 Flavin reductase (NADPH) 
                 BLVRB 
                 6 
               
               
                 P32119 
                 Peroxiredoxin-2 
                 PRDX2 
                 6 
               
               
                 C9J0K6 
                 Sorcin 
                 SRI 
                 6 
               
               
                 P27105 
                 Erythrocyte band 7 integral membrane protein 
                 STOM  
                 6 
               
               
                 P84077 
                 ADP-ribosylation factor 1; ADP-ribosylation factor 3; 
                 ARF1; 
                 6 
               
               
                   
                 ADP-ribosylation factor 5; ADP-ribosylation factor 4 
                 ARF3; 
                   
               
               
                   
                   
                 ARF5; 
                   
               
               
                   
                   
                 ARF4 
                   
               
               
                 P61981 
                 14-3-3 protein gamma; 14-3-3 protein gamma, N-terminally processed 
                 YWHAG 
                 5 
               
               
                 P09211 
                 Glutathione 5-transferase P 
                 GSTP1 
                 5 
               
               
                 P13489 
                 Ribonuclease inhibitor 
                 RNH1 
                 5 
               
               
                 Q96PU5 
                 E3 ubiquitin-protein ligase NEDD4-like 
                 NEDD4L 
                 5 
               
               
                 Q5SRN7 
                 HLA class I histocompatibility antigen, A;  
                 HLA-A; 
                 5 
               
               
                   
                 HLA class I histocompatibility antigen, B; 
                 HLA-C; 
                   
               
               
                   
                 HLA class I histocompatibility antigen, Cw 
                 HLA-B 
                   
               
               
                 P02042 
                 Hemoglobin subunit delta 
                 HBD 
                 5 
               
               
                 A0A087WU29 
                 Glycophorin-A 
                 GYPA 
                 5 
               
               
                 P00390 
                 Glutathione reductase, mitochondrial 
                 GSR 
                 5 
               
               
                 Q9UBV8 
                 Peflin 
                 PEF1 
                 5 
               
               
                 Q8VVVM8 
                 Sec1 family domain-containing protein 1 
                 SCFD1  
                 5 
               
               
                 F6TLX2 
                 Glyoxalase domain-containing protein 4 
                 GLOD4 
                 5 
               
               
                 H3BQF1 
                 Adenine phosphoribosyltransferase 
                 APRT 
                 5 
               
               
                 Q07960 
                 Rho GTPase-activating protein 1 
                 ARHGAP1 
                 5 
               
               
                 F6XSS0 
                 Blood group Rh(CE) polypeptide; 
                 RHCE; 
                 5 
               
               
                   
                 Blood group Rh(D) polypeptide 
                 RHD 
                   
               
               
                 A0A087WY55 
                 Vacuolar protein sorting-associated protein VTA1 homolog 
                 VTA1 
                 5 
               
               
                 G5E9W8 
                 Glycogenin-1 
                 GYG1 
                 5 
               
               
                 P07451 
                 Carbonic anhydrase 3 
                 CA3 
                 5 
               
               
                 Q08722 
                 Leukocyte surface antigen CD47 
                 CD47 
                 5 
               
               
                 X6RA14 
                 S-formylglutathione hydrolase 
                 ESD 
                 5 
               
               
                 Q8IU18 
                 Cytokine receptor-like factor 3 
                 CRLF3 
                 5 
               
               
                 Q5VW32 
                 BRO1 domain-containing protein BROX 
                 BROX 
                 5 
               
               
                 P61026 
                 Ras-related protein Rab-10 
                 RAB10 
                 5 
               
               
                 A0A087WWY3 
                 Filamin-A 
                 FLNA 
                 5 
               
               
                 H0YGX7 
                 Rho GDP-dissociation inhibitor 2 
                 ARHGDIB  
                 5 
               
               
                 Q92783 
                 Signal transducing adapter molecule 1 
                 STAM 
                 5 
               
               
                 Q7Z6Z7 
                 E3 ubiquitin-protein ligase HUWE1 
                 HUWE1 
                 5 
               
               
                 H0YHC3 
                 Nucleosome assembly protein 1-like 1 
                 NAP1L1  
                 5 
               
               
                 Q5QPM7 
                 Proteasomeinhibitor PI31 subunit 
                 PSMF1  
                 5 
               
               
                 P09104 
                 Gamma-enolase; Enolase 
                 ENO2 
                 5 
               
               
                 Q5T2B5 
                 Cullin-2 
                 CUL2 
                 5 
               
               
                 Q8WW22 
                 DnaJ homolog subfamily A member 4 
                 DNAJA4  
                 5 
               
               
                 P61201 
                 COP9 signalosome complex subunit 2 
                 COPS2 
                 5 
               
               
                 X6R433 
                 Protein-tyrosine-phosphatase;  
                 PTPRC 
                 5 
               
               
                   
                 Receptor-type tyrosine-protein phosphatase C 
                   
                   
               
               
                 P63000 
                 Ras-related C3 botulinum toxin substrate 1 
                 RAC1 
                 5 
               
               
                 F5GXM3 
                 IST1 homolog 
                 IST1 
                 5 
               
               
                 H3BLU7 
                 Aflatoxin B1 aldehyde reductase member 2 
                 AKR7A2 
                 5 
               
               
                 P25325 
                 3-mercaptopyruvate sulfurtransferase; Sulfurtransferase 
                 MPST 
                 5 
               
               
                 A0A087X0K1 
                 Calcium-binding protein 39 
                 CAB39 
                 5 
               
               
                 P23381 
                 Tryptophan--tRNA ligase, cytoplasmic; T1-TrpRS; T2-TrpRS 
                 WARS 
                 5 
               
               
                 P01116 
                 GTPaseKRas; GTPase KRas, N-terminally processed  
                 KRAS 
                 5 
               
               
                 P30040 
                 Endoplasmic reticulum resident protein 29 
                 ERP29 
                 5 
               
               
                 P05198 
                 Eukaryotic translation initiation factor 2 subunit 1 
                 EIF2S1 
                 5 
               
               
                 Q6UX06 
                 Olfactomedin-4 
                 OLFM4 
                 5 
               
               
                 Q96KP4 
                 Cytosolic non-specific dipeptidase 
                 CNDP2 
                 5 
               
               
                 Q04760 
                 Lactoylglutathione lyase 
                 GLO1 
                 5 
               
               
                 J3Q539 
                 Ubiquitin-60S ribosomal protein L40;  
                 UBB; 
                 5 
               
               
                   
                 Ubiquitin; 60S ribosomal protein L40;  
                 RPS27A; 
                   
               
               
                   
                 Ubiquitin-40S ribosomal protein S27a; 
                 UBC;  
                   
               
               
                   
                 Ubiquitin; 40S ribosomal protein S27a; 
                 UBA52; 
                   
               
               
                   
                 Polyubiquitin-B; Ubiquitin; 
                 UBBP4 
                   
               
               
                   
                 Polyubiquitin-C; Ubiquitin 
                   
                   
               
               
                 P06702 
                 Protein S100-A9 
                 S100A9 
                 5 
               
               
                 P15531 
                 Nucleoside diphosphate kinase A;  
                 NME1; 
                 5 
               
               
                   
                 Nucleoside diphosphate kinase;  
                 NME2; 
                   
               
               
                   
                 Nucleoside diphosphate kinase B 
                 NME1-NME2 
                   
               
               
                 E7EV99 
                 Alpha-adducin 
                 ADD1 
                 5 
               
               
                 P51149 
                 Ras-related protein Rab-7a 
                 RAB7A 
                 4 
               
               
                 K7N7A8 
                 Aquaporin-1 
                 AQP1 
                 4 
               
               
                 P61020 
                 Ras-related protein Rab-5B 
                 RAB5B 
                 4 
               
               
                 X6R4N5 
                 Erythroid membrane-associated protein 
                 ERMAP 
                 4 
               
               
                 E5RJR5 
                 S-phase kinase-associated protein 1 
                 SKP1 
                 4 
               
               
                 Q9Y315 
                 Deoxyribose-phosphate aldolase 
                 DERA 
                 4 
               
               
                 X6R8F3 
                 Neutrophil gelatinase-associated lipocalin 
                 LCN2 
                 4 
               
               
                 O75396 
                 Vesicle-trafficking protein SEC22b 
                 SEC22B 
                 4 
               
               
                 Q15102 
                 Platelet-activating factor acetylhydrolase IB subunit gamma 
                 PAFAH1B3 
                 4 
               
               
                 P51665 
                 26S proteasome non-ATPase regulatory subunit 7 
                 PSMD7 
                 4 
               
               
                 Q96FZ7 
                 Charged multivesicular body protein 6 
                 CHMP6 
                 4 
               
               
                 Q9NRQ2 
                 Phospholipid scramblase 4 
                 PLSCR4 
                 4 
               
               
                 F8VWS0 
                 60S acidic ribosomal protein P0; 60S acidic ribosomal protein P0-like 
                 RPLP0; 
                 4 
               
               
                   
                   
                 RPLP0P6 
                   
               
               
                 O14964 
                 Hepatocyte growth factor-regulated tyrosine kinase substrate 
                 HGS 
                 4 
               
               
                 A0A0A0MTJ9 
                 Neutral cholesterol ester hydrolase 1 
                 NCEH1 
                 4 
               
               
                 A0A087VVY82 
                 Junctional adhesion molecule A 
                 F11R 
                 4 
               
               
                 J3Q5B7 
                 Purine nucleoside phosphorylase; 
                 MTAP 
                 4 
               
               
                   
                 S-methyl-5-thioadenosine phosphorylase 
                   
                   
               
               
                 Q5WQ6 
                 Ubiquitin thioesterase OTU1 
                 YOD1 
                 4 
               
               
                 P36543 
                 V-type proton ATPase subunit E 1 
                 ATP6V1E1 
                 4 
               
               
                 Q9B540 
                 Latexin 
                 LXN 
                 4 
               
               
                 P47755 
                 F-actin-capping protein subunit alpha-2 
                 CAPZA2 
                 4 
               
               
                 Q9GZT8 
                 NIF3-like protein 1 
                 NIF3L1 
                 4 
               
               
                 H6UYS7 
                 Alpha-synuclein 
                 SNCA 
                 4 
               
               
                 P60953 
                 Cell division control protein 42 homolog 
                 CDC42 
                 4 
               
               
                 Q14773 
                 Intercellular adhesion molecule 4 
                 ICAM4 
                 4 
               
               
                 H0Y6T7 
                 Nicastrin 
                 NCSTN 
                 4 
               
               
                 P69891 
                 Hemoglobin subunit gamma-1 
                 HBG1 
                 4 
               
               
                 P14625 
                 Endoplasmin 
                 HSP90B1 
                 4 
               
               
                 Q96GD0 
                 Pyridoxal phosphate phosphatase 
                 PDXP  
                 4 
               
               
                 P08311 
                 Cathepsin G 
                 CTSG 
                 4 
               
               
                 Q9H9Q2 
                 COP9 signalosome complex subunit 7b 
                 COPS7B 
                 4 
               
               
                 P09417 
                 Dihydropteridine reductase 
                 QDPR 
                 4 
               
               
                 F8WE6 
                 Peptidyl-prolyl cis-trans isomerase;  
                 PPIA 
                 4 
               
               
                   
                 Peptidyl-prolyl cis-trans isomerase A 
                   
                   
               
               
                 O15173 
                 Membrane-associatedprogesterone receptor component 2 
                 PGRMC2  
                 4 
               
               
                 P28072 
                 Proteasome subunit beta type-6; Proteasome subunit beta type 
                 PSMB6 
                 4 
               
               
                 H3BSW0 
                 Leucine-rich repeat-containing protein 57 
                 LRRC57 
                 4 
               
               
                 Q9UBW8 
                 COP9 signalosome complex subunit 7a 
                 COPS7A 
                 4 
               
               
                 O00560 
                 Syntenin-1 
                 SDCBP 
                 4 
               
               
                 F5H157 
                 Ras-related protein Rab-35 
                 RAB35 
                 4 
               
               
                 Q9H479 
                 Fructosamine-3-kinase 
                 FN3K 
                 4 
               
               
                 Q04917 
                 14-3-3 protein eta 
                 YWHAH 
                 4 
               
               
                 C9JJ47 
                 AP-2 complex subunit mu 
                 AP2M1 
                 4 
               
               
                 C9JIG9 
                 Serine/threonine-protein kinase OSR1 
                 OXSR1 
                 4 
               
               
                 Q13336 
                 Urea transporter 1 
                 SLC14A1 
                 4 
               
               
                 P46926 
                 Glucosamine-6-phosphate isomerase 1; 
                 GNPDA1; 
                 4 
               
               
                   
                 Glucosamine-6-phosphate isomerase; 
                 GNPDA2 
                   
               
               
                   
                 Glucosamine-6-phosphate isomerase 2  
                   
                   
               
               
                 O43633 
                 Charged multivesicular body protein 2a 
                 CHMP2A 
                 4 
               
               
                 F8VVB9 
                 Tubulin alpha-1A chain; Tubulin alpha-1C chain; 
                 TUBA1B; 
                 4 
               
               
                   
                 Tubulin alpha-1B chain; Tubulin alpha-3C/D chain; 
                 TUBA1C; 
                   
               
               
                   
                 Tubulin alpha-3E chain 
                 TUBA1A; 
                   
               
               
                   
                   
                 TUBA3C; 
                   
               
               
                   
                   
                 TUBA3E 
                   
               
               
                 A6PVN5 
                 Serine/threonine-protein phosphatase 2A activator 
                 PPP2R4 
                 4 
               
               
                 B8ZZB8 
                 CB1 cannabinoid receptor-interacting protein 1 
                 CNRIP1 
                 4 
               
               
                 Q9P2R3 
                 Rabankyrin-5 
                 ANKFY1 
                 4 
               
               
                 Q86YS7 
                 C2 domain-containing protein 5 
                 C2CD5 
                 4 
               
               
                 R4GMR5 
                 26S proteasome non-ATPase regulatory subunit 8 
                 PSMD8 
                 4 
               
               
                 E7EM64 
                 COP9 signalosome complex subunit 6 
                 COPS6 
                 4 
               
               
                 J3KNI6 
                 Integrin beta; Integrin beta-2 
                 ITGB2 
                 4 
               
               
                 H0Y5R6 
                 Uroporphyrinogen decarboxylase 
                 UROD 
                 4 
               
               
                 M0R165 
                 Epidermal growth factor receptor substrate 15-like 1 
                 EPS15L1 
                 4 
               
               
                 O00487 
                 26S proteasome non-ATPase regulatory subunit 14 
                 PSMD14 
                 4 
               
               
                 Q13630 
                 GDP-L-fucose synthase 
                 TSTA3 
                 4 
               
               
                 P55060 
                 Exportin-2 
                 CSE1L 
                 4 
               
               
                 P20020 
                 Plasma membrane calcium-transporting ATPase 1;  
                 ATP2B1  
                 4 
               
               
                   
                 Calcium-transporting ATPase 
                   
                   
               
               
                 Q9NYU2 
                 UDP-glucose: glycoprotein glucosyltransferase 1 
                 UGGT1 
                 4 
               
               
                 H3BND8 
                 Ubiquitin carboxyl-terminal hydrolase; 
                 USP7 
                 4 
               
               
                   
                 Ubiquitin carboxyl-terminal hydrolase 7 
                   
                   
               
               
                 Q9GZP4 
                 PITH domain-containing protein 1 
                 PITHD1 
                 4 
               
               
                 D6RD66 
                 WD repeat-containing protein 1 
                 WDR1  
                 4 
               
               
                 P48729 
                 Caseinkinase I isoform alpha 
                 CSNK1A1  
                 4 
               
               
                 P25685 
                 DnaJ homolog subfamily B member 1 
                 DNAJB1 
                 4 
               
               
                 P14550 
                 Alcohol dehydrogenase [NADP(+)] 
                 AKR1A1 
                 4 
               
               
                 Q6PCE3 
                 Glucose 1,6-bisphosphate synthase 
                 PGM2L1 
                 4 
               
               
                 Q9UPN7 
                 Serine/threonine-protein phosphatase 6 regulatory subunit 1 
                 PPP6R1 
                 4 
               
               
                 P62805 
                 Histone H4 
                 HIST1H4A 
                 4 
               
               
                 P62937 
                 Peptidyl-prolyl cis-trans isomerase A 
                 PPIA 
                 4 
               
               
                 P30046 
                 D-dopachrome decarboxylase; D-dopachrome decarboxylase-like protein 
                 DDT; DDTL 
                 4 
               
               
                 Q08495 
                 Dematin 
                 DMTN 
                 4 
               
               
                 K7EIJ0 
                 WW domain-binding protein 2 
                 WBP2 
                 4 
               
               
                 E5RHP7 
                 Carbonic anhydrase 1 
                 CA1 
                 4 
               
               
                 P09105 
                 Hemoglobin subunit theta-1 
                 HBQ1 
                 4 
               
               
                 E7ESC6 
                 Exportin-7 
                 XPO7 
                 4 
               
               
                 P61225 
                 Ras-related protein Rap-2b;  
                 RAP2B; 
                 4 
               
               
                   
                 Ras-related protein Rap-2c; 
                 RAP2A; 
                   
               
               
                   
                 Ras-related protein Rap-2a 
                 RAP2C 
                   
               
               
                 O15400 
                 Syntaxin-7 
                 STX7 
                 3 
               
               
                 Q5VZR0 
                 Golgi-associated plant pathogenesis-related protein 1 
                 GLIPR2 
                 3 
               
               
                 P40199 
                 Carcinoembryonic antigen-related cell adhesion molecule 6 
                 CEACAM6 
                 3 
               
               
                 P27348 
                 14-3-3 protein theta 
                 YWHAQ 
                 3 
               
               
                 P62820 
                 Ras-related protein Rab-1A 
                 RAB1A 
                 3 
               
               
                 C9JEN3 
                 Protein lifeguard 3 
                 TMBIM1 
                 3 
               
               
                 Q9UDX3 
                 SEC14-like protein 4 
                 SEC14L4 
                 3 
               
               
                 Q9Y570 
                 Protein phosphatase methylesterase 1 
                 PPME1 
                 3 
               
               
                 Q96GG9 
                 DCN1-like protein 1; DCN1-like protein 
                 DCUN1D1 
                 3 
               
               
                 B0YJC4 
                 Vimentin 
                 VIM 
                 3 
               
               
                 Q86VN1 
                 Vacuolar protein-sorting-associated protein 36 
                 VPS36 
                 3 
               
               
                 F8WFB9 
                 Endophilin-B2 
                 SH3GLB2 
                 3 
               
               
                 A0A087WVQ9 
                 Elongation factor 1-alpha 1; Putative elongation factor 1-alpha-like 3 
                 EEF1A1; 
                 3 
               
               
                   
                   
                 EEF1A1P5 
                   
               
               
                 Q53TN4 
                 Cytochromeb reductase 1 
                 CYBRD1  
                 3 
               
               
                 P10809 
                 60 kDa heat shock protein, mitochondrial 
                 HSPD1 
                 3 
               
               
                 F5H7X1 
                 26S proteasome non-ATPase regulatory subunit 9 
                 PSMD9  
                 3 
               
               
                 E9PNW4 
                 CD59 glycoprotein 
                 CD59  
                 3 
               
               
                 E9PS74 
                 Solute carrier family 43 member 3 
                 SLC43A3 
                 3 
               
               
                 P53985 
                 Monocarboxylate transporter 1 
                 SLC16A1 
                 3 
               
               
                 Q8WWI5 
                 Choline transporter-like protein 1 
                 SLC44A1 
                 3 
               
               
                 E9PIR7 
                 Thioredoxin reductase 1, cytoplasmic 
                 TXNRD1 
                 3 
               
               
                 Q5TD07 
                 Ribosyldihydronicotinamide dehydrogenase [quinone] 
                 NQO2 
                 3 
               
               
                 Q9UL25 
                 Ras-related protein Rab-21 
                 RAB21 
                 3 
               
               
                 P27824 
                 Calnexin 
                 CANX 
                 3 
               
               
                 U3KPS2 
                 Myeloblastin 
                 PRTN3 
                 3 
               
               
                 Q9UKU0 
                 Long-chain-fatty-acid--CoA ligase 6 
                 ACSL6 
                 3 
               
               
                 P24666 
                 Low molecular weight phosphotyrosine protein phosphatase 
                 ACP1 
                 3 
               
               
                 H7C2G2 
                 NAD(P)(+)--arginine ADP-ribosyltransferase; Ecto-ADP-ribosyltransferase 4 
                 ART4 
                 3 
               
               
                 I3L1K6 
                 Myosin light chain 4 
                 MYL4 
                 3 
               
               
                 Q9UK41 
                 Vacuolar protein sorting-associated protein 28 homolog 
                 VPS28 
                 3 
               
               
                 Q9NUQ9 
                 Protein FAM49B 
                 FAM49B  
                 3 
               
               
                 Q9UBQ7 
                 Glyoxylate reductase/hydroxypyruvate reductase 
                 GRHPR 
                 3 
               
               
                 B8ZZG1 
                 MAGUK p55 subfamily member 6 
                 MPP6 
                 3 
               
               
                 Q10567 
                 AP-1 complex subunit beta-1 
                 AP1B1 
                 3 
               
               
                 O75387 
                 Large neutral amino acids transporter small subunit 3 
                 SLC43A1 
                 3 
               
               
                 Q9BTU6 
                 Phosphatidylinositol 4-kinase type 2-alpha 
                 PI4K2A 
                 3 
               
               
                 J3K522 
                 L-xylulose reductase 
                 DCXR 
                 3 
               
               
                 O15498 
                 Synaptobrevin homolog YKT6  
                 YKT6  
                 3 
               
               
                 Q08211 
                 ATP-dependent RNA helicase 
                 ADHX9  
                 3 
               
               
                 P50416 
                 Carnitine O-palmitoyltransferase 1, liver isoform 
                 CPT1A 
                 3 
               
               
                 P08237 
                 ATP-dependent 6-phosphofructokinase, muscle type 
                 PFKM 
                 3 
               
               
                 P14735 
                 Insulin-degrading enzyme 
                 IDE 
                 3 
               
               
                 Q9H0R3 
                 Transmembrane protein 222 
                 TMEM222 
                 3 
               
               
                 Q14166 
                 Tubulin--tyrosine ligase-like protein 12 
                 TTLL12 
                 3 
               
               
                 Q14558 
                 Phosphoribosyl pyrophosphate synthase-associated protein 1 
                 PRPSAP1 
                 3 
               
               
                 A0A087WTB8 
                 Ubiquitin carboxyl-terminal hydrolase; 
                 UCHL3 
                 3 
               
               
                   
                 Ubiquitin carboxyl-terminal hydrolase isozyme L3 
                   
                   
               
               
                 Q9NPQ8 
                 Synembryn-A 
                 RIC8A 
                 3 
               
               
                 F6WQW2 
                 Ran-specific GTPase-activating protein 
                 RANBP1 
                 3 
               
               
                 Q15691 
                 Microtubule-associated protein RP/EB family member 1 
                 MAPRE1  
                 3 
               
               
                 A0A0A0MR50 
                 Cullin-4A 
                 CUL4A 
                 3 
               
               
                 Q96IU4 
                 Alpha/beta hydrolase domain-containing protein 14B 
                 ABHD14B 
                 3 
               
               
                 Q9P0L0 
                 Vesicle-associated membrane protein-associated protein A 
                 VAPA  
                 3 
               
               
                 E9PRY8 
                 Elongation factor 1-delta 
                 EEF1D 
                 3 
               
               
                 Q16543 
                 Hsp90 co-chaperone Cdc37 
                 CDC37  
                 3 
               
               
                 P06702 
                 Protein S100-A9 
                 S100A9 
                 3 
               
               
                 P13639 
                 Elongation factor 2 
                 EEF2 
                 3 
               
               
                 E9PJC7 
                 Tetraspanin; CD82 antigen 
                 CD82 
                 3 
               
               
                 Q01432 
                 AMP deaminase 3 
                 AMPD3  
                 3 
               
               
                 B1AUU8 
                 Epidermal growth factor receptor substrate 15 
                 EPS15 
                 3 
               
               
                 P54709 
                 Sodium/potassium-transporting ATPase subunit beta-3 
                 ATP1B3 
                 3 
               
               
                 P54727 
                 UV excision repair protein RAD23 homolog B 
                 RAD23B 
                 3 
               
               
                 P36507 
                 Dual specificity mitogen-activated protein kinase kinase 2 
                 MAP2K2 
                 3 
               
               
                 Q9Y2V2 
                 Calcium-regulated heat stable protein 1 
                 CARHSP1 
                 3 
               
               
                 P31146 
                 Coronin-1A; Coronin 
                 CORO1A 
                 3 
               
               
                 Q8IY17 
                 Neuropathy target esterase 
                 PNPLA6  
                 3 
               
               
                 E7EQR4 
                 Ezrin 
                 EZR 
                 3 
               
               
                 F8WDS9 
                 LanC-like protein 1 
                 LANCL1 
                 3 
               
               
                 X6RJP6 
                 Transgelin-2 
                 TAGLN2 
                 3 
               
               
                 A0A0J9YXM6 
                 WD repeat-containing protein 81 
                 WDR81  
                 3 
               
               
                 P62140 
                 Serine/threonine-protein phosphatase PP1-beta catalytic subunit;  
                 PPP1CB 
                 3 
               
               
                   
                 Serine/threonine-protein phosphatase 
                   
                   
               
               
                 H0YLJ3 
                 Mortality factor 4-like protein 1 
                 MORF4L1 
                 3 
               
               
                 E7EPV7 
                 Alpha-synuclein 
                 SNCA 
                 3 
               
               
                 K7EK07 
                 Histone H3 
                 H3F3B 
                 3 
               
               
                 P05109 
                 Protein S100-A8; Protein S100-A8, N-terminally processed 
                 S100A8 
                 3 
               
               
                 13L0A0 
                 Ubiquitin-conjugating enzyme E2 variant 1; 
                 TMEM189- 
                 3 
               
               
                   
                 Ubiquitin-conjugating enzyme E2 variant 2 
                 UBE2V1;  
                   
               
               
                   
                   
                 UBE2V1; 
                   
               
               
                   
                   
                 UBE2V2 
                   
               
               
                 Q6B0K9 
                 Hemoglobin subunit mu 
                 HBM 
                 3 
               
               
                 O75368 
                 SH3 domain-binding glutamic acid-rich-like protein 
                 SH3BGRL 
                 3 
               
               
                 A0A0J9YXB3 
                 Ras-related protein Rap-1b; Ras-related protein Rap-1A; 
                 RAP1B; 
                 3 
               
               
                   
                 Ras-related protein Rap-1b-like protein 
                 RAP1A 
                   
               
               
                 P60953 
                 Cell division control protein 42 homolog 
                 CDC42 
                 3 
               
               
                 A0A087WTI1 
                 Ras-related protein Rab-1B; 
                 RAB1B; 
                 3 
               
               
                   
                 Ras-related protein Rab-1A 
                 RAB1A 
                   
               
               
                 B5MDF5 
                 GTP-binding nuclear protein Ran 
                 RAN 
                 3 
               
               
                 P61088 
                 Ubiquitin-conjugating enzyme E2 N 
                 UBE2N 
                 3 
               
               
                 Q00013 
                 55 kDa erythrocytemembrane protein 
                 MPP1  
                 3 
               
               
                 B1AKQ8 
                 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1;  
                 GNB1; 
                 3 
               
               
                   
                 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3; 
                 GNB2; 
                   
               
               
                   
                 Guanine nucleotide-binding protein 
                 GNB3 
                   
               
               
                   
                 G(I)/G(S)/G(T) subunit beta-2 
                   
                   
               
               
                 P04406 
                 Glyceraldehyde-3-phosphate dehydrogenase 
                 GAPDH  
                 3 
               
               
                 Q9UJC5 
                 SH3 domain-binding glutamic acid-rich-like protein 2 
                 SH3BGRL2 
                 3 
               
               
                 P04921 
                 Glycophorin-C 
                 GYPC 
                 2 
               
               
                 Q9NP59 
                 Solute carrier family 40 member 1 
                 SLC40A1 
                 2 
               
               
                 K7EKH5 
                 Fructose-bisphosphate aldolase; Fructose-bisphosphate aldolase C 
                 ALDOC 
                 2 
               
               
                 P11233 
                 Ras-related protein Ral-A 
                 RALA 
                 2 
               
               
                 F8WBR5 
                 Calmodulin 
                 CALM2; 
                 2 
               
               
                   
                   
                 CALM3; 
                   
               
               
                   
                   
                 CALM1 
                   
               
               
                 P00441 
                 Superoxide dismutase [Cu-Zn] 
                 SOD1 
                 2 
               
               
                 H0YDI1 
                 Lymphocyte function-associated antigen 3 
                 CD58 
                 2 
               
               
                 H0YNE9 
                 Ras-related protein Rab-8B 
                 RAB8B 
                 2 
               
               
                 J3KN67 
                   
                 TPM3 
                 2 
               
               
                 P20160 
                 Azurocidin 
                 AZU1 
                 2 
               
               
                 A0A087WZZ4 
                 Ammoniumtransporter Rh type A 
                 RHAG  
                 2 
               
               
                 F5GXS0 
                 Complement C4-A; Complement C4-B 
                 C4B; C4A 
                   
               
               
                 Q8ND76 
                 Cyclin-Y 
                 CCNY 
                 2 
               
               
                 Q14739 
                 Lamin-B receptor 
                 LBR  
                 2 
               
               
                 Q15181 
                 Inorganic pyrophosphatase 
                 PPA1 
                 2 
               
               
                 J3QS92 
                 Galectin-9 
                 LGALS9 
                 2 
               
               
                 I3L471 
                 Phosphatidylinositol transfer protein alpha isoform 
                 PITPNA 
                 2 
               
               
                 P01111 
                 GTPase NRas 
                 NRAS; KRAS 
                 2 
               
               
                 F5H4Q5 
                 Vacuolar protein sorting-associated protein 37C 
                 VPS37C 
                 2 
               
               
                 A0A0A0MSW4 
                 Phosphatidylinositol transfer protein beta isoform 
                 PITPNB 
                 2 
               
               
                 P67775 
                 Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform; 
                 PPP2CA; 
                   
               
               
                   
                 Serine/threonine-protein phosphatase 
                 PP2P2CB 
                   
               
               
                 P41091 
                 Eukaryotic translation initiation factor 2 subunit 3; 
                 E1F2S3; 
                 2 
               
               
                   
                 Putative eukaryotic translation initiation 
                 EIF2S3L 
                   
               
               
                   
                 factor 2 subunit 3-like protein 
                   
                   
               
               
                 A0A087WWS7 
                 Syntaxin-binding protein 2 
                 STXBP2 
                 2 
               
               
                 F8VQX6 
                 Methyltransferase-like protein 7A 
                 METTL7A 
                 2 
               
               
                 B3KT28 
                 FAS-associated factor 1 
                 FAF1 
                 2 
               
               
                 K7EIJ8 
                 Katanin p60 ATPase-containing subunit A-like 2 
                 KATNAL2 
                 2 
               
               
                 P20339 
                 Ras-related protein Rab-5A 
                 RAB5A 
                 2 
               
               
                 O95456 
                 Proteasome assembly chaperone 1 
                 PSMG1 
                 2 
               
               
                 K7EK45 
                 Polypyrimidine tract-binding protein 1 
                 PTBP1 
                 2 
               
               
                 Q15365 
                 Poly(rC)-binding protein 1; Poly(rC)-binding protein 3 
                 PCBP1; 
                 2 
               
               
                   
                   
                 PCBP3 
                   
               
               
                 Q9BSJ8 
                 Extended synaptotagmin-1 
                 ESYT1 
                 2 
               
               
                 H3BP35 
                 Diphosphomevalonate decarboxylase 
                 MVD 
                 2 
               
               
                 H0Y8C4 
                 Serine/threonine-protein phosphatase 2A  
                 PPP2R5D 
                 2 
               
               
                   
                 56 kDa regulatory subunit delta isoform 
                   
                   
               
               
                 K7EP09 
                 Bifunctional coenzyme A synthase; 
                 COASY 
                 2 
               
               
                   
                 Phosphopantetheine adenylyltransferase; 
                   
                   
               
               
                   
                 Dephospho-CoA kinase 
                   
                   
               
               
                 F8VNT9 
                 Tetraspanin; CD63 antigen 
                 CD63 
                 2 
               
               
                 Q8NEV1 
                 Casein kinase II subunit alpha 3; 
                 CSNK2A3; 
                 2 
               
               
                   
                 Casein kinase II subunit alpha 
                 CSNK2A1 
                   
               
               
                 F8VTQ5 
                 Heterogeneous nuclear ribonucleoprotein A1 
                 HNRNPA1 
                 2 
               
               
                 A0A087X2E2 
                 Carcinoembryonic antigen-related cell adhesion molecule 8; 
                 CEACAM8; 
                 2 
               
               
                   
                 Carcinoembryonic antigen-related cell adhesion molecule 1; 
                 CEACAM5; 
                   
               
               
                   
                 Carcinoembryonic antigen-related cell adhesion molecule 5 
                 CEACAM1 
                   
               
               
                 H0YAS8 
                 Clusterin; Clusterin beta chain; Clusterin alpha chain; Clusterin 
                 CLU 
                 2 
               
               
                 E9PP54 
                 Tubulin-specific chaperone cofactor E-like protein 
                 TBCEL 
                 2 
               
               
                 P43034 
                 Platelet-activating factor acetylhydrolase IB subunit alpha 
                 PAFAH1B1  
                 2 
               
               
                 Q9NT62 
                 Ubiquitin-like-conjugating enzyme ATG3  
                 ATG3  
                 2 
               
               
                 K7ERZ3 
                 Perilipin-3 
                 PLIN3 
                 2 
               
               
                 Q6DD88 
                 Atlastin-3 
                 ATL3 
                 2 
               
               
                 Q15084-3 
                 Proteindisulfide-isomerase A6 
                 PDIA6  
                 2 
               
               
                 K7EQH4 
                 ATP synthase subunit alpha, mitochondrial 
                 ATP5A1  
                 2 
               
               
                 G3V1U5 
                 Vesicle transport protein GOT1B 
                 GOLT1B 
                 2 
               
               
                 O00186 
                 Syntaxin-binding protein 3 
                 STXBP3 
                 2 
               
               
                 Q5T6W2 
                 Heterogeneous nuclear ribonucleoprotein K 
                 HNRNPK 
                 2 
               
               
                 H0YEY4 
                 ADP-sugar pyrophosphatase 
                 NUDT5 
                 2 
               
               
                 P35580 
                 Myosin-10 
                 MYH10 
                 2 
               
               
                 F5H081 
                 Solute carrier family 2, facilitated glucose transporter member 4 
                 SLC2A4 
                 2 
               
               
                 Q9H1C7 
                 Cysteine-rich and transmembrane domain-containing protein 1 
                 CYSTM1 
                 2 
               
               
                 K7EJ83 
                 Cyclin-dependent kinase 2; Cyclin-dependent kinase 3 
                 CDK3; 
                 2 
               
               
                   
                   
                 CDK2 
                   
               
               
                 C9J352 
                 Importin subunit alpha-5; 
                 KPNA1 
                 2 
               
               
                   
                 Importin subunit alpha-5, N-terminally processed 
                   
                   
               
               
                 H9KV75 
                 Alpha-actinin-1; Alpha-actinin-4; 
                 ACTN1; 
                 2 
               
               
                   
                 Alpha-actinin-2; Alpha-actinin-3 
                 ACTN4; 
                   
               
               
                   
                   
                 ACTN3; 
                   
               
               
                   
                   
                 ACTN2 
                   
               
               
                 A0A0A0MQS1 
                 Pyrroline-5-carboxylate reductase;  
                 PYCRL 
                 2 
               
               
                   
                 Pyrroline-5-carboxylate reductase 3 
                   
                   
               
               
                 D6RBY0 
                 Rieske domain-containing protein 
                 RFESD 
                 2 
               
               
                 C9JC71 
                 Low affinity immunoglobulin gamma Fc region receptor III-A 
                 FCGR3A 
                 2 
               
               
                 P51811 
                 Membrane transport protein XK 
                 XK 
                 2 
               
               
                 C9J1G2 
                 DnaJ homolog subfamily B member 2 
                 DNAJB2 
                 2 
               
               
                 Q9UN37 
                 Vacuolar protein sorting-associated protein 4A; 
                 VPS4A; 
                 2 
               
               
                   
                 Vacuolar protein sorting-associated protein 
                 VPS4B; 
                   
               
               
                   
                 4B; Fidgetin-like protein 1 
                 FIGNL1 
                   
               
               
                 P61160 
                 Actin-related protein 2 
                 ACTR2 
                 2 
               
               
                 P16930 
                 Fumarylacetoacetase 
                 FAH 
                 2 
               
               
                 A0A087X0K4 
                 CUB and sushi domain-containing protein 2 
                 CSMD2 
                 2 
               
               
                 P10746 
                 Uroporphyrinogen-III synthase 
                 UROS 
                 2 
               
               
                 K7EQ02 
                 DAZ-associated protein 1 
                 DAZAP1 
                 2 
               
               
                 F5GYN4 
                 Ubiquitin thioesterase OTUB1 
                 OTUB1 
                 2 
               
               
                 P10599 
                 Thioredoxin 
                 TXN 
                 2 
               
               
                 O95197 
                 Reticulon-3 
                 RTN3 
                 2 
               
               
                 E7ETB3 
                 Aspartyl aminopeptidase 
                 DNPEP 
                 2 
               
               
                 P14868 
                 Aspartate--tRNA ligase, cytoplasmic 
                 DARS 
                 2 
               
               
                 Q08AM6 
                 Protein VAC14 homolog 
                 VAC14  
                 2 
               
               
                 Q93034 
                 Cullin-5 
                 CUL5 
                 2 
               
               
                 Q9BQA1 
                 Methylosome protein 50 
                 WDR77 
                 2 
               
               
                 A0A0B4J2G9 
                 Ubiquitin-conjugating enzyme E2 L3 
                 UBE2L3 
                 2 
               
               
                 Q04446 
                 1,4-alpha-glucan-branching enzyme 
                 GBE1 
                 2 
               
               
                 Q96NA2 
                 Rab-interacting lysosomal protein 
                 RILP 
                 2 
               
               
                 Q92539 
                 Phosphatidate phosphatase LPIN2 
                 LPIN2 
                 2 
               
               
                 P28482 
                 Mitogen-activated protein kinase 1 
                 MAPK1 
                 2 
               
               
                 Q7Z406 
                 Myosin-14; Myosin-11 
                 MYH14; 
                 2 
               
               
                   
                   
                 MYH11 
                   
               
               
                 Q8IU68 
                 Transmembrane channel-like protein 8 
                 TMC8 
                 2 
               
               
                 
                   Q96BJ3 
                 
                 
                   Axin interactor, dorsalization-associated protein 
                 
                 
                   AIDA 
                 
                 
                   2 
                 
               
               
                 P20042 
                 Eukaryotic translation initiation factor 2 subunit 2 
                 EIF252 
                 2 
               
               
                 A0A0A0MQR0 
                 Docosahexaenoic acid omega-hydroxylase CYP4F3; 
                 CYP4F2; 
                   
               
               
                   
                 Phylloquinone omega-hydroxylase CYP4F2; 
                 CYP4F3; 
                   
               
               
                   
                 Cytochrome P450 4F12; 
                 CYP4F11; 
                   
               
               
                   
                 Phylloquinone omega-hydroxylase CYP4F11  
                 CYP4F12 
                   
               
               
                 Q9B526 
                 Endoplasmic reticulum resident protein 44 
                 ERP44 
                 2 
               
               
                 O00178 
                 GTP-binding protein 1 
                 GTPBP1 
                 2 
               
               
                 P27797 
                 Calreticulin 
                 CALR 
                 2 
               
               
                 G3V0E5 
                 Transferrin receptor protein 1; 
                 TFRC 
                 2 
               
               
                   
                 Transferrin receptor protein 1, serum form 
                   
                   
               
               
                 P48147 
                 Prolyl endopeptidase 
                 PREP 
                 2 
               
               
                 H7BZC1 
                 Hippocalcin-like protein 1; Neuron-specific calcium-binding  
                 HPCAL1; 
                 2 
               
               
                   
                 protein hippocalcin; Neurocalcin-delta 
                 NCALD; 
                   
               
               
                   
                   
                 HPCA 
                   
               
               
                 F8VPD4 
                 CAD protein; Glutamine-dependent carbamoyl-phosphate synthase; 
                 CAD 
                 2 
               
               
                   
                 Aspartate carbamoyltransferase; Dihydroorotase 
                   
                   
               
               
                 Q9NTJ5 
                 Phosphatidylinositide phosphatase SAC1 
                 SACM1L 
                 2 
               
               
                 P26447 
                 Protein S100-A4 
                 S100A4  
                 2 
               
               
                 Q9UIW2 
                 Plexin-A1 
                 PLXNA1 
                 2 
               
               
                 H0YJS0 
                 V-type proton ATPase subunit D 
                 ATP6V1D 
                 2 
               
               
                 P25445 
                 Tumor necrosis factor receptor superfamily member 6 
                 FAS 
                 2 
               
               
                 C9JEU5 
                 Fibrinogen gamma chain 
                 FGG 
                 2 
               
               
                 F5H562 
                 Copper-transporting ATPase 2; WND/140 kDa 
                 ATP7B  
                 2 
               
               
                 B5MCF3 
                 Protein GUCD1 
                 GUCD1 
                 2 
               
               
                 Q96TA1 
                 Niban-like protein 1 
                 FAM129B 
                 2 
               
               
                 F5GWT4 
                 Serine/threonine-protein kinase WNK1 
                 WNK1 
                 2 
               
               
                 E9PLT1 
                 Platelet glycoprotein 4 
                 CD36 
                 2 
               
               
                 Q8TDB8 
                 Solute carrier family 2, facilitated glucose transporter member 14; 
                 SLC2A14; 
                 2 
               
               
                   
                 Solute carrier family 2, 
                 SLC2A3 
                   
               
               
                   
                 facilitated glucose transporter member 3  
                   
                   
               
               
                 B4DDD6 
                 Drebrin-like protein 
                 DBNL 
                 2 
               
               
                 E9P1I3 
                 Band 4.1-like protein 2 
                 EPB41L2  
                 2 
               
               
                 E9PNF5 
                 Glutamine-dependent NAD(+) synthetase 
                 NADSYN1 
                 2 
               
               
                 K7ELL7 
                 Glucosidase 2 subunit beta 
                 PRKCSH 
                 2 
               
               
                 Q9BV20 
                 Methylthioribose-1-phosphate isomerase 
                 MRI1 
                 2 
               
               
                 J3KNB4 
                 Cathelicidin antimicrobial peptide; Antibacterial  
                   
                   
               
               
                   
                 protein FALL-39; Antibacterial protein LL-37 
                 CAMP 
                 2 
               
               
                 Q5T1Z0 
                 Phospholysine phosphohistidine inorganic pyrophosphate phosphatase 
                 LHPP 
                 2 
               
               
                 H3BLV0 
                 Complement decay-accelerating factor 
                 CD55 
                 2 
               
               
                 Q9Y3E7 
                 Charged multivesicular body protein 3 
                 CHMP3  
                 2 
               
               
                 Q5T6H7 
                 Xaa-Pro aminopeptidase 1 
                 XPNPEP1 
                 2 
               
               
                 O94779 
                 Contactin-5 
                 CNTN5 
                 2 
               
               
                 E9PNR2 
                 Ras and Rab interactor 1 
                 RIN1 
                 2 
               
               
                 E7ESJ7 
                 Protein FAM114A2 
                 FAM114A2  
                 2 
               
               
                 A0A0A0MS99 
                 Multidrug resistance-associated protein 1 
                 ABCC1 
                 2 
               
               
                 A0A0G2JM15 
                 Large neutral amino acids transporter small subunit 4 
                 SLC43A2 
                 2 
               
               
                 H0YBF7 
                 Art-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1; 
                 ASAP1; 
                 2 
               
               
                   
                 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2 
                 ASAP2 
                   
               
               
                 P29992 
                 Guanine nucleotide-binding protein subunit alpha-11 
                 GNA11 
                 2 
               
               
                 F8WF69 
                 Clathrin light chain A 
                 CLTA 
                 2 
               
               
                 B5MCN0 
                 Atlastin-2 
                 ATL2 
                 2 
               
               
                 F8W9F9 
                 Serine/threonine-protein kinase WNK2; Serine/threonine-protein kinase WNK3 
                 WNK2; 
                 2 
               
               
                   
                   
                 WNK3 
                   
               
               
                 A2A3F3 
                 Transient receptor potential cation channel subfamily M member 3 
                 TRPM3 
                 2 
               
               
                 Q5KU26 
                 Collectin-12 
                 COLEC12 
                 2 
               
               
                 O14523 
                 C2 domain-containing protein 2-like 
                 C2CD2L 
                 2 
               
               
                 Q96DG6 
                 Carboxymethylenebutenolidase homolog 
                 CMBL 
                 2 
               
               
                 Q5THJ4 
                 Vacuolar protein sorting-associated protein 13D 
                 VPS13D 
                 2 
               
               
                 Q02790 
                 Peptidyl-prolyl cis-trans isomerase FKBP4;  
                 FKBP4 
                 2 
               
               
                   
                 Peptidyl-prolyl cis-trans isomerase FKBP4,  
                   
                   
               
               
                   
                 N-terminally processed 
                   
                   
               
               
                 A0A0G2JQD2 
                 Glutathione S-transferase theta-1 
                 GSTT1 
                 2 
               
               
                 Q9NV96 
                 Cell cycle control protein 50A; Cell cycle control protein 50B 
                 TMEM30A; 
                 2 
               
               
                   
                   
                 TMEM30B 
                   
               
               
                 P62330 
                 ADP-ribosylation factor 6 
                 ARF6 
                 2 
               
               
                 Q9UPU5 
                 Ubiquitin carboxyl-terminal hydrolase 24 
                 USP24 
                 2 
               
               
                 B2R459 
                 Histone H2B 
                 HIST1H2BI 
                 2 
               
               
                 P10599 
                 Thioredoxin 
                 TXN 
                 2 
               
               
                 R4GN98 
                 Protein S100; Protein S100-A6 
                 S100A6 
                 2 
               
               
                 H3B566 
                 Small integral membrane protein 1 
                 SMIM1 
                 2 
               
               
                 Q8NHG7 
                 Small VCP/p97-interacting protein 
                 SVIP 
                 2 
               
               
                 C9JIG9 
                 Serine/threonine-protein kinase OSR1; 
                 OXSR1; 
                 2 
               
               
                   
                 STE20/SPS1-related proline-alanine-rich protein kinase 
                 STK39 
                   
               
               
                 Q5VZR0 
                 Golgi-associated plant pathogenesis-related protein 1 
                 GLIPR2 
                 2 
               
               
                 F8WD49 
                 Anion exchange protein 3; Anion exchange protein; 
                 SLC4A3; 
                 2 
               
               
                   
                 Anion exchange protein 2 
                 SLC4A2 
                   
               
               
                 P61626 
                 Lysozyme C; Lysozyme 
                 LYZ  
                 2 
               
               
                 Q5T123 
                 SH3 domain-binding glutamic acid-rich-like protein 3 
                 SH3BGRL3 
                 2 
               
               
                 F5H571 
                 Ubiquitin carboxyl-terminal hydrolase 5 
                 USP5 
                 2 
               
               
                 Q9H3K6 
                 BoLA-like protein 2 
                 BOLA2; 
                 2 
               
               
                   
                   
                 BOLA2B 
                   
               
               
                 P05164 
                 Myeloperoxidase; Myeloperoxidase; 89 kDa myeloperoxidase;  
                 MPO 
                 2 
               
               
                   
                 84 kD amyeloperoxidase; Myeloperoxidase light chain; 
                   
                   
               
               
                   
                 Myeloperoxidase heavy chain 
                   
                   
               
               
                 P50395 
                 Rab GDP dissociation inhibitor beta 
                 GDI2 
                 2 
               
               
                 G3V2U7 
                 Acylphosphatase; Acylphosphatase-1 
                 ACYP1 
                 2 
               
               
                 J3KNB4 
                 Cathelicidin antimicrobial peptide;  
                 CAMP 
                 2 
               
               
                   
                 Antibacterial protein FALL-39;  
                   
                   
               
               
                   
                 Antibacterial protein LL-37 
                   
                   
               
               
                 H0Y9X3 
                 Programmed cell death protein 6 
                 PDCD6 
                 2 
               
               
                 A6NJA2 
                 Ubiquitin carboxyl-terminal hydrolase; 
                 USP14 
                 2 
               
               
                   
                 Ubiquitin carboxyl-terminal hydrolase 14 
                   
                   
               
               
                 P35998 
                 26S protease regulatory subunit 7 
                 PSMC2 
                 2 
               
               
                 P30041 
                 Peroxiredoxin-6 
                 PRDX6 
                 2 
               
               
                 P35612 
                 Beta-adducin 
                 ADD2 
                 2 
               
               
                 P00918 
                 Carbonic anhydrase 2 
                 CA2 
                 2 
               
               
                 A0A0C4DGH5 
                 Cullin-associated NEDD8-dissociated protein 1  
                 CANDI 
                 2 
               
               
                 C9JZN1 
                 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit 
                 GNB2; 
                 1 
               
               
                   
                 beta-2; Guanine nucleotide-binding protein subunit beta-4 
                 GNB4 
                   
               
               
                 I3L4X8 
                 Integrin beta; Integrin beta-3 
                 ITGB3 
                 1 
               
               
                 H7BZJ3 
                   
                 PDIA3 
                 1 
               
               
                 P17066 
                 Heat shock 70 kDa protein 6; Putative heat shock 70 kDa protein 7 
                 HSPA6; 
                   
               
               
                   
                   
                 HSPA7 
                 1 
               
               
                 J3KT70 
                 Arf-GAP with dual PH domain-containing protein 2 
                 ADAP2; 
                 1 
               
               
                   
                   
                 CENTA2 
                   
               
               
                 Q9Y6M5 
                 Zinc transporter 1 
                 SLC30A1 
                 1 
               
               
                 P54725 
                 UV excision repair protein RAD23 homolog A 
                 RAD23A  
                 1 
               
               
                 F8WD59 
                 40S ribosomal protein SA 
                 RPSA; 
                 1 
               
               
                   
                   
                 RPSAP58  
                   
               
               
                 P06753 
                   
                   
                 1 
               
               
                 E9PMI6 
                 Methylosome subunit pICIn 
                 CLNS1A 
                 1 
               
               
                 Q9BVK6 
                 Transmembrane emp24 domain-containing protein 9  
                 TMED9 
                 1 
               
               
                 C9JJV6 
                 Myeloid-associated differentiation marker 
                 MYADM 
                 1 
               
               
                 Q8IXQ3 
                 Uncharacterized protein C9orf40 
                 C9orf40 
                 1 
               
               
                 Q8NDC0 
                 MAPK-interacting and spindle-stabilizing protein-like 
                 MAPK1IP1L 
                 1 
               
               
                 Q99747 
                 Gamma-soluble NSF attachment protein 
                 NAPG 
                 1 
               
               
                 E7EWE1 
                 Ubiquitin-like modifier-activating enzyme 5 
                 UBA5 
                 1 
               
               
                 J3KNE3 
                 Platelet-activating factor acetylhydrolase IB subunit beta 
                 PAFAH1B2  
                 1 
               
               
                 Q8IUI8 
                 Cytokine receptor-like factor 3 
                 CRLF3 
                 1 
               
               
                 Q9BTX7 
                 Alpha-tocopherol transfer protein-like 
                 TTPAL 
                 1 
               
               
                 P63261 
                 Actin, cytoplasmic 2; Actin, cytoplasmic 2, N-terminally processed 
                 ACTG1 
                 1 
               
               
                 P31153 
                 S-adenosylmethionine synthase isoform type-2 
                 MAT2A 
                 1 
               
               
                 O00560 
                 Syntenin-1 
                 SDCBP 
                 1 
               
               
                 Q4VB86 
                 Protein 4.1 
                 EPB41 
                 1 
               
               
                 Q8WUD1 
                 Ras-related protein Rab-2B 
                 RAB2B; 
                 1 
               
               
                   
                   
                 DKFZ 
                   
               
               
                   
                   
                 p313C1541 
                   
               
               
                 Q9NVVV4 
                 UPF0587 protein C1orf123 
                 C1orf123  
                 1 
               
               
                 Q9Y2Z0 
                 Suppressor of G2 allele of SKP1 homolog 
                 SUGT1 
                 1 
               
               
                 H0YK48 
                 Tropomyosin alpha-1 chain 
                 TPM1 
                 1 
               
               
                 H3BS66 
                 Small integral membrane protein 1 
                 SMIM1 
                 1 
               
               
                 Q5VTS0 
                 Neurensin-1 
                 NRSN1 
                 1 
               
               
                 H0Y904 
                 Multidrug resistance-associated protein 7 
                 ABCC10 
                 1 
               
               
                 P08F94 
                 Fibrocystin 
                 PKHD1 
                 1 
               
               
                 G3V5X4 
                 Nesprin-2 
                 SYNE2 
                 1 
               
               
                 P48507 
                 Glutamate--cysteine ligase regulatory subunit 
                 GCLM 
                 1 
               
               
                 H3BUF4 
                 Cyclin-D1-binding protein 1 
                 CCNDBP1 
                 1 
               
               
                 F8WB30 
                 Target of Myb protein 1 
                 TOM1 
                 1 
               
               
                 E5RJI8 
                   
                 CA1 
                 1 
               
               
                 S4R3E5 
                 Importin subunit alpha-7 
                 KPNA6 
                 1 
               
               
                 E7EVS6 
                   
                 ACTB 
                 1 
               
               
                 P04206 
                 Ig kappa chain V-III region GOL;  
                 1 
                   
               
               
                   
                 Ig kappa chain V-III region WOL; 
                   
                   
               
               
                   
                 Ig kappa chain V-III region Ti; 
                   
                   
               
               
                   
                 Ig kappa chain V-III region SIE 
                   
                   
               
               
                 Q5SSV3 
                 N(G),N(G)-dimethylarginine dimethylaminohydrolase 2 
                 DDAH2 
                 1 
               
               
                 H0YG54 
                 Oligoribonuclease, mitochondrial 
                 REXO2 
                 1 
               
               
                 P08246 
                 Neutrophil elastase 
                 ELANE 
                 1 
               
               
                 P40926 
                 Malate dehydrogenase, mitochondrial 
                 MDH2 
                 1 
               
               
                 P98172 
                 Ephrin-B1 
                 EFNB1 
                 1 
               
               
                 Q96DD7 
                 Protein shisa-4 
                 SHISA4 
                 1 
               
               
                 Q71RC9 
                 Small integral membrane protein 5 
                 SMIM5 
                 1 
               
               
                 P68133 
                 Actin, alpha skeletal muscle; 
                 ACTA1; 
                 1 
               
               
                   
                 Actin, alpha cardiac muscle 1; 
                 ACTC1; 
                   
               
               
                   
                 Actin, gamma-enteric smooth muscle; 
                 ACTG2; 
                   
               
               
                   
                 Actin, aortic smooth muscle  
                 ACTA2 
                   
               
               
                 H0Y9Q6 
                 Clathrin light chain B 
                 CLTB 
                 1 
               
               
                 G3V5P0 
                   
                 KTN1 
                 1 
               
               
                 Q9NVVX6 
                 Probablet RNA(His) guanylyltransferase 
                 THG1L  
                 1 
               
               
                 Q15404 
                 Ras suppressor protein 1 
                 RSU1 
                 1 
               
               
                 B2R459 
                 Histone H2B 
                 HIST1H2B 
                 1 
               
               
                 K7EK06 
                 Phenylalanine--tRNA ligase alpha subunit 
                 FARSA 
                 1 
               
               
                 H7C3S9 
                 COP9 signalosome complex subunit 
                 COPS8 
                 8  
               
               
                 J3KRV4 
                 Dual specificity mitogen-activated protein kinase kinase 3 
                 MAP2K3 
                 1 
               
               
                 Q15042 
                 Rab3 GTPase-activating protein catalytic subunit 
                 RAB3GAP1  
                 1 
               
               
                 P01893 
                 Putative HLA class 1 histocompatibility antigen, alpha chain H; 
                 HLA-H; 
                 1 
               
               
                   
                 HLA class I histocompatibility antigen, Cw-6 alpha chain; 
                 HLA-C; 
                   
               
               
                   
                 HLA class I histocompatibility antigen, B-38 alpha chain; 
                 HLA-B 
                   
               
               
                   
                 HLA class I histocompatibility antigen, B-67 alpha chain; 
                   
                   
               
               
                   
                 HLA class I histocompatibility antigen, B-82 alpha chain; 
                   
                   
               
               
                   
                 HLA class I histocompatibility antigen, B-39 alpha chain; 
                   
                   
               
               
                   
                 HLA class I histocompatibility antigen, Cw-18 alpha chain; 
                   
                   
               
               
                   
                 HLA class I histocompatibility antigen, Cw-7 alpha chain; 
                   
                   
               
               
                   
                 HLA class I histocompatibility antigen, B-42 alpha chain; 
                   
                   
               
               
                   
                 HLA class I histocompatibility antigen, B-14 alpha chain; 
                   
                   
               
               
                   
                 HLA class I histocompatibility antigen, B-8 alpha chain; 
                   
                   
               
               
                   
                 HLA class I histocompatibility antigen, B-7 alpha chain 
                   
                   
               
               
                 Q9UNW1 
                 Multiple inositol polyphosphate phosphatase 1 
                 MINPP1 
                 1 
               
               
                 Q6B0K9 
                 Hemoglobin subunit mu 
                 HBM  
                 1 
               
               
                 O75915 
                 PRA1 family protein 3 
                 ARL6IP5 
                 1 
               
               
                 O95376 
                 E3 ubiquitin-protein ligase ARIH2 
                 ARIH2  
                 1 
               
               
                 E9PBW4 
                 Hemoglobin subunit gamma-2 
                 HBG2 
                 1 
               
               
                 C9J1X0 
                 WD repeat-containing protein 91 
                 WDR91  
                 1 
               
               
                 Q8NCV1 
                   
                   
                 1 
               
               
                 Q9Y4P8 
                 WD repeat domain phosphoinositide-interacting protein 2 
                 WIPI2  
                 1 
               
               
                 A0A087WUX6 
                 Proteasomal ubiquitin receptor ADRM1 
                 ADRM1 
                 1 
               
               
                 Q9NQS7 
                 Inner centromere protein 
                 INCENP 
                 1 
               
               
                 P62805 
                 Histone H4 
                 HIST1H4A 
                 1 
               
               
                 Q8TDY2 
                 RB1-inducible coiled-coil protein 1 
                 RB1CC1 
                 1 
               
               
                 C9JFM5 
                 Syntaxin-4 
                 STX4 
                 1 
               
               
                 B0QZ43 
                 Erlin-2; Erlin-1 
                 ERLIN1; 
                 1 
               
               
                   
                   
                 ERLIN2 
                   
               
               
                 C9J8T0 
                 Selenocysteine-specific elongation factor 
                 EEFSEC 
                 1 
               
               
                 P61224 
                 Ras-related protein Rap-1b; Ras-related protein Rap-1b-like protein 
                 RAP1B 
                 1 
               
               
                 Q99828 
                 Calcium and integrin-binding protein 1 
                 CIB1 
                 1 
               
               
                 Q53GQ0 
                 Very-long-chain 3-oxoacyl-CoA reductase 
                 HSD17612 
                 1 
               
               
                 H0Y9Q9 
                 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 2 
                 BST1 
                 1 
               
               
                 R4GN98 
                 Protein S100; Protein S100-A6 
                 S100A6 
                 1 
               
               
                 Q8TB73 
                 Protein NDNF 
                 NDNF 
                 1 
               
               
                 Q6P1A2 
                 Lysophospholipid acyltransferase 5 
                 LPCAT3 
                 1 
               
               
                 F2Z2Y4 
                 Pyridoxal kinase 
                 PDXK 
                 1 
               
               
                 Q9HA65 
                 TBC1 domain family member 17 
                 TBC1D17 
                 1 
               
               
                 G3V126 
                 V-type proton ATPase subunit H 
                 ATP6V1H 
                 1 
               
               
                 D6RGE2 
                 Isochorismatase domain-containing protein 1 
                 ISOC1 
                 1 
               
               
                 A0A0B4J222 
                 ADP-ribosylation factor-like protein 15 
                 ARL15 
                 1 
               
               
                 F8W7W4 
                 Androglobin 
                 ADGB 
                 1 
               
               
                 Q9GZR7 
                   
                   
                 1 
               
               
                 A0A087WVC4 
                 cAMP-dependent protein kinase catalytic subunit beta 
                 PRKACB 
                 1 
               
               
                 A8MU39 
                 Serine/threonine-protein phosphatase; 
                 PPP5C 
                 1 
               
               
                   
                 Serine/threonine-protein phosphatase 5 
                   
                   
               
               
                 G3V1N2 
                   
                 HBA2 
                 1 
               
               
                 P69892 
                 Hemoglobin subunit gamma-2 
                 HBG2 
                 1 
               
               
                 F8WEZ0 
                 1-phosphatidylinositol 3-phosphate 5-kinase 
                 PIKFYVE 
                 1 
               
               
                 A0A087WZZ4 
                 Ammonium transporter Rh type A 
                 RHAG 
                 1 
               
               
                 Q1JUQ3 
                 Peptidyl-prolyl cis-trans isomerase; 
                 FKBP12- 
                 1 
               
               
                   
                 Peptidyl-prolyl cis-trans isomerase FKBP1A 
                 Exin; 
                   
               
               
                   
                   
                 FKBP1A 
                   
               
               
                 F8VWZ5 
                 H2.0-like homeobox protein 
                 HLX 
                 1 
               
               
                 P62877 
                 E3 ubiquitin-protein ligase RBX1; 
                 RBX1 
                 1 
               
               
                   
                 E3 ubiquitin-protein ligase RBX1, N-terminally processed 
                   
                   
               
               
                 Q7Z5P9 
                 Mucin-19 
                 MUC19 
                 1 
               
               
                 F8VPB3 
                   
                 TPK1 
                 1 
               
               
                 F8WBF4 
                 Transmembrane protein 50B 
                 TMEM50B 
                 1 
               
               
                 C9JL85 
                 Myotrophin 
                 MTPN 
                 1 
               
               
                 Q53EQ6 
                 Tigger transposable element-derived protein 5 
                 TIGD5 
                 1 
               
               
                 E3W974 
                   
                 DNPEP 
                 1 
               
               
                 H7BYV1 
                 Interferon-induced transmembrane protein 1; 
                 IFITM2; 
                 1 
               
               
                   
                 Interferon-induced transmembrane protein 2; 
                 IFITM3; 
                   
               
               
                   
                 Interferon-induced transmembrane protein 3 
                 IFITM1 
                   
               
               
                 D6RC06 
                 Histidine triad nucleotide-binding protein 1 
                 HINT1 
                 1 
               
               
                 E9PNW4 
                 CD59 glycoprotein 
                 CD59 
                 1 
               
               
                 H7C2Z6 
                 Grancalcin 
                 GCA 
                 1 
               
               
                 Q9H1C7 
                 Cysteine-rich and transmembrane domain-containing protein 1 
                 CYSTM1 
                 1 
               
               
                 H0YK07 
                 ATP-dependentClpprotease ATP-binding subunit cIpX-like, mitochondrial 
                 CLPX 
                 1 
               
               
                 E9PG15 
                 14-3-3 protein theta 
                 YWHAQ 
                 1 
               
               
                 K7ENK9 
                 Vesicle-associated membrane protein 3; 
                 VAMP2; 
                 1 
               
               
                   
                 Vesicle-associated membrane protein 2 
                 VAMP3 
                   
               
               
                 F8WDD6 
                 Cation channel sperm-associated protein subunit gamma 
                 CATSPERG 
                 1 
               
               
                 P35754 
                 Glutaredoxin-1 
                 GLRX 
                 1 
               
               
                 Q5THJ4 
                 Vacuolar protein sorting-associated protein 13D 
                 VPS13D 
                 1 
               
               
                 B4E3H6 
                 Transforming acidic coiled-coil-containing protein 1 
                 TACC1 
                 1 
               
               
                 B0YJC4 
                 Vimentin 
                 VIM 
                 1 
               
               
                 H7C5R6 
                 AT-rich interactive domain-containing protein 4B 
                 ARID4B 
                 1 
               
               
                 P49755 
                 Transmembrane emp24 domain-containing protein 10 
                 TMED10 
                 1 
               
               
                 E9PMJ3 
                 Ribonuclease inhibitor 
                 RNH1 
                 1 
               
               
                 B1AHA9 
                 DNA replication licensing factor MCM5 
                 MCM5 
                 1 
               
               
                 P23634 
                 Plasma membrane calcium-transporting ATPase 4 
                 ATP2B4 
                 1 
               
               
                 Q14152 
                 Eukaryotic translation initiation factor 3 subunit A 
                 EIF3A 
                 1 
               
               
                 C9IY70 
                 60S ribosomal export protein NMD3 
                 NMD3 
                 1 
               
               
                 A0A087WUS7 
                 Ig delta chain C region 
                 IGHD 
                 1 
               
               
                 P07384 
                 Calpain-1 catalytic subunit 
                 CAPN1 
                 1 
               
               
                 G3V2C9 
                 Guanine nucleotide-binding protein subunit gamma; 
                 GNG2 
                 1 
               
               
                   
                 Guanine nucleotide-binding protein G(I)/G(S)/G(O)  
                   
                   
               
               
                   
                 subunit gamma-2 
                   
                   
               
               
                 Q9Y2Y8 
                 Proteoglycan 3 
                 PRG3 
                 1 
               
               
                 V9GY70 
                   
                 DNAJB12 
                 1 
               
               
                 U5GXS0 
                 MAM and LDL-receptor class A domain-containing protein 1 
                 MALRD1 
                   
               
               
                 Q92625 
                 Ankyrin repeat and SAM domain-containing protein 1A 
                 ANKS1A 
                 1 
               
               
                   
               
            
           
         
       
     
     The present description refers to a number of documents, the contents of which are herein incorporated by reference in their entirety. 
     REFERENCES 
     
         
         Cox et al.,  Nat Biotechnol  (2008); 26(12):1367-72. 
         Havlis et al.,  Anal Chem  (2003); 75(6):1300-6. 
         Lacroix et al,  Journal of Thrombosis and Haemostasis  (2012), 10:437-446. 
         Lotvall et al.,  J Extracell Vesicles  (2014), 3:26913. 
         Maere et al.,  Bioinformatics  (2005); 21(16):3448-9. 
         Martinez-Martin et al.,  Parkinsonism  &amp;  related disorders  (2015). 21(1):50-4. 
         Minetti et al.,  Biochem J  (2004); 377(Pt 2):489-97. 
         Prudent et al.,  Transfus Apher Sci . (2015). 53(2):153-8. 
         R Core Team (2016). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/. 
         Rousseau et al.,  PLoS One  (2015), 10(1):e0116812. 
         Shevchenko et al.,  Anal Chem  (1996); 68(5):850-8. 
         Suzuki et al.,  Bioinformatics  (2006); 22(12):1540-2. 
         Wither et al., Mass Spectrometry-Based Bottom-Up Proteomics: Sample Preparation, LC-MS/MS Analysis, and Database Query Strategies.  Curr Protoc Protein Sci  (2016); 86:16.4.1-16.4.20.