General Mass Research Articles

Driving efficiency in a high-throughput metabolic stability assay through a generic high-resolution accurate mass method and automated data mining

Improving analytical throughput is the focus of many quantitative workflows being developed for early drug discovery. For drug candidate screening, it is common practice to use ultra-high performance liquid chromatography (U-HPLC) coupled with triple quadrupole mass spectrometry. This approach certainly results in short analytical run time; however, in assessing the true throughput, all aspects of the workflow needs to be considered, including instrument optimization and the necessity to re-run samples when information is missed. Here we describe a high-throughput metabolic stability assay with a simplified instrument set-up which significantly improves the overall assay efficiency. In addition, as the data is acquired in a non-biased manner, high information content of both the parent compound and metabolites is gathered at the same time to facilitate the decision of which compounds to proceed through the drug discovery pipeline.

The performance of the risk of ovarian malignancy algorithm

The performance of the risk of ovarian malignancy algorithm

Sequestering by global symmetries in Calabi–Yau string models

We study the possibility of realizing an effective sequestering between visible and hidden sectors in generic heterotic string models, generalizing previous work on orbifold constructions to smooth Calabi–Yau compactifications. In these theories, genuine sequestering is spoiled by interactions mixing chiral multiplets of the two sectors in the effective Kähler potential. These effective interactions however have a specific current–current-like structure and can be interpreted from an M-theory viewpoint as coming from the exchange of heavy vector multiplets. One may then attempt to inhibit the emergence of generic soft scalar masses in the visible sector by postulating a suitable global symmetry in the dynamics of the hidden sector. This mechanism is however not straightforward to implement, because the structure of the effective contact terms and the possible global symmetries is a priori model-dependent. To assess whether there is any robust and generic option, we study the full dependence of the Kähler potential on the moduli and the matter fields. This is well known for orbifold models, where it always leads to a symmetric scalar manifold, but much less understood for Calabi–Yau models, where it generically leads to a non-symmetric scalar manifold. We then examine the possibility of an effective sequestering by global symmetries, and argue that whereas for orbifold models this can be put at work rather naturally, for Calabi–Yau models it can only be implemented in rather peculiar circumstances.

Reply: The performance of the risk of ovarian malignancy algorithm

Reply: The performance of the risk of ovarian malignancy algorithm

Poorly soluble particulates: Searching for a unifying denominator of nanoparticles and fine particles for DNEL estimation

Under the new European chemicals regulation, REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) a Derived No-Effect Level (DNEL), i.e., the level of exposure above which humans should not be exposed, is defined. The focus of this paper is to develop a weight-of-evidence-based DNEL-approach for inhaled poorly soluble particles. Despite the common mode of action of inhaled insoluble, spherical particulate matter (PM), a unifying, most appropriate metric conferring pulmonary biopersistence and toxicity has yet not been demonstrated. Nonetheless, there is compelling evidence from repeated rat inhalation exposure studies suggesting that the particle displacement volume is the most prominent unifying denominator linking the pulmonary retained dose with toxicity. Procedures were developed to analyze and model the pulmonary toxicokinetics from short-term to long-term exposure. Six different types of poorly soluble nano- to submicron PMs were compared: ultrafine and pigmentary TiO 2, synthetic iron oxide (Fe 3O 4, magnetite), two aluminum oxyhydroxides (AlOOH, Boehmite) with primary isometric particles approximately of either 10 or 40 nm, and MWCNT. The specific agglomerate densities of these materials ranged from 0.1 g/cm 3 (MWCNT) to 5 g/cm 3 (Fe 3O 4). Along with all PM, due to their long retention half-times and associated biopersistence in the lung, even short-term inhalation studies may require postexposure periods of at least 3 months to reveal PM-specific dispositional and toxicological characteristics. This analysis provides strong evidence that pulmonary toxicity (sustained inflammation) is dependent on the volume-based cumulative lung exposure dose. Lung toxicity, evidenced by PMN in BAL occurred at lung doses exceeding 10-times the overload threshold. Furthermore, the conclusion is supported that repeated inhalation studies on rats should utilize an experimental window of cumulative volume loads of respirable PM in the range of 1 μl/lung (no-adverse-effect range); however, not exceeding ≈10 μl/lung that would lead to retention half-times increasing 1 year. This can be targeted best by computational toxicology, i.e., the modeling of particle deposition and lung retention biokinetics during the exposure and recovery periods. Inhalation studies exceeding that threshold volume may lead to meaningless findings difficult to extrapolate to any real-life scenario. In summary, this analysis supports a volume-based generic mass concentration of 0.5 μl PM respirable/m 3 × agglomerate density, independent on nano- or submicron-sized properties, as a generic no-adverse effect level in both rats and humans.

Stop reconstruction with tagged tops

At the LHC combinatorics make it unlikely that we will be able to observe stop pair production with a decay to a semi-leptonic top pair and missing energy for generic supersymmetric mass spectra. Using a Standard-Model top tagger on fully hadronic top decays we can not only extract the stop signal but also measure the top momentum. To illustrate the promise of tagging tops with moderate boost we include a detailed discussion of our HEPTopTagger algorithm.

Special Focus on Top‐down Proteomics

Without doubt, so-called “shotgun” or “bottom-up” proteomics dealing with peptides obtained upon chemical or enzymatic breakdown of proteins has been the driving force behind the tremendous progress and possibilities that we have seen and are still seeing in proteome analysis. Nevertheless, as the term indicates, “shooting” at pieces of proteins with a shotgun leaves one ambiguous about the actual target. Moreover, the real objects of desire in proteomic analyses are the intact proteins, their function, location, modifications, concentration, interactions, and relevance in biological processes. Many of these latter aspects may get lost or overseen when breaking down proteins to their corresponding peptide fragments. In due consequence, it is not surprising that from the very beginning of intact protein mass spectrometry, which has been primarily facilitated by the introduction of electrospray ionization and matrix-assisted laser desorption/ionization, researchers have been trying to investigate proteins at the intact molecule level, including all posttranslational modifications and sequence variations. This strategy of approaching proteomes via intact protein analysis has been termed “top-down” proteomics, striving to directly derive sequences and identification information from fragment spectra of intact proteins. While shotgun approaches have the advantage of dealing with peptides having relatively homogenous chemical and physical properties, which facilitates the application of quite generic separation and mass spectrometric identification routines, top-down technologies struggle with the immense structural diversity and the corresponding broad range of physical and chemical properties of proteins. Therefore, a significantly larger, multifaceted, and more sophisticated toolbox is required in order to handle intact proteins efficiently on a global scale. This toolbox includes one- and multidimensional separation methods, elaborate fragmentation techniques, technologies for high-resolution and highly accurate mass analysis, and finally, algorithms for automated interpretation of mass spectrometric and chromatographic data. We are indebted to researchers in the field, kindly following our invitation to contribute to this Focus Issue devoted to top-down proteomics in order to demonstrate the current status of the technology. The articles collected in this issue cover a significant portion of the major challenges of top-down protein analysis, including technical aspects such as gas-phase ion chemistry of intact proteins, automated software platforms for large-scale top-down proteomics, and the high-resolution single- and multidimensional separation and detection of intact proteins. Applications of the top-down technologies presented in this issue range from the investigation of ribosomal proteins and histones, the phyloproteomic classification of bacterial proteins, the characterization of hemoglobin variants, to the characterization of integral plant membrane protein complexes. Some of the contributions to this Focus Issue also shed light on the possibilities and limitations both of shotgun and top-down approaches, revealing both methods as highly complementary and thereby enabling more comprehensive investigations into biological problems. We thank all contributing authors for investing their time and sharing with us valuable insights into the world of top-down proteome analysis. We hope that the workflows and data presented in this issue will stimulate you own new ideas and approaches to problem solving in biological, biochemical, or biomedical analysis involving intact proteins. Enjoy reading, Sincerely, Christian Huber University of Salzburg Lukas Huber Innsbruck Medical University

Decreasing CO2partial pressure triggered Mg-Fe-Ca carbonate formation in ancient Martian crust preserved in the ALH84001 Meteorite

We retrace hydrogeochemical processes leading to the formation of Mg–Fe–Ca carbonate concretions (first distinct carbonate population, FDCP) in Martian meteorite ALH84001 by generic hydrogeochemical equilibrium and mass transfer modeling. Our simple conceptual models assume isochemical equilibration of orthopyroxenite minerals with pure water at varying water-to-rock ratios, temperatures and CO2 partial pressures. Modeled scenarios include CO2 partial pressures ranging from 10.1325 to 0.0001 MPa at water-to-rock ratios between 4380 and 43.8 mol mol−1 and different temperatures (278, 303 and 348 K) and enable the precipitation of Mg–Fe–Ca solid solution carbonate. Modeled range and trend of carbonate compositional variation from magnesio-siderite (core) to magnesite (rim), and the precipitation of amorphous SiO2 and magnetite coupled to magnesite-rich carbonate are similar to measured compositional variation. The results of this study suggest that the early Martian subsurface had been exposed to a dynamic gas pressure regime with decreasing CO2 partial pressure at low temperatures (approximately 1.0133 to 0.0001 MPa at 278 K or 6 to 0.0001 MPa at 303 K). Moderate water-to-rock ratios of ca. 438 mol mol−1 and isochemical weathering of orthopyroxenite are additional key prerequisites for the formation of secondary phase assemblages similar to ALH84001’s ‘FDCP’. Outbursts of water and CO2(g) from confined ground water in fractured orthopyroxenite rocks below an unstable CO2 hydrate-containing cryosphere provide adequate environments on the early Martian surface.

Thermoacoustic Modeling of a Gas Turbine Using Transfer Functions Measured Under Full Engine Pressure

Thermoacoustic transfer functions of a full-scale gas turbine burner operating under full engine pressure have been measured. The excitation of the high-pressure test facility was done using a siren that modulated a part of the combustion airflow. Pulsation probes have been used to record the acoustic response of the system to this excitation. In addition, the flame’s luminescence response was measured by multiple photomultiplier probes and a light spectrometer. Three techniques to obtain the thermoacoustic transfer function are proposed and employed: two acoustic-optical techniques and a purely acoustic technique. The first acoustical-optical technique uses one single optical signal capturing the chemiluminescence intensity of the flame as a measure for the heat release in the flame. This technique only works if heat release fluctuations in the flame have only one generic source, e.g., equivalence ratio or mass flow fluctuations. The second acoustic-optical technique makes use of the different response of the flame’s luminescence at different optical wavelengths bands to acoustic excitation. It also works, if the heat release fluctuations have two contributions, e.g., equivalence ratio and mass flow fluctuation. For the purely acoustic technique, a new method was developed in order to obtain the flame transfer function, burner transfer function, and flame source term from only three pressure transducer signals. The purely acoustic method could be validated by the results obtained from the acoustic-optical techniques. The acoustic and acoustic-optical methods have been compared and a discussion on the benefits and limitations of each is given. The measured transfer functions have been implemented into a nonlinear, three-dimensional, time domain network model of a gas turbine with an annular combustion chamber. The predicted pulsation behavior shows a good agreement with pulsation measurements on a field gas turbine.

Framework for Modeling Mass Disasters

This paper introduces a generic mass Disaster Modeling Framework (DMF) to support integrated sociophysical risk assessment and management of disasters. The DMF draws on the principles that disasters have many common features regardless of their instigating hazards and are the outcome of interaction between a hazard and society. The modular architecture of the DMF weakly couples three key applications: the Community Simulation Model (CSM), the Hazard Simulation Model (HSM), and the Evacuation Simulation Model (ESM). The CSM utilizes census, cadastral, and other data to construct an individual-based representation of the potentially impacted community. The CSM estimates people and built environment at risk at any given time of the day, week, and year. The CSM assessment along with the hazard simulation of the HSM feed into the ESM to simulate the progression of fatalities throughout the event. Dam failures, for which vivid and detailed accounts of human interaction with the incoming flood exist, served as case studies.

SU-GG-T-226: Reproducible QA of RapidArc Treatment Plans with MapCHECK2 and MapPHAN

Purpose: To report on an investigation of “best practices” for achieving precise and reproducible results with the MapCHECK2/MapPHAN (MC2/MP) dosimetry system (Sun Nuclear Corporation) for QA of RapidArc (Varian Medical Systems) volumetric modulated arc therapy (VMAT) treatments. Method and Materials: MapCHECK2 (MC2) is a 2D diode array developed for planar IMRTdosimetry; MapPHAN (MP) is a water equivalent phantom that adapts MC2 for rotational dosimetry. The MC2/MP system was checked to verify uniform and equivalent response to 6 MV photon beams incident from anterior and posterior directions. A CT scan of the system was ported to the Eclipse planning system, (v8.0) where it was assigned a generic mass density of 1.05 g/cm^3. RapidArc treatment plans (15 prostate, 2 SBRTlung, and lhead/neck) were projected onto this phantom and planar dose was computed at 5 cm depth. Parameters for specification of phantom and QA delivery were varied to deduce best practices for reproducible QA of RapidArc VMAT plans. Parameters included mass density assignment, collimator/MLC rotation, position of diode array relative to MLC leaves, and resolution of the dose plane exported from Eclipse. QA results were evaluated by absolute dose agreement and by the percentage of points passing a Gamma analysis with criteria 3% dose difference or 3 mm distance to agreement. Results: The most important steps for reproducible QA of RapidArc plans with MC2/MP were zero collimator rotation for QA beam delivery, and a positional offset of the diode array by half the width of an MLC leaf. These actions enhanced the ability of MC2 to measure dose modulation, and increased the percentage of points passing the Gamma analysis by approximately 5% and 3%, respectively. Conclusion: With simple setup interventions, the MapCHECK2/MapPHAN system is capable of measuring precise and reproducible QA of RapidArc‐delivered VMAT plans.

Maximum or minimum entropy production? How to select a necessary criterion of stability for a dissipative fluid or plasma

Ten necessary criteria for stability of various dissipative fluids and plasmas are derived from the first and the second principle of thermodynamics applied to a generic small mass element of the system, under the assumption that local thermodynamic equilibrium holds everywhere at all times. We investigate the stability of steady states of a mixture of different chemical species at the same temperature against volume-preserving perturbations. We neglect both electric and magnetic polarization, and assume negligible net mass sources and particle diffusion. We assume that both conduction- and radiation-induced heat losses increase with increasing temperature. We invoke no Onsager symmetry, no detailed model of heat transport and production, no "Extended Thermodynamics," no "Maxent" method, and no "new" universal criterion of stability for steady states of systems with dissipation. Each criterion takes the form of--or is a consequence of--a variational principle. We retrieve maximization of entropy for isolated systems at thermodynamic equilibrium, as expected. If the boundary conditions keep the relaxed state far from thermodynamic equilibrium, the stability criterion we retrieve depends also on the detailed balance of momentum of a small mass element. This balance may include the nablap-related force, the Lorenz force of electromagnetism and the forces which are gradients of potentials. In order to be stable, the solution of the steady-state equations of motion for a given problem should satisfy the relevant stability criterion. Retrieved criteria include (among others) Taylor's minimization of magnetic energy with the constraint of given magnetic helicity in relaxed, turbulent plasmas, Rayleigh's criterion of stability in thermoacoustics, Paltridge 's maximum entropy production principle for Earth's atmosphere, Chandrasekhar' minimization of the adverse temperature gradient in Bénard's convective cells, and Malkus' maximization of viscous power with the constraint of given mean velocity for turbulent shear flow in channels. It turns out that characterization of systems far from equilibrium, e.g., by maximum entropy production is not a general property but--just like minimum entropy production--is reserved to special systems. A taxonomy of stability criteria is derived, which clarifies what is to be minimized, what is to be maximized and with which constraint for each problem.

Improved formulation of global QCD analysis with zero-mass hard cross sections

The zero-mass (ZM) parton formalism is widely used in high-energy physics because of its simplicity and historical importance, even while massive quarks $(c,b,t)$ are playing an increasingly prominent role in particle phenomenology, including global QCD analyses of parton distributions based on the more precise general-mass (GM) QCD formalism. In view of this dichotomy, we show how the obvious inconsistencies of the conventional implementation of the ZM formalism can be corrected, while preserving the simplicity of its hard matrix elements. The resulting intermediate-mass (IM) scheme for perturbative QCD calculation can be considered either as improved ZM formulation with realistic treatment of heavy-flavor kinematics; or as a simplified GM formulation with approximate ZM hard cross sections. Phenomenologically, global analyses based on IM calculations can effectively reproduce, within the present estimated uncertainty bands, the more correct GM results on parton distributions, as well as their predictions for a wide range of collider processes of current interest.

The chiral condensate in a finite volume

Chiral perturbation theory at finite four-volume V( = L3T) is reconsidered with a view towards finding a computational scheme that can deal with any value of MπL, where Mπ is a generic Nambu-Goldstone mass. The momentum zero modes that cause the usual p-expansion to fail in the chiral limit are treated separately, and partly integrated out to all orders. In this way the theory remains infrared finite in the perturbative expansion, and the chiral limit can be considered at finite volume. We illustrate the technique by computing the quark condensate in a finite volume, smoothly connecting standard results in the p-regime for larger masses with those of the -regime for smaller masses. From the partially quenched theory we also obtain the spectral density of the Dirac operator, a smooth function from the microscopic region to the bulk region of the p-regime.

Generic Friedberg-Lee symmetry of Dirac neutrinos

We write out the generic Dirac neutrino mass operator which possesses the Friedberg-Lee symmetry and find that its corresponding neutrino mass matrix is asymmetric. Following a simple way to break the Friedberg-Lee symmetry, we calculate the neutrino mass eigenvalues and show that the resultant neutrino mixing pattern is nearly tri-bimaximal. Imposing the Hermitian condition on the neutrino mass matrix, we also show that the simplified ansatz is consistent with current experimental data and favors the normal neutrino mass hierarchy.

On dispersion for Klein Gordon equation with periodic potential in 1D

By exploiting estimates on Bloch functions obtained in a previous paper, we prove decay estimates for Klein Gordon equations with a time independent potential periodic in space in 1D and with generic mass.

Final spin from the coalescence of two black holes

We provide a compact analytic formula to compute the spin of the black hole produced by the coalescence of two black holes following a quasicircular inspiral. Without additional fits than those already available for binaries with aligned or antialigned spins, but with a minimal set of assumptions, we derive an expression that can model generic initial spin configurations and mass ratios, thus covering all of the 7-dimensional space of parameters. A comparison with simulations already shows very accurate agreements with all of the numerical data available to date, but we also suggest a number of ways in which our predictions can be further improved.

Extending the diffuse layer model of surface acidity constant behaviour: II. Estimation of intrinsic acidity and electrolyte ion site binding constants

The two-pK metal oxide surface acidity constant model relies on generic mass action expressions of the form: Ka(3−x) = [>SOHx−2x−1]aH+EXP(–ΔGexcess/RT)/[>SOHxx−1] where x equals 1 or 2. While all current two-pK surface complexation models require numerical estimates of “intrinsic” acidity constants (i.e., Kavalues when ΔGexcess equals zero), there exists a large range in metal oxide intrinsic acidity constant values reported in the literature.This paper describes improved procedures for obtaining intrinsic acidity constants from quality published metal oxide titrimetic datasets. Because of the observed ionic strength sensitivity of acidity constant estimates at zero charge densities, these constants were interpreted within the context of a new procedure for estimating historical electrolyte ion site binding reactions of the form: >SOH+2 + An−⇔>SOH2An and >SO− + Cat+⇔>SOCat. Correcting zero charge density effective acidity constants with electrolyte ion site binding constants reduced the observed ionic strength variations in intrinsic acidity constant estimates by approximately 50%. The estimated constants obtained in the study are given below.Table A1SystemDatasetpKa1,intrinsic1pKa2,intrinsicKAn_KCat+Goethite, NaClLumsdon & Evans (1994)5.92±0.1511.68±0.0222.43.66rundum, NaNO3Hayes and Leckie (1991)6.21±0.0411.62±0.109.698.18Hematite, KNO3Fokkink (1987)5.77±0.1411.53±0.204.061.72Rutile, KNO3Fokkink (1987)2.88±0.098.22±0.1412.010.3Anatase, NaClSprycha (1984)3.61±0.048.71±0.1910.229.5γ-Al2O3, NaClHuang & Stumm (1973)5.86±0.1611.15±0.0921.515.11 The “±” notation designates 1/2 of the range of observed values.

N-dimensional Vaidya metric with a cosmological constant in double-null coordinates

A recently proposed approach to the construction of the Vaidya metric in double-null coordinates for generic mass functions is extended to the $n$-dimensional ($ng2$) case and to allow the inclusion of a cosmological constant. The approach is based on a qualitative study of the null geodesics, allowing the description of light cones and revealing many features of the underlying causal structure. Possible applications are illustrated by explicit examples. Some new exact solutions are also presented and discussed. The results presented here can simplify considerably the study of spherically symmetric gravitational collapse and mass accretion in arbitrary dimensions.

Quantitative Proteomics Profiling of Sarcomere Associated Proteins in Limb and Extraocular Muscle Allotypes

The sarcomere is the major structural and functional unit of striated muscle. Approximately 65 different proteins have been associated with the sarcomere, and their exact composition defines the speed, endurance, and biology of each individual muscle. Past analyses relied heavily on electrophoretic and immunohistochemical techniques, which only allow the analysis of a small fraction of proteins at a time. Here we introduce a quantitative label-free, shotgun proteomics approach to differentially quantitate sarcomeric proteins from microgram quantities of muscle tissue in a fast and reliable manner by liquid chromatography and mass spectrometry. The high sequence similarity of some sarcomeric proteins poses a problem for shotgun proteomics because of limitations in subsequent database search algorithms in the exclusive assignment of peptides to specific isoforms. Therefore multiple sequence alignments were generated to improve the identification of isoform specific peptides. This methodology was used to compare the sarcomeric proteome of the extraocular muscle allotype to limb muscle. Extraocular muscles are a unique group of highly specialized muscles with distinct biochemical, physiological, and pathological properties. We were able to quantitate 40 sarcomeric proteins; although the basic sarcomeric proteins in extraocular muscle are similar to those in limb muscle, key proteins stabilizing the connection of the Z-bands to thin filaments and the costamere are augmented in extraocular muscle and may represent an adaptation to the eccentric contractions known to normally occur during eye movements. Furthermore, a number of changes are seen that closely relate to the unique nature of extraocular muscle.