One-Pot Cu/SAPO-34 for Continuous Methane Selective Oxidation to Methanol.

Cu/SAPO-34 synthesized via a one-pot method with relatively low silicon content and copper loading at around 2 wt.% facilitated continuous oxidation of methane to methanol with a methanol space time yield of 504 µmolCH3OH/gcat/h. Remarkably, the methanol yield exceeded 1800 mmolCH3OH/molCu/h at 623 K. Typically, the presence of trace oxygen in the system was the key to maintaining the high selectivity to methanol. Characterization results from a series of techniques, including XRD, SEM, TEM, H2-TPR, NH3-TPD, UV-vis, and FTIR, indicated that Cu2+ existed in the position where it moves from hexagonal rings to elliptical cages as the active center.

Prediagnostic plasma proteomics profile for hepatocellular carcinoma.

OBJECTIVE: Proteomics may discover pathophysiological changes related to hepatocellular carcinoma, an aggressive and lethal type of cancer with low sensitivity for early stage diagnosis. DESIGN: We measured 1305 prediagnostic (median = 12.7 years) SomaScan proteins from 54 pairs of healthy individuals who subsequently developed hepatocellular carcinoma and matched non-hepatocellular carcinoma control individuals from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP). RESULTS: In NHS and HPFS, we identified 56 elevated proteins in hepatocellular carcinoma with an absolute fold change of more than 1.2 and a Wald test P value less than .05 in conditional logistic regression analysis. Ingenuity pathway analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins-chitinase-3-like protein 1, growth differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin-showed strong positive associations with hepatocellular carcinoma and were thus validated by enzyme-linked immunosorbent assay (odds ratio = 2.48-14.7, all P < .05) in the NHS and HPFS and by Olink platform (hazard ratio = 1.90-3.93, all P < .05) in the UKB-PPP. Adding these 4 proteins to a logistic regression model of traditional hepatocellular carcinoma risk factors increased the area under the curve from 0.67 to 0.87 in the NHS and HPFS. Consistently, model area under the curve was 0.88 for hepatocellular carcinoma risk prediction in the UKB-PPP. CONCLUSION: However, the limited number of hepatocellular carcinoma patients in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations.

Meteorological influence on persistent O3 pollution events in Wuxi in the Yangtze River Delta, China.

The number of O3 pollution days indicates an overall increasing trend over 2014-2021 in Wuxi in the Yangtze River Delta, with the pollution concentrations of MDA8-O3 between 186 and 200 µg·m-3. Specifically, a total of 62 POPEs (persistent O3 pollution events), defined as episodes with 3 or more continuous O3 pollution days, were observed for the 8 years. Using a multi-linear regression model, we find that the meteorology can explain approximately 56.5 % of the O3 variations for the 8 years in Wuxi, with temperature being the most crucial meteorological factor, followed by relative humidity (RH) and wind speeds. High temperature, low RH, low wind speeds and downward airflows significantly correlate with POPE-O3 changes. Three types of synoptic circulations are further identified during the POPEs from 2014 to 2021 by the T-mode (T-PCA) classification method. The primary circulation patterns governing the interannual changes of POPEs are characterized by the largest positive anomalies of temperature and planetary boundary layer (PBL) height; moreover, a distinct vertical mixing process is observed with uplifting airflows in the convective PBL during the afternoon and sinking airflows in the stable PBL at night, which is incredibly conducive to the downward transport of O3 after its upward delivery during daytime and substantially contributes to midnight O3 at the surface. The other two circulation types are associated with uniform descending flows in the PBL; as a result, surface O3 accumulates only near the ground and decreases significantly at night due to the titration effect. This study systematically highlights the influence of critical meteorological factors regulated by different synoptic circulations on the POPE in Wuxi, which provides a scientific basis for pollution control and prediction.

Aptamer-Based Proteomics Measuring Preoperative Cerebrospinal Fluid Protein Alterations Associated with Postoperative Delirium.

Delirium is a common postoperative complication among older patients with many adverse outcomes. Due to a lack of validated biomarkers, prediction and monitoring of delirium by biological testing is not currently feasible. Circulating proteins in cerebrospinal fluid (CSF) may reflect biological processes causing delirium. Our goal was to discover and investigate candidate protein biomarkers in preoperative CSF that were associated with the development of postoperative delirium in older surgical patients. We employed a nested case-control study design coupled with high multiplex affinity proteomics analysis to measure 1305 proteins in preoperative CSF. Twenty-four matched delirium cases and non-delirium controls were selected from the Healthier Postoperative Recovery (HiPOR) cohort, and the associations between preoperative protein levels and postoperative delirium were assessed using t-test statistics with further analysis by systems biology to elucidate delirium pathophysiology. Proteomics analysis identified 32 proteins in preoperative CSF that significantly associate with delirium (t-test p < 0.05). Due to the limited sample size, these proteins did not remain significant by multiple hypothesis testing using the Benjamini-Hochberg correction and q-value method. Three algorithms were applied to separate delirium cases from non-delirium controls. Hierarchical clustering classified 40/48 case-control samples correctly, and principal components analysis separated 43/48. The receiver operating characteristic curve yielded an area under the curve [95% confidence interval] of 0.91 [0.80-0.97]. Systems biology analysis identified several key pathways associated with risk of delirium: inflammation, immune cell migration, apoptosis, angiogenesis, synaptic depression and neuronal cell death. Proteomics analysis of preoperative CSF identified 32 proteins that might discriminate individuals who subsequently develop postoperative delirium from matched control samples. These proteins are potential candidate biomarkers for delirium and may play a role in its pathophysiology.

DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway.

Defective in cullin neddylation 1 domain containing 1 (DCUN1D1) is an E3 ligase for the neddylation, a post-translational process similar to and occurring in parallel to ubiquitin proteasome pathway. Although established as an oncogene in a variety of squamous cell carcinomas, the precise role of DCUN1D1 in prostate cancer (PCa) has not been previously explored thoroughly. Here, we investigated the role of DCUN1D1 in PCa and demonstrated that DCUN1D1 is upregulated in cell lines as well as human tissue samples. Inhibition of DCUN1D1 significantly reduced PCa cell proliferation and migration and remarkably inhibited xenograft formation in mice. Applying both genomics and proteomics approaches, we provide novel information about the DCUN1D1 mechanism of action. We identified CUL3, CUL4B, RBX1, CAND1 and RPS19 proteins as DCUN1D1 binding partners. Our analysis also revealed the dysregulation of genes associated with cellular growth and proliferation, developmental, cell death and cancer pathways and the WNT/ß-catenin pathway as potential mechanisms. Inhibition of DCUN1D1 leads to the inactivation of ß-catenin through its phosphorylation and degradation which inhibits the downstream action of ß-catenin, reducing its interaction with Lef1 in the Lef1/TCF complex that regulates Wnt target gene expression. Together our data point to an essential role of the DCUN1D1 protein in PCa which can be explored for potential targeted therapy.

Aptamer proteomics of serum exosomes from patients with Primary Raynaud's and patients with Raynaud's at risk of evolving into Systemic Sclerosis.

BACKGROUND: A major unmet need for Systemic Sclerosis (SSc) clinical management is the lack of biomarkers for the early diagnosis of patients with Raynaud's Phenomenon at high risk of evolving into SSc. OBJECTIVE: To identify proteins contained within serum exosomes employing an aptamer proteomic analysis that may serve to reveal patients with Raynaud's Phenomenon at risk of developing SSc. METHODS: Exosomes were isolated from serum samples from patients with Primary Raynaud's Phenomenon and from patients with Raynaud's Phenomenon harbouring serum antinuclear antibodies (ANA) who may be at high risk of evolving into SSc. The expression of 1,305 proteins was quantified using SOMAscan aptamer proteomics, and associations of the differentially elevated or reduced proteins with the clinical subsets of Raynaud's Phenomenon were assessed. RESULTS: Twenty one differentially elevated and one differentially reduced (absolute fold change >|1.3|) proteins were identified. Principal component analysis using these 22 most differentially expressed proteins resulted in excellent separation of the two Raynaud's Phenomenon clinical subsets. Remarkably, the most differentially elevated proteins are involved in enhanced inflammatory responses, immune cell activation and cell migration, and abnormal vascular functions. CONCLUSION: Aptamer proteomic analysis of circulating exosomes identified differentially elevated or reduced proteins between Raynaud's Phenomenon at high risk of evolving into SSc and Primary Raynaud's Phenomenon patients. Some of these proteins are involved in relevant biological pathways that may play a role in SSc pathogenesis including enhanced inflammatory responses, immune cell activation, and endothelial cell and vascular abnormalities.

Serum Protein Signatures Using Aptamer-Based Proteomics for Minimal Change Disease and Membranous Nephropathy.

Introduction: Minimal change disease (MCD) and membranous nephropathy (MN) are glomerular diseases (glomerulonephritis [GN]) that present with the nephrotic syndrome. Although circulating PLA2R antibodies have been validated as a biomarker for MN, the diagnosis of MCD and PLA2R-negative MN still relies on the results of kidney biopsy or empirical corticosteroids in children. We aimed to identify serum protein biomarker signatures associated with MCD and MN pathogenesis using aptamer-based proteomics. Methods: Quantitative SOMAscan proteomics was applied to the serum of adult patients with MCD (n = 15) and MN (n = 37) and healthy controls (n = 20). Associations between the 1305 proteins detected with SOMAscan were assessed using multiple statistical tests, expression pattern analysis, and systems biology analysis. Results: A total of 208 and 244 proteins were identified that differentiated MCD and MN, respectively, with high statistical significance from the healthy controls (Benjamin-Hochberg [BH] P < 0.0001). There were 157 proteins that discriminated MN from MCD (BH P < 0.05). In MCD, 65 proteins were differentially expressed as compared with MN and healthy controls. When compared with MCD and healthy controls, 44 discriminatory proteins were specifically linked to MN. Systems biology analysis of these signatures identified cell death and inflammation as key pathways differentiating MN from MCD and healthy controls. Dysregulation of fatty acid metabolism pathways was confirmed in both MN and MCD as compared with the healthy subjects. Conclusion: SOMAscan represents a promising proteomic platform for biomarker development in GN. Validation of a greater number of discovery biomarkers in larger patient cohorts is needed before these data can be translated for clinical care.

Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms.

Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 (7322 proteoforms of 6596 proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses' Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r ≥ 0.75 and 87% had an ICC/r ≥ 0.40 in Olink compared to 44% with an ICC/r ≥ 0.75 and 72% with an ICC/r ≥ 0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r ≥ 0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r > 0.75) for 14.7% and poor (r < 0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable.

Metformin for treatment of cytopenias in children and young adults with Fanconi anemia.

Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824.

Environmental Regulation, Corporate Economic Performance and Spatial Technology Spillover: Evidence from China's Heavily Polluting Listed Corporations.

The relationship between environmental regulation, technology spillover, and economic performance has been the subject of intense scholarly debate in environmental economics for many years. The famous Porter hypothesis states that environmental regulation promotes both the economic performance and the environmental performance of corporations. However, the existing literature has paid relatively little attention to micro-level research and spatial spillover effects. This article endeavors to fill this gap by an empirical analysis of a sample of 900 of China's heavily polluting listed corporations for the period of 2013-2016. By utilizing spatial econometric methods to measure spatial direct and indirect effects and decomposing total factor productivity change into technical change, pure efficiency change, and scale efficiency change, we find that environmental regulation promotes corporate total factor productivity but widens the disparity between profitable and unprofitable corporations. Our results also suggest that the direct and indirect effects of environmental regulation and corporate profitability on promoting total factor productivity rely heavily on the efficiency changes, while the contribution of the key component, technical change, is insignificant.

Proteome-Wide Analysis Using SOMAscan Identifies and Validates Epidermal Growth Factor as a Disease Marker of Collagenous Gastritis.

Background and Aims: Collagenous gastritis (CG) is a rare disorder characterized by increased subepithelial collagen deposition and inflammatory infiltrates. The mechanisms involved in CG pathogenesis are poorly understood, and no CG-associated biomarkers have been identified. This proteomics study identified serum biomarkers and pathogenic pathways to provide new knowledge about the pathobiology of CG, a disease reported in less than 100 patients. Methods: Nine serum samples from pediatric patients diagnosed with CG were evaluated using novel aptamer-based proteomic technology and systems biology to generate new knowledge about the complex interactions between the differentially expressed proteins and candidate upstream regulators, using the Ingenuity Pathway Analysis in patients with non-CG and patients with normal gastric biopsies or nongastritis (NG). Results: SOMAscan analysis identified 63 proteins significantly dysregulated in CG as compared to non-CG or NG patients that converged around enhanced inflammatory response and immune cell migration but reduced vascular functions. Principal component analysis using 15 of those proteins accurately separated the CG cases from the 2 comparator control groups. Using immunoassays, serum epidermal growth factor concentrations in CG patients, a protein involved in collagen production, were confirmed to be significantly lower than those in gastritis/NG patients. Conclusion: This is the first comprehensive analysis of the proteome in CG patients that reveals metabolic pathways relating inflammation and fibrosis as well as a new potential role of epidermal growth factor as a disease biomarker.

Parenteral lipid emulsions induce unique ileal fatty acid and metabolomic profiles but do not increase the risk of necrotizing enterocolitis in preterm pigs.

Necrotizing enterocolitis (NEC) is a manifestation of maladaptive intestinal responses in preterm infants centrally medicated by unattenuated inflammation. Early in the postnatal period, preterm infants develop a deficit in arachidonic and docosahexaenoic acid, both potent regulators of inflammation. We hypothesized that the fatty acid composition of parenteral lipid emulsions uniquely induces blood and intestinal fatty acid profiles which, in turn, modifies the risk of NEC development. Forty-two preterm pigs were randomized to receive one of three lipid emulsions containing 100% soybean oil (SO), 15% fish oil (MO15), or 100% fish oil (FO100) with enteral feedings over an 8-day protocol. Blood and distal ileum tissue were collected for fatty acid analysis. The distal ileum underwent histologic, proteomic, and metabolomic analyses. Eight pigs [3/14 SO (21%), 3/14 MO15 (21%), and 2/14 FO100 (14%)] developed NEC. No differences in NEC risk were evident between groups despite differences in induced fatty acid profiles in blood and ileal tissue. Metabolomic analysis of NEC versus no NEC tissue revealed differences in tryptophan metabolism and arachidonic acid-containing glycerophospholipids. Proteomic analysis demonstrated no differences by lipid group; however, 15 proteins differentiated NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling. Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC development. Metabolomic and proteomic analyses of NEC versus no NEC intestinal tissue provide mechanistic insights into the pathogenesis of NEC in preterm infants.NEW & NOTEWORTHY Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC risk in preterm pigs. Metabolomic and proteomic analyses provide mechanistic insights into NEC pathogenesis. Compared with healthy ileal tissue, metabolites in tryptophan metabolism and arachidonic acid-containing glycerophospholipids are increased in NEC tissue. Proteomic analysis differentiates NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling.

Neutrophil activation in systemic capillary leak syndrome (Clarkson disease).

Systemic capillary leak syndrome (SCLS; Clarkson disease) is a rare orphan disorder characterized by transient yet recurrent episodes of hypotension and peripheral oedema due to diffuse vascular leakage of fluids and proteins into soft tissues. Humoral mediators, cellular responses and genetic features accounting for the clinical phenotype of SCLS are virtually unknown. Here, we searched for factors altered in acute SCLS plasma relative to matched convalescent samples using multiplexed aptamer-based proteomic screening. Relative amounts of 612 proteins were changed greater than twofold and 81 proteins were changed at least threefold. Among the most enriched proteins in acute SCLS plasma were neutrophil granule components including bactericidal permeability inducing protein, myeloperoxidase and matrix metalloproteinase 8. Neutrophils isolated from blood of subjects with SCLS or healthy controls responded similarly to routine pro-inflammatory mediators. However, acute SCLS sera activated neutrophils relative to remission sera. Activated neutrophil supernatants increased permeability of endothelial cells from both controls and SCLS subjects equivalently. Our results suggest systemic neutrophil degranulation during SCLS acute flares, which may contribute to the clinical manifestations of acute vascular leak.

Enantioselective Hydrogenation of Racemic α-Arylamino Lactones to Chiral Amino Diols with Site-Specifically Modified Chiral Spiro Iridium Catalysts.

A protocol for highly enantioselective hydrogenation of racemic α-arylamino lactones with catalysis by site-specifically modified chiral spiro iridium complexes has been developed. With the optimized catalyst, racemic α-arylamino-γ-lactones and α-arylamino-δ-lactones could be hydrogenated to the corresponding chiral 2-amino diols with good to excellent enantioselectivities.

Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl.

Axl expression is deregulated in several cancer types, predicts poor overall patient survival and is linked to resistance to drug therapy. Here, we evaluated a library of natural compounds for inhibitors of Axl and identified dihydroartemisinin, the active principle of the anti-malarial drug artemisinin, as an Axl-inhibitor in prostate cancer. Dihydroartemisinin blocks Axl expression leading to apoptosis, decrease in cell proliferation, migration, and tumor development of prostate cancer cells. Dihydroartemisinin treatment synergizes with docetaxel, a standard of care in metastatic prostate cancer increasing overall survival of mice with human xenografts. Dihydroartemisinin control of miR-34a and miR-7 expression leads to inhibition of Axl expression in a process at least partially dependent on regulation of chromatin via methylation of histone H3 lysine 27 residues by Jumonji, AT-rich interaction domain containing 2 (JARID2), and the enhancer of zeste homolog 2. Our discovery of a previously unidentified miR-34a/miR-7/JARID2 pathway controlling dihydroartemisinin effects on Axl expression and inhibition of cancer cell proliferation, migration, invasion, and tumor formation provides new molecular mechanistic insights into dihydroartemisinin anticancer effect on prostate cancer with potential therapeutic implications.

Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin-5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps.

BACKGROUND: Exosomes are secreted epithelial-derived vesicles that contain a conserved protein array representative of their parent cell. Exosomes may be reproducibly and noninvasively purified from nasal mucus. The exosomal proteome can be quantified using SOMAscanTM , a highly multiplexed, aptamer-based proteomic platform. The purpose of this study was to determine whether chronic rhinosinusitis with nasal polyps (CRSwNP) has a unique predictive exosomal proteomic biosignature. METHODS: Exosomes were isolated from whole mucus sampled from control and CRSwNP patients (n = 20 per group) by differential ultracentrifugation. The SOMAscanTM platform was used to simultaneously quantify 1310 biologically relevant human proteins. Matched tissue and whole mucus proteomes were also analyzed. Differential protein expression and discriminatory power were calculated using the unweighted pair group method with arithmetic-mean and principal component analysis, respectively. Bioinformatic analysis was performed using Ingenuity Pathway, MetaCore, and GeneMANIA analyses. RESULTS: The exosomal proteome demonstrated 123 significantly (p < 0.05) differentially regulated proteins in CRSwNP relative to control. Eighty of these proteins overlapped with the matched CRSwNP tissue proteome as compared with only 4 among matched whole mucus samples. Forty-three significantly dysregulated pathway networks overlapped between the exosomal and tissue proteome in CRSwNP as compared with only 3 among matched whole mucus samples. The best-performing protein set (cystatin-SN, peroxiredoxin-5, and glycoprotein VI) achieved an area under the curve (AUC) value of up to 99%. CONCLUSION: Our data contribute a significant advance in the development of a reproducible, noninvasive, serial, and quantitative "liquid biopsy" for rhinosinusitis. The exosomal proteomic approach has revealed a unique biosignature associated with CRSwNP, which outperforms whole mucus sampling, and thus provides a method of noninvasive disease detection and proposes new potential therapeutic targets.

Increased levels of circulating MMP3 correlate with severe rejection in face transplantation.

Face transplantation is a viable treatment option for carefully selected patients with devastating injuries to the face. However, acute rejection episodes occur in more than 80% of recipients in the first postoperative year. Unfortunately, neither a correlation between histological grades of rejection and anti-rejection treatment nor systemic surrogate markers of rejection in face transplantation are established in clinical routine. Therefore, we utilized next generation aptamer-based SOMAscan proteomics platform for non-invasive rejection biomarker discovery. Longitudinal serum samples from face transplant recipients with long-term follow-up were included in this study. From the 1,310 proteins analyzed by SOMAscan, a 5-protein signature (MMP3, ACY1, IL1R2, SERPINA4, CPB2) was able to discriminate severe rejection from both no-rejection and nonsevere rejection samples. Technical validation on ELISA platform showed high correlation with the SOMAscan data for the MMP3 protein (rs = 0.99). Additionally, MMP3 levels were significantly increased during severe rejection as compared to no-rejection (p = 0.0009) and nonsevere rejection (p = 0.0173) episodes. Pathway analyses revealed significant activation of the metallopeptidase activity during severe face transplant rejection. This pilot study demonstrates the feasibility of SOMAscan to identify non-invasive candidate biomarkers of rejection in face transplantation. Further validation in a larger independent patient cohort is needed.

Stability and reproducibility of proteomic profiles measured with an aptamer-based platform.

The feasibility of SOMAscan, a multiplex, high sensitivity proteomics platform, for use in studies using archived plasma samples has not yet been assessed. We quantified 1,305 proteins from plasma samples donated by 16 Nurses' Health Study (NHS) participants, 40 NHSII participants, and 12 local volunteers. We assessed assay reproducibility using coefficients of variation (CV) from duplicate samples and intra-class correlation coefficients (ICC) and Spearman correlation coefficients (r) of samples processed (i.e., centrifuged and aliquoted into separate components) immediately, 24, and 48 hours after collection, as well as those of samples collected from the same individuals 1 year apart. CVs were <20% for 99% of proteins overall and <10% for 92% of proteins in heparin samples compared to 66% for EDTA samples. We observed ICC or Spearman r (comparing immediate vs. 24-hour delayed processing) ≥0.75 for 61% of proteins, with some variation by anticoagulant (56% for heparin and 70% for EDTA) and protein class (ranging from 49% among kinases to 83% among hormones). Within-person stability over 1 year was good (ICC or Spearman r ≥ 0.4) for 91% of proteins. These results demonstrate the feasibility of SOMAscan for analyses of archived plasma samples.

Tie2 protects the vasculature against thrombus formation in systemic inflammation.

Disordered coagulation contributes to death in sepsis and lacks effective treatments. Existing markers of disseminated intravascular coagulation (DIC) reflect its sequelae rather than its causes, delaying diagnosis and treatment. Here we show that disruption of the endothelial Tie2 axis is a sentinel event in septic DIC. Proteomics in septic DIC patients revealed a network involving inflammation and coagulation with the Tie2 antagonist, angiopoietin-2 (Angpt-2), occupying a central node. Angpt-2 was strongly associated with traditional DIC markers including platelet counts, yet more accurately predicted mortality in 2 large independent cohorts (combined N = 1,077). In endotoxemic mice, reduced Tie2 signaling preceded signs of overt DIC. During this early phase, intravital imaging of microvascular injury revealed excessive fibrin accumulation, a pattern remarkably mimicked by Tie2 deficiency even without inflammation. Conversely, Tie2 activation normalized prothrombotic responses by inhibiting endothelial tissue factor and phosphatidylserine exposure. Critically, Tie2 activation had no adverse effects on bleeding. These results mechanistically implicate Tie2 signaling as a central regulator of microvascular thrombus formation in septic DIC and indicate that circulating markers of the Tie2 axis could facilitate earlier diagnosis. Finally, interventions targeting Tie2 may normalize coagulation in inflammatory states while averting the bleeding risks of current DIC therapies.