Plasma Proteome Profiling to Assess Human Health and Disease

SummaryProteins in the circulatory system mirror an individual’s physiology. In daily clinical practice, protein levels are generally determined using single-protein immunoassays. High-throughput, quantitative analysis using mass-spectrometry-based proteomics of blood, plasma, and serum would be advantageous but is challenging because of the high dynamic range of protein abundances. Here, we introduce a rapid and robust “plasma proteome profiling” pipeline. This single-run shotgun proteomic workflow does not require protein depletion and enables quantitative analysis of hundreds of plasma proteomes from 1 μl single finger pricks with 20 min gradients. The apolipoprotein family, inflammatory markers such as C-reactive protein, gender-related proteins, and >40 FDA-approved biomarkers are reproducibly quantified (CV <20% with label-free quantification). Furthermore, we functionally interpret a 1,000-protein, quantitative plasma proteome obtained by simple peptide pre-fractionation. Plasma proteome profiling delivers an informative portrait of a person’s health state, and we envision its large-scale use in biomedicine

The scalar gluonium correlator: large-beta_0 and beyond

The investigation of the scalar gluonium correlator is interesting because it carries the quantum numbers of the vacuum and the relevant hadronic current is related to the anomalous trace of the QCD energy-momentum tensor in the chiral limit. After reviewing the purely perturbative corrections known up to next-next-to-leading order, the behaviour of the correlator is studied to all orders by means of the large-beta_0 approximation. Similar to the QCD Adler function, the large-order behaviour is governed by the leading ultraviolet renormalon pole. The structure of infrared renormalon poles, being related to the operator product expansion are also discussed, as well as a low-energy theorem for the correlator that provides a relation to the renormalisation group invariant gluon condensate, and the vacuum matrix element of the trace of the QCD energy-momentum tensor.Comment: 14 pages, references added, discussion of IR renormalon pole at u=3 extended, similar version to appear in JHE

A streamlined mass spectrometry-based proteomics workflow for large scale FFPE tissue analysis

Formalin fixation and paraffin-embedding (FFPE) is the most common method to preserve human tissue for clinical diagnosis, and FFPE archives represent an invaluable resource for biomedical research. Proteins in FFPE material are stable over decades but their efficient extraction and streamlined analysis by mass spectrometry (MS)-based proteomics has so far proven challenging. Herein we describe a MS-based proteomic workflow for quantitative profiling of large FFPE tissue cohorts directly from histopathology glass slides. We demonstrate broad applicability of the workflow to clinical pathology specimens and variable sample amounts, including low-input cancer tissue isolated by laser microdissection. Using state-of-the-art data dependent acquisition (DDA) and data independent acquisition (DIA) MS workflows, we consistently quantify a large part of the proteome in 100 min single-run analyses. In an adenoma cohort comprising more than 100 samples, total workup took less than a day. We observed a moderate trend towards lower protein identification in long-term stored samples (>15 years), but clustering into distinct proteomic subtypes was independent of archival time. Our results underscore the great promise of FFPE tissues for patient phenotyping using unbiased proteomics and they prove the feasibility of analyzing large tissue cohorts in a robust, timely, and streamlined manner

The Factorized S-Matrix of CFT/AdS

We argue that the recently discovered integrability in the large-N CFT/AdS system is equivalent to diffractionless scattering of the corresponding hidden elementary excitations. This suggests that, perhaps, the key tool for finding the spectrum of this system is neither the gauge theory's dilatation operator nor the string sigma model's quantum Hamiltonian, but instead the respective factorized S-matrix. To illustrate the idea, we focus on the closed fermionic su(1|1) sector of the N=4 gauge theory. We introduce a new technique, the perturbative asymptotic Bethe ansatz, and use it to extract this sector's three-loop S-matrix from Beisert's involved algebraic work on the three-loop su(2|3) sector. We then show that the current knowledge about semiclassical and near-plane-wave quantum strings in the su(2), su(1|1) and sl(2) sectors of AdS_5 x S^5 is fully consistent with the existence of a factorized S-matrix. Analyzing the available information, we find an intriguing relation between the three associated S-matrices. Assuming that the relation also holds in gauge theory, we derive the three-loop S-matrix of the sl(2) sector even though this sector's dilatation operator is not yet known beyond one loop. The resulting Bethe ansatz reproduces the three-loop anomalous dimensions of twist-two operators recently conjectured by Kotikov, Lipatov, Onishchenko and Velizhanin, whose work is based on a highly complex QCD computation of Moch, Vermaseren and Vogt.Comment: 38 pages, LaTeX, JHEP3.cl

Graviton 1-loop partition function for 3-dimensional massive gravity

The graviton 1-loop partition function in Euclidean topologically massive gravity (TMG) is calculated using heat kernel techniques. The partition function does not factorize holomorphically, and at the chiral point it has the structure expected from a logarithmic conformal field theory. This gives strong evidence for the proposal that the dual conformal field theory to TMG at the chiral point is indeed logarithmic. We also generalize our results to new massive gravity.Comment: 19 pages, v2: major revision, considerably stronger conclusions, added comparison with LCFT partition function, confirmation of LCFT conjecture, added autho

Regulation of Translesion Synthesis DNA Polymerase η by Monoubiquitination

DNA polymerase eta is a Y family polymerase involved in translesion synthesis (TLS). Its action is initiated by simultaneous interaction between the PIP box in pol eta and PCNA and between the UBZ in pol eta and monoubiquitin attached to PCNA. Whereas monoubiquitination of PCNA is required for its interaction with pol eta during TLS, we now show that monoubiquitination of pol eta inhibits this interaction, preventing its functions in undamaged cells. Identification of monoubiquitination sites within pol eta nuclear localization signal (NLS) led to the discovery that pol eta NLS directly contacts PCNA, forming an extended pol eta-PCNA interaction surface. We name this the PCNA-interacting region (PIR) and show that its monoubiquitination is downregulated by various DNA-damaging agents. We propose that this mechanism ensures optimal availability of nonubiquitinated, TLS-competent pol eta after DNA damage. Our work shows how monoubiquitination can either positively or negatively regulate the assembly of a protein complex, depending on which substrates are targeted by ubiquitin

Planar N=4 Gauge Theory and the Hubbard Model

Recently it was established that a certain integrable long-range spin chain describes the dilatation operator of N=4 gauge theory in the su(2) sector to at least three-loop order, while exhibiting BMN scaling to all orders in perturbation theory. Here we identify this spin chain as an approximation to an integrable short-ranged model of strongly correlated electrons: The Hubbard model.Comment: 35 pages, 2 figures; v2: typos and references fixed, published versio