Machine learning assistive rapid, label-free molecular phenotyping of blood with two-dimensional NMR correlational spectroscopy

Peng, Weng Kung; Ng, Tian-Tsong; Loh, Tze Ping

doi:10.1038/s42003-020-01262-z

Cited by 28 publications

(25 citation statements)

References 53 publications

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“…Next, we used a 2D-NMR sparse sampling method (2D-NMR with fast acquisition) which provides similar results within a shorter time frame than conventional T 1 /T 2 correlations experiments. A recent study reported that water peaks (A-ratio) in the T 1 /T 2 correlation spectra can be used to predict the degree of water-protein interactions in the fibrinogen-plasma system 17 . Compared to plasma fibrinogen control (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Increased water-protein interactions drastically reduce the motion of the water proton, leading to reduced relaxation times for T 1 and T 2 . It appears that T 2 relaxation is more effective than T 1 relaxation 17 . Fibers are formed when fibrinogen monomers aggregate into protofibrils, resulting in structural heterogeneity within the fibrin gel 38 , 41 .…”

Section: Discussionmentioning

confidence: 98%

“…Molecular fingerprints of complex biological fluids such as blood have been encoded using two-dimensional (2D) T 1 /T 2 correlations. NMR relaxometry has been used to investigate oxygenated (oxy-Hb), deoxygenated (deoxy-Hb), and oxidized (oxidized Hb) hemoglobin (Hb) derivatives with respect to their altered T 1 /T 2 relaxation states 17 . Spin–spin (T 2 ) relaxation times have also been used to probe fibrin clot structure via paramagnetic properties of hemoglobin in erythrocytes entrapped within whole blood clots 18 – 20 .…”

Section: Introductionmentioning

confidence: 99%

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Tracking oxidation-induced alterations in fibrin clot formation by NMR-based methods

Lau

White

Yeo

et al. 2021

Sci Rep

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Plasma fibrinogen is an important coagulation factor and susceptible to post-translational modification by oxidants. We have reported impairment of fibrin polymerization after exposure to hypochlorous acid (HOCl) and increased methionine oxidation of fibrinogen in severely injured trauma patients. Molecular dynamics suggests that methionine oxidation poses a mechanistic link between oxidative stress and coagulation through protofibril lateral aggregation by disruption of AαC domain structures. However, experimental evidence explaining how HOCl oxidation impairs fibrinogen structure and function has not been demonstrated. We utilized polymerization studies and two dimensional-nuclear magnetic resonance spectrometry (2D-NMR) to investigate the hypothesis that HOCl oxidation alters fibrinogen conformation and T2 relaxation time of water protons in the fibrin gels. We have demonstrated that both HOCl oxidation of purified fibrinogen and addition of HOCl-oxidized fibrinogen to plasma fibrinogen solution disrupted lateral aggregation of protofibrils similarly to competitive inhibition of fibrin polymerization using a recombinant AαC fragment (AαC 419–502). DOSY NMR measurement of fibrinogen protons demonstrated that the diffusion coefficient of fibrinogen increased by 17.4%, suggesting the oxidized fibrinogen was more compact and fast motion in the prefibrillar state. 2D-NMR analysis reflected that water protons existed as bulk water (T2) and intermediate water (T2i) in the control plasma fibrin. Bulk water T2 relaxation time was increased twofold and correlated positively with the level of HOCl oxidation. However, T2 relaxation of the oxidized plasma fibrin gels was dominated by intermediate water. Oxidation induced thinner fibers, in which less water is released into the bulk and water fraction in the hydration shell was increased. We have confirmed that T2 relaxation is affected by the self-assembly of fibers and stiffness of the plasma fibrin gel. We propose that water protons can serve as an NMR signature to probe oxidative rearrangement of the fibrin clot.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Tracking oxidation-induced alterations in fibrin clot formation by NMR-based methods

Lau

White

Yeo

et al. 2021

Sci Rep

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“…To further de ne water-protein interactions, including the hydration of bers via water-water proton interaction, we next de ned T 1 /T 2 ratio as A-ratio to predict the degree of water-protein and/or water-water interactions as previously described 17 . Control plasma solutions demonstrated an A-ratio = 57.2 (Fig.…”

Section: Oxidation Alters T 2 Relaxation Of Water Protons In Brinogenmentioning

confidence: 99%

“…Molecular ngerprints of complex biological uids such as blood have been encoded using two-dimensional (2D) T 1 /T 2 correlations. NMR relaxometry has been used to investigate oxygenated (oxy-Hb), deoxygenated (deoxy-Hb) and oxidized (oxidized Hb) hemoglobin (Hb) derivatives with respect to their altered T 1 /T 2 relaxation states 17 . Spin-spin (T 2 ) relaxation times have also been used to probe brin clot structure via paramagnetic properties of hemoglobin in erythrocytes entrapped within whole blood clots [18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Tracking oxidation-induced alterations in fibrin clot formation by NMR-based methods

Lau

White

Yeo

et al. 2021

Preprint

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Plasma fibrinogen is an important coagulation factor that is susceptible to post-translational modification by oxidants. We have reported altered fibrin polymerization and increased methionine oxidation in fibrinogen after exposure to hypochlorous acid (HOCl), and similarly in the fibrinogen of severely injured trauma patients. Molecular dynamics suggests that methionine oxidation offers a mechanistic link between oxidative stress and coagulation through fibrin protofibril lateral aggregation by disruption of AαC domain structures. However, experimental evidence explaining how HOCl oxidation impairs fibrinogen structure and function has not been demonstrated. We used polymerization studies and two dimensional-nuclear magnetic resonance spectrometry (2D-NMR) to test the hypothesis that HOCl oxidation alters fibrinogen conformation in the prefibrillar state and T2 water surface relaxation of fibrin fiber assemblies. We found that both HOCl oxidation of purified fibrinogen and addition of HOCl-oxidized fibrinogen to plasma disrupted fibrin polymerization similarly to competitive inhibition of polymerization using a recombinant AαC fragment (AαC 419–502). DOSY NMR measurement of 1H fibrinogen at 25oC demonstrated that fibrinogen oxidation increased translational diffusion coefficient by 17.4%, suggesting a more compact and rapidly translational motion of the protein with oxidation. 2D-NMR analysis of control plasma fibrin gels indicated that water existed in two states, namely intermediate (T2i) in the hydration shell of fibrin fibers, and bulk (T2) within the gel. T2 relaxation of bulk water protons was decreased 2-fold in oxidized fibrin gels and was inversely proportional to gel fiber density (T2). The fast exchange of water protons between hydration shell (T2i) and bulk water, indicating oxidation increased fiber hydration and formed densely packed fibrin gels. We have confirmed experimentally that HOCl oxidation affected native fibrinogen and fibrin gel structures and have demonstrated that NMR can serve as a valuable tool to probe the oxidative rearrangement of fibrin clot structure.

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Clustering Nuclear Magnetic Resonance: Machine learning assistive rapid two‐dimensional relaxometry mapping

Peng

2021

Engineering Reports

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Low‐field nuclear magnetic resonance (NMR) relaxometry is an attractive approach from point‐of‐care testing medical diagnosis to in situ oil‐gas exploration. One of the problems, however, is the inherently long relaxation time of the (liquid) samples, (and hence low signal‐to‐noise ratio) which causes unnecessarily long repetition time. In this work, a new class of methodology is presented for rapid and accurate object classification using NMR relaxometry with the aid of machine learning. It is demonstrated that the sensitivity and specificity of the classification is substantially improved with higher order of (pseudo)‐dimensionality (e.g., 2D‐ or multi‐dimensional). This new methodology (termed as ‘Clustering NMR’) may be extremely useful for rapid and accurate object classification (in less than a minute) using low‐field NMR.

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Machine learning assistive rapid, label-free molecular phenotyping of blood with two-dimensional NMR correlational spectroscopy

Cited by 28 publications

References 53 publications

Tracking oxidation-induced alterations in fibrin clot formation by NMR-based methods

Tracking oxidation-induced alterations in fibrin clot formation by NMR-based methods

Tracking oxidation-induced alterations in fibrin clot formation by NMR-based methods

Clustering Nuclear Magnetic Resonance: Machine learning assistive rapid two‐dimensional relaxometry mapping

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