Mobility Mass Research Articles

Design and synthesis of peptides as stabilizers of histone deacetylase 4.

Histone deacetylase 4 (HDAC4) contributes to gene repression by complex formation with HDAC3 and the corepressor silencing mediator for retinoid or thyroid hormone receptors (SMRT). We hypothesized that peptides derived from the class IIa specific binding site of SMRT would stabilize a specific conformation of its target protein and modulate its activity. Based on the SMRT-motif 1 (SM1) involved in the interaction of SMRT with HDAC4, we systematically developed cyclic peptides that exhibit Ki values that are 9 to 56 times lower than that of the linear SMRT peptide. The peptide macrocycles stabilize the wildtype of the catalytic domain of HDAC4 (cHDAC4) considerably better than its thermally more stable 'gain-of-function' (GOF) variant, cHDAC4-H976Y. Molecular docking and mutagenesis studies indicated that the cyclic peptides bind in a similar but not identical manner as the linear SMRT peptide to a discontinuous binding site. Ion mobility mass spectrometry showed no major changes in the protein fold upon peptide binding. Consistent with these results, preliminary hydrogen-deuterium exchange mass spectrometry measurements indicated only minor conformational changes. Taken together, the cyclic SMRT peptides most likely stabilize the apo form of cHDAC4.

First Generic Teriparatide: Structural and Biological Sameness to Its Reference Medicinal Product

Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential similarity between synthetic teriparatide BGW and the reference medicinal product (RMP), and thus to ensure the development of the first generic teriparatide drug. Hence, an extensive side-by-side comparative exercise, focusing on structural and biological activity, was performed using a wide range of state-of-the-art orthogonal methods. Nuclear magnetic resonance (NMR), ion mobility–mass spectrometry (IM–MS), UV, circular dichroism (CD) and Fourier transform infrared (FTIR) demonstrated the structural similarity between teriparatide BGW and the RMP. Comparative cell-based bioassays showed that the synthetic and recombinant peptides have identical behaviors. Teriparatide BGW, as a generic drug, provides an available treatment option for patients with osteoporosis and offers clinical benefits identical to those provided by the RMP.

Structural Insights into Linkage-Specific Ubiquitin Chains Using Ion Mobility Mass Spectrometry.

The structural characterization and differentiation of four types of oligoubiquitin conjugates [linear (Met1)-, Lys11-, Lys48-, Lys63-linked di-, tri-, and tetraubiquitin chains] using ion mobility mass spectrometry are reported. A comparison of collision cross sections for the same linkage of di-, tri-, and tetraubiquitin chains shows differences in conformational elongation for higher charge states due to the interplay of linkage-derived structure and Coulombic repulsion. For di- and triubiquitin chains, this elongation results in a single narrow feature representing an elongated conformation type for multiple higher charge state species. In contrast, higher charge state tetraubiquitin species do not form a single conformer type as readily. A comparison of different linkages in tetraubiquitin chains reveals greater similarity in conformation type at lower charge states; with increasing charge state, the four linkage types diverge in the relative proportions of elongated conformer types with Met1- ≥ Lys11- > Lys63- > Lys48-linkage. These differences in conformational trends could be discussed with respect to biological functions of linkage-specific polyubiquitinated proteins.

On the level of literacy of the population Kostroma and Yaroslavl provinces in the late 19th – early 20th centuries

The reforms carried out in Russia in the 1860-70s contributed to the industrial development of the country, but along with the changes in the economy changes in the socio-cultural sphere were no less large-scale. Due to the mass mobility of the population after the abolition of serfdom, representatives of different estates were involved in the general socio-cultural movement. One of the important indicators of the social modernisation of Russian society included the changed level of literacy of the population, caused by the need for competent personnel for the growing industry, transport, communications and management. Using the example of Kostroma and Yaroslavl provinces, the article shows the dynamics of changes in the literacy rate of the population in the late 19th – early 20th centuries which exceeded all-Russian indicators, both for urban and rural populations and was associated with the successful implementation of state policy in the field of education, the consequences of the introduction of the new Military Charter as of 1874 and the peculiarities of the socio-economic development of the provinces associated with the developed craftsmen’s internal migration.

Current Progress and Development Trend of Gas Injection to Enhance Gas Recovery in Gas Reservoirs

Conventional recovery enhancement techniques are aimed at reducing the abandonment pressure, but there is an upper limit for recovery enhancement due to the energy limitation of reservoirs. Gas injection for energy supplementation has become an effective way to enhance gas recovery by reducing hydrocarbon saturation in gas reservoirs. This review systematically investigates progress in gas injection for enhanced gas recovery in three aspects: experiments, numerical simulations and field examples. It summarizes and analyzes the current research results on gas injection for EGR and explores further prospects for future research. The research results show the following: (1) Based on the differences in the physical properties of CO2, N2 and natural gas, effective cushion gas can be formed in bottom reservoirs after gas injection to achieve the effects of pressurization, energy replenishment and gravity differentiation water resistance. However, further experimental evaluation is needed for the degree of increase in penetration ability. (2) It is more beneficial to inject N2 before CO2 or the mixture of N2 and CO2 in terms of EGR effect and cost. (3) According to numerical simulation studies, water drive and condensate gas reservoirs exhibit significant recovery effects, while CO2-EGR in depleted gas reservoirs is more advantageous for burial and storage; current numerical simulations only focus on mobility mass and saturation changes and lack a mixed-phase percolation model, which leads to insufficient analysis of injection strategies and a lack of distinction among different gas extraction effects. Therefore, a mixed-phase-driven percolation model that can characterize the fluid flow path is worth studying in depth. (4) The De Wijk and Budafa Szinfelleti projects have shown that gas injection into water drive and depleted reservoirs has a large advantage for EGR, as it can enhance recovery by more than 10%. More experiments, simulation studies and demonstration projects are needed to promote the development of gas injection technology for enhanced recovery in the future.

Comparative Efficacy of Different Protein Supplements on Muscle Mass, Strength, and Physical Indices of Sarcopenia among Community-Dwelling, Hospitalized or Institutionalized Older Adults Undergoing Resistance Training: A Network Meta-Analysis of Randomized Controlled Trials.

Aging-related sarcopenia exerts harmful impacts on muscle mass, strength, and physical mobility. Protein supplementation has been demonstrated to augment efficacy of resistance training (RT) in elderly. This study compared the relative effects of different protein supplements on muscle mass, strength, and mobility outcomes in middle-aged and older individuals undergoing RT. A comprehensive search of online databases was performed to identify randomized controlled trials (RCTs) examining the efficacy of protein supplement plus RT in untrained community-dwelling adults, hospitalized, or institutionalized residents who suffered acute or chronic health conditions. Network meta-analysis (NMA) was performed using a frequentist method for all analyses. Treatment effects for main outcomes were expressed as standard mean difference (SMD) with 95% confidence interval (CI). We used the surface-under-the cumulative-ranking (SUCRA) scores to rank probabilities of effect estimation among all identified treatments. Meta-regression analyses were performed to identify any relevant moderator of the treatment efficacy and results were expressed as β with 95% credible interval (CrI). We finally included 78 RCTs (5272 participants) for analyses. Among the six protein sources identified in this NMA, namely whey, milk, casein, meat, soy, and peanut, whey supplement yielded the most effective treatments augmenting efficacy of RT on muscle mass (SMD = 1.29, 95% CI: 0.96, 1.62; SUCRA = 0.86), handgrip strength (SMD = 1.46, 95% CI: 0.92, 2.00; SUCRA = 0.85), and walking speed (SMD = 0.73, 95% CI: 0.39, 1.07; SUCRA = 0.84). Participant's health condition, sex, and supplementation dose were significant factors moderating the treatment efficacy on muscle mass (β = 0.74; 95% CrI: 0.22, 1.25), handgrip strength (β = -1.72; 95% CrI: -2.68, -0.77), and leg strength (β = 0.76; 95% CrI: 0.06, 1.47), respectively. Our findings suggest whey protein yields the optimal supplements to counter sarcopenia in older individuals undergoing RT.

Ion mobility-tandem mass spectrometry of mucin-type O-glycans

The dense O-glycosylation of mucins plays an important role in the defensive properties of the mucus hydrogel. Aberrant glycosylation is often correlated with inflammation and pathology such as COPD, cancer, and Crohn’s disease. The inherent complexity of glycans and the diversity in the O-core structure constitute fundamental challenges for the analysis of mucin-type O-glycans. Due to coexistence of multiple isomers, multidimensional workflows such as LC-MS are required. To separate the highly polar carbohydrates, porous graphitized carbon is often used as a stationary phase. However, LC-MS workflows are time-consuming and lack reproducibility. Here we present a rapid alternative for separating and identifying O-glycans released from mucins based on trapped ion mobility mass spectrometry. Compared to established LC-MS, the acquisition time is reduced from an hour to two minutes. To test the validity, the developed workflow was applied to sputum samples from cystic fibrosis patients to map O-glycosylation features associated with disease.

Exploring the Aggregation Propensity of PHF6 Peptide Segments of the Tau Protein Using Ion Mobility Mass Spectrometry Techniques.

Peptide and protein aggregation involves the formation of oligomeric species, but the complex interplay between oligomers of different conformations and sizes complicates their structural elucidation. Using ion mobility mass spectrometry (IM-MS), we aim to reveal these early steps of aggregation for the Ac-PHF6-NH2 peptide segment from tau protein, thereby distinguishing between different oligomeric species and gaining an understanding of the aggregation pathway. An important factor that is often neglected, but which can alter the aggregation propensity of peptides, is the terminal capping groups. Here, we demonstrate the use of IM-MS to probe the early stages of aggregate formation of Ac-PHF6-NH2, Ac-PHF6, PHF6-NH2, and uncapped PHF6 peptide segments. The aggregation propensity of the four PHF6 segments is confirmed using thioflavin T fluorescence assays and transmission electron microscopy. A novel approach based on post-IM fragmentation and quadrupole selection on the TIMS-Qq-ToF (trapped ion mobility) spectrometer was developed to enhance oligomer assignment, especially for the higher-order aggregates. This approach pushes the limits of IM identification of isobaric species, whose signatures appear closer to each other with increasing oligomer size, and provides new insights into the interpretation of IM-MS data. In addition, TIMS collision cross section values are compared with traveling wave ion mobility (TWIMS) data to evaluate potential instrumental bias in the trapped ion mobility results. The two IM-MS instrumental platforms are based on different ion mobility principles and have different configurations, thereby providing us with valuable insight into the preservation of weakly bound biomolecular complexes such as peptide aggregates.

Abstract 7090: A scaled proteomic discovery study for prostate cancer diagnostic signatures using Proteograph workflow with trapped ion mobility mass spectrometry

Abstract Background and Aims: The low cancer specificity of serum Prostate-Specific Antigen (PSA), the principal biomarker for prostate cancer detection, leads to a high frequency of unwarranted prostate biopsies. To alleviate this deficit, we executed a proteomic discovery study seeking PSA reflex signatures using the Proteograph™ Product Suite, a multi-nanoparticle-based deep plasma/serum proteomics workflow (Seer, Inc.), with timsTOF Pro mass spectrometry (Bruker) to interrogate over 900 serum specimens from patients that underwent prostate biopsy due to elevated PSA and/or abnormal digital rectal exam. Methods: Our study followed rigorous design principles including uniform collection, randomization and blinding of specimens, all of which were processed with the Proteograph Product Suite. Liquid chromatography-mass spectrometry (LC-MS) analyses leveraged the Bruker timsTOF Pro MS platform utilizing 30-minute reversed-phase chromatography and a label-free dia-PASEF (data independent acquisition - parallel accumulation serial fragmentation) data acquisition method. Peptides deriving from a chosen subset of specimens designed to maximize peptide diversity were pooled, fractionated and analyzed using DDA (data-dependent acquisition)-PASEF to build a spectral reference library. Results: The DIA-NN algorithm was employed through the cloud-based Proteograph Analysis Suite (PAS) to search LC-MS data. Leveraging our study-specific spectral library proteomic depth achieved was approximately 3600 protein groups identified (median) per patient serum specimen and more than 4400 in at least 25% of samples across the study. Customized machine learning workflows and the SeerML pipeline were used to identify and assess diagnostic power of new proteomic signatures. Conclusions: Our data demonstrate the remarkable proteomic depth achievable in a scaled patient serum specimen discovery study using a combination of Proteograph and timsTOF platforms. This significant effort revealed serum proteomic signatures with increased diagnostic performance over that provided by PSA blood measurement and traditional patient-associated metadata alone, providing a foundation for future clinical tests aimed to reduce the current high frequency of unnecessary prostate biopsy. Citation Format: Mark Flory, Matthew Chang, Jessie May Cartier, Jane Lange, Travis Moore, James McGann, Ryan Kopp, Michael Liss, Robin Leach, Brenna Albracht, James Dai, Michael Krawitzky, Eltaher Elgierari, Jessica Chu, Paul Pease, Max Mahoney, Shadi Ferdosi, Ryan Benz, Khatereh Motamedchaboki, Asim Siddiqui, Mahdi Zamanighomi, Amir Alavi, Harendra Guturu, Daniel Hornburg, Serafim Batzoglou. A scaled proteomic discovery study for prostate cancer diagnostic signatures using Proteograph workflow with trapped ion mobility mass spectrometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7090.

Ion Mobility Mass Spectrometry for Large Synthetic Molecules: Expanding the Analytical Toolbox.

Understanding the composition, structure and stability of larger synthetic molecules is crucial for their design, yet currently the analytical tools commonly used do not always provide this information. In this perspective, we show how ion mobility mass spectrometry (IM-MS), in combination with tandem mass spectrometry, complementary techniques and computational methods, can be used to structurally characterize synthetic molecules, make and predict new complexes, monitor disassembly processes and determine stability. Using IM-MS, we present an experimental and computational framework for the analysis and design of complex molecular architectures such as (metallo)supramolecular cages, nanoclusters, interlocked molecules, rotaxanes, dendrimers, polymers and host-guest complexes.

Exploring the potential of using ion mobility-mass spectrometry to separate matrix interferences from analytes in food control

During residue analysis in complex matrices for food safety purposes, interfering signals can sometimes overlap with those of the analyte of interest. Access to an additional separation dimension besides chromatographic and mass separation, such as ion mobility, can aid in removing interfering signals, allowing for correct analyte identification in these cases. In our laboratory, during routine LC−MS/MS analysis of liver samples for growth promoter residues, an interfering signal was found that matches the retention time and m/z values for stanozolol, a synthetic anabolic steroid. In the present work, the performance of a liquid chromatography coupled to ion mobility mass spectrometry (LC−IM−MS) method has been evaluated to study whether this LC−MS/MS false positive in liver samples could be eliminated by LC−IM−MS analysis. A cyclic ion mobility system already allowed the separation of stanozolol from the interfering peak after only one pass, showing a significant improvement compared to the conventional LC−MS/MS method. Additionally, collisional cross section (CCS) values were calculated and successfully compared with those from literature for identification purposes, eventually allowing both the identification and quantification of stanozolol in this complex matrix.

Potential of ion mobility mass spectrometry in cellulose ether analysis: substitution pattern of hydroxyethyl celluloses

Ion mobility mass spectrometry (ESI-tims-ToF–MS, syringe pump infusion) has been applied to glucose and oligosaccharide ethers derived from hydroxyethyl-methyl celluloses (HEMC) and hydroxyethyl celluloses (HEC) after permethylation and partial depolymerization: by hydrolysis without or with subsequent reductive amination with m-amino benzoic acid (mABA) or by reductive cleavage. As model compounds without tandem substitution methoxyethylated methylcellulose was used. Regioisomeric glucose ethers were separated according to their ion mobility, and positions of substitution could be assigned. Glucose ethers including isomers with tandem substitution showed additional signals with a smaller collision cross-section (CCS) than core-substituted isomers. Positional isomers of cellobiose ethers were only partly resolved due to too high complexity but showed a characteristic fingerprint that might allow classifying samples. Relative intensities of signals of glucose ether isomers could only be quantified in case of ABA derivatives with its fixed charge, while sodium adducts of methoxyethyl ethers showed an influence of the MeOEt position on ion yield. Results were in very good agreement with reference analysis. [M + Na]+ adducts of α- and β-anomers of glucose derivatives were separated in IM, complicating position assignment. This could be overcome by reductive cleavage of the permethylated HE(M)C yielding 1,5-anhydroglucitol-terminated oligosaccharides, showing the best resolved fingerprints of the cellobiose ethers of a particular cellulose ether. With this first application of ion mobility MS to the analysis of complex cellulose ethers, the promising potential of this additional separation dimension in mass spectrometry is demonstrated and discussed.Graphical abstract

Exploring the Effects of Cyclosporin A to Isocyclosporin A Rearrangement on Ion Mobility Separation.

Cyclosporin A (CycA) is a peptide secondary metabolite derived from fungi that plays a crucial role in transplantation surgery. Cyclic traveling wave ion mobility mass spectrometry (IM-MS) revealed an N → O peptidyl shift in singly protonated CycA to isocyclosporin A (isoA), whereas no such isomerization was observed for doubly protonated and sodiated molecules. CycA and isoA were able to be separated by considering doubly protonated precursors using a specific ion fragment. In parallel, sodium ion stabilization facilitated the simultaneous separation and quantitation of singly charged cyclosporin isomers with the limit of detection and coefficient of determination of 1.3% and 0.9908 for CycA in isoA and 1.0% and 0.9830 for isoA in CycA, respectively. Finally, 1H-13C gHSQC NMR experiments permitted parallel recording of up to 11 cyclosporin conformers. The ratios were determined by integrating the volume of cross-peaks of the upfield resonating hydrogen in the diastereotopic methylene group of sarcosine-3.

Improving the Sensitivity and Linear Range of Photoionization Ion Mobility Spectrometry via Confining the Ion Recombination and Space Charge Effects Assisted by Theoretical Modeling.

Photoionization (PI) is an efficient ionization source for ion mobility spectrometry (IMS) and mass spectrometry. Its hyphenation with IMS (PI-IMS) has been employed in various on-site analysis scenarios targeting a wide range of compounds. However, the signal intensity and linear dynamic range of PI-IMS at ambient pressure usually do not follow the Beer-Lambert law predictions, and the factors causing that negative deviation remain unclear. In this work, a variable pressure PI-IMS system was developed to examine the ion loss effects from factors like ion recombination and space charge by varying its working pressure from 1 to 0.1 bar. Assisted by theoretical modeling, it was found that ion recombination could contribute up to 90% of signal intensity loss for ambient pressure PI-IMS setups. Lowering the pressure and increasing the electric field in PI-IMS helped suppress the ion recombination process and thus an optimal pressure Poptimal appeared for best signal intensity, despite the decreased net ion number density and the increased space charge effect. A simplified theoretical equation taking ion recombination as the primary ion loss factor was derived to link Poptimal with analyte concentration and electric field in PI-IMS, enabling a swift optimization of the PI-IMS performance. For example, compared to ambient pressure, PI-IMS at a Poptimal of 0.4 bar provided a signal intensity increment of more than 400% for 0.716 ppmv toluene and also expanded the linear dynamic range by more than two times. Revealing factors influencing the PI-IMS response would also benefit the applications of other chemical ionization sources in IMS or mass spectrometry (MS).

Differentiating enantiomers by directional rotation of ions in a mass spectrometer

Conventional mass spectrometry does not distinguish between enantiomers, or mirror-image isomers. Here we report a technique to break the chiral symmetry and to differentiate enantiomers by inducing directional rotation of chiral gas-phase ions. Dual alternating current excitations were applied to manipulate the motions of trapped ions, including the rotation around the center of mass and macro movement around the center of the trap. Differences in collision cross section were induced, which could be measured by ion cloud profiling at high resolutions above 10,000. High-field ion mobility and tandem mass spectrometry analyses of the enantiomers were combined and implemented by using a miniature ion trap mass spectrometer. The effectiveness of the developed method was demonstrated with a variety of organic compounds including amino acids, sugars, and several drug molecules, as well as a proof-of-principle ligand optimization study for asymmetric hydrogenation.

Two-dimensional carbon allotrope with remarkable electron mobility and tunable band gap under uniaxial strain engineering

Exploring two-dimensional (2D) materials with unique structures and excellent photoelectric properties has always been the foundation content of carbon-based material science and condensed matter physics research. In this work, on the basis of density functional theory, the structural, mechanical, electrical and optical properties of the pure sp2 hybrid 2D carbon allotropes Orth-C14 and Orth-C16 were comprehensively predicted, and the regulatory mechanism of the uniaxial strain on the stability, elastic mechanics and electronic properties were analysed. Orth-C16 and Orth-C14 are semiconductors and metals with extremely narrow bandgaps, respectively. Interestingly, their electronic properties could be tuned to indirect band gap semiconductors, metals or half-metallic states with Dirac cones by applying uniaxial strain. In addition, the extremely low effective mass (0.009 m0) and remarkable room temperature electron mobility (69,708 cm2V-1s-1) of approximately 70 times greater than that of black phosphorene (1100 ∼ 1140 cm2V-1s-1), as well as the strong absorption capacity of visible light, all of these advantages indicate that Orth-C16 has crucial development potential in the field of electronic information and optoelectronics.

AutonoMS: Automated Ion Mobility Metabolomic Fingerprinting.

Automation is dramatically changing the nature of laboratory life science. Robotic lab hardware that can perform manual operations with greater speed, endurance, and reproducibility opens an avenue for faster scientific discovery with less time spent on laborious repetitive tasks. A major bottleneck remains in integrating cutting-edge laboratory equipment into automated workflows, notably specialized analytical equipment, which is designed for human usage. Here we present AutonoMS, a platform for automatically running, processing, and analyzing high-throughput mass spectrometry experiments. AutonoMS is currently written around an ion mobility mass spectrometry (IM-MS) platform and can be adapted to additional analytical instruments and data processing flows. AutonoMS enables automated software agent-controlled end-to-end measurement and analysis runs from experimental specification files that can be produced by human users or upstream software processes. We demonstrate the use and abilities of AutonoMS in a high-throughput flow-injection ion mobility configuration with 5 s sample analysis time, processing robotically prepared chemical standards and cultured yeast samples in targeted and untargeted metabolomics applications. The platform exhibited consistency, reliability, and ease of use while eliminating the need for human intervention in the process of sample injection, data processing, and analysis. The platform paves the way toward a more fully automated mass spectrometry analysis and ultimately closed-loop laboratory workflows involving automated experimentation and analysis coupled to AI-driven experimentation utilizing cutting-edge analytical instrumentation. AutonoMS documentation is available at https://autonoms.readthedocs.io.

CE-MS/MS and CE-timsTOF to separate and characterize intramolecular disulfide bridges of monoclonal antibody subunits and their application for the assessment of subunit reduction protocols

Characterization at the subunit level enables detailed mass spectrometric characterization of posttranslational modifications (PTMs) of monoclonal antibodies (mAbs). The implemented reduction often leaves the intramolecular disulfide bridges intact. Here, we present a capillary electrophoretic (CE) method based on a neutral-coated capillary for the separation of immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) digested and reduced mAb subunits followed by mass spectrometry (MS), MS/MS identification, and trapped ion mobility mass spectrometry (timsTOF). Our CE approach enables the separation of (i) different subunit moieties, (ii) various reduction states, and (iii) positional isomers of these partly reduced subunit moieties. The location of the remaining disulfide bridges can be determined by middle-down electron transfer higher energy collisional dissociation (EThcD) experiments. All these CE-separated variants show differences in ion mobility in the timsTOF measurements. Applying the presented CE-MS/MS method, reduction parameters such as the use of chaotropic salts were studied. For the investigated antibodies, urea improved the subunit reduction significantly, whereas guanidine hydrochloride (GuHCl) leads to multiple signals of the same subunit in the CE separation. The presented CE-MS method is a powerful tool for the disulfide-variant characterization of mAbs on the subunit level. It enables understanding disulfide bridge reduction processes in antibodies and potentially other proteins.

Flow front mobility of rock avalanches as a function of flow volume, grain size, channel width, basal friction and flow scale

AbstractThe ability to predict the mobility of rock avalanches is necessary when designing strategies to mitigate the risks they pose. A popular mobility indicator of the flow front is the Heim’s apparent friction coefficient $${\mu }_{H}$$ μ H . In the field, $${\mu }_{H}$$ μ H shows a decrease in value as flow volume V increases. But this correlation has been a mystery as to whether it is due to a causal relationship between V and mobility since: (1) field data of $${\mu }_{H}$$ μ H do not collapse onto a single curve because typically widely scattered and (2) laboratory experiments have shown an opposite volume effect on the center of mass mobility of miniature flows. My numerical simulations confirm for the first time the existence of a functional relationship of scaling parameters where $${\mu }_{H}$$ μ H decreases as V increases in unsteady and nonuniform 3D flows. Data scatter is caused by $${\mu }_{H}$$ μ H that is affected by numerous other variables besides V. The interplay of these variables produces different granular regimes with opposite volume effects. In particular, $${\mu }_{H}$$ μ H decreases as V increases in the regime characterized by a relatively rough subsurface. The relationship holds for large-scale flows that, like rock avalanches, consist of a very large number of fine clasts traveling in wide channels. In these dense flows, flow front mobility increases as flow volume increases, as channel width increases, as grain size decreases, as basal friction decreases and as flow scale increases. Larger-scale flows are more mobile because they have larger Froude number values.

Nitrile Imines as Peptide and Oligonucleotide Photo-Cross-Linkers in Gas-Phase Ions.

Nitrile imines produced by photodissociation of 2,5-diaryltetrazoles undergo cross-linking reactions with amide groups in peptide-tetrazole (tet-peptide) conjugates and a tet-peptide-dinucleotide complex. Tetrazole photodissociation in gas-phase ions is efficient, achieving ca. 50% conversion with 2 laser pulses at 250 nm. The formation of cross-links was detected by CID-MS3 that showed structure-significant dissociations by loss of side-chain groups and internal peptide segments. The structure and composition of cross-linking products were established by a combination of UV-vis action spectroscopy and cyclic ion mobility mass spectrometry (c-IMS). The experimental absorption bands were found to match the bands calculated for vibronic absorption spectra of nitrile imines and cross-linked hydrazone isomers. The calculated collision cross sections (CCSth) for these ions were related to the matching experimental CCSexp from multipass c-IMS measurements. Loss of N2 from tet-peptide conjugates was calculated to be a mildly endothermic reaction with ΔH0 = 80 kJ mol-1 in the gas phase. The excess energy in the photolytically formed nitrile imine is thought to drive endothermic proton transfer, followed by exothermic cyclization to a sterically accessible peptide amide group. The exothermic nitrile imine reaction with peptide amides is promoted by proton transfer and may involve an initial [3 + 2] cycloaddition followed by cleavage of the oxadiazole intermediate. Nucleophilic groups, such as cysteine thiol, did not compete with the amide cyclization. Nitrile imine cross-linking to 2'-deoxycytidylguanosine was found to be >80% efficient and highly specific in targeting guanine. The further potential for exploring nitrile-imine cross-linking for biomolecular structure analysis is discussed.