Assessing r2SCAN meta-GGA functional for structural parameters, cohesive energy, mechanical modulus, and thermophysical properties of 3d, 4d, and 5d transition metals.

The recent development of accurate and efficient semilocal density functionals on the third rung of Jacob's ladder of density functional theory, such as the revised regularized strongly constrained and appropriately normed (r2SCAN) density functional, could enable rapid and highly reliable prediction of the elasticity and temperature dependence of thermophysical parameters of refractory elements and their intermetallic compounds using the quasi-harmonic approximation (QHA). Here, we present a comparative evaluation of equilibrium cell volumes, cohesive energy, mechanical moduli, and thermophysical properties (Debye temperature and thermal expansion coefficient) for 22 transition metals using semilocal density functionals, including the local density approximation (LDA), Perdew-Burke-Ernzerhof (PBE) and PBEsol generalized gradient approximations (GGAs), and the r2SCAN meta-GGA. PBEsol and r2SCAN deliver the same level of accuracies for structural, mechanical, and thermophysical properties. PBE and r2SCAN perform better than LDA and PBEsol for calculating cohesive energies of transition metals. Among the tested density functionals, r2SCAN provides an overall well-balanced performance for reliably computing cell volumes, cohesive energies, mechanical properties, and thermophysical properties of various 3d, 4d, and 5d transition metals using QHA. Therefore, we recommend that r2SCAN could be employed as a workhorse method to evaluate thermophysical properties of transition metal compounds and alloys in high throughput workflows.

Improved ion adsorption capacities and diffusion dynamics in surface anchored MoS2⊥Mo4/3B2 and MoS2⊥Mo4/3B2O2 heterostructures as anodes for alkaline metal-ion batteries.

First-principles calculations were performed to analyze the atomic structures and electrochemical energy storage properties of novel MoS2⊥boridene heterostructures by anchoring MoS2 nanoflakes on Mo4/3B2 and Mo4/3B2O2 monolayers. Both thermodynamic and thermal stabilities of each heterostructure were thoroughly evaluated from the obtained binding energies and through first-principles molecular dynamics simulations at room temperature, confirming the high formability of the heterostructures. The electrochemical properties of MoS2⊥Mo4/3B2 and MoS2⊥Mo4/3B2O2 heterostructures were investigated for their potential use as anodes for alkaline metal ion batteries (Li+, Na+ and K+). It was revealed that Li+ and Na+ can form multiple stable full adsorption layers on both heterostructures, while K+ forms only a single full adsorption layer. The presence of a negative electron cloud (NEC) contributes to the stabilization of a multi-layer adsorption mechanism. For all investigated alkaline metal ions, the predicted ion diffusion dynamics are relatively sluggish for the adsorbates in the first full adsorption layer on MoS2⊥boridene heterostructures due the relatively large migration energies (>0.50 eV), compared to those of second or third full adsorption layers (<0.30 eV). MoS2⊥Mo4/3B2O2 exhibited higher onset and mean open circuit voltages as anodes for alkaline metal-ion batteries than MoS2⊥Mo4/3B2 hybrids because of enhanced interactions between the adsorbate and the Mo4/3B2O2 monolayer with the presence of O-terminations. Tailoring the size and horizontal spacing between two neighboring MoS2 nano-flakes in heterostructures led to high theoretical capacities for LIBs (531 mA h g-1), SIBs (300 mA h g-1) and PIBs (131 mA h g-1) in the current study.

Mass spectrometry quantifies target engagement for a KRASG12C inhibitor in FFPE tumor tissue.

BACKGROUND: Quantification of drug-target binding is critical for confirming that drugs reach their intended protein targets, understanding the mechanism of action, and interpreting dose-response relationships. For covalent inhibitors, target engagement can be inferred by free target levels before and after treatment. Targeted mass spectrometry assays offer precise protein quantification in complex biological samples and have been routinely applied in pre-clinical studies to quantify target engagement in frozen tumor tissues for oncology drug development. However, frozen tissues are often not available from clinical trials so it is critical that assays are applicable to formalin-fixed, paraffin-embedded (FFPE) tissues in order to extend mass spectrometry-based target engagement studies into clinical settings. METHODS: Wild-type RAS and RASG12C was quantified in FFPE tissues by a highly optimized targeted mass spectrometry assay that couples high-field asymmetric waveform ion mobility spectrometry (FAIMS) and parallel reaction monitoring (PRM) with internal standards. In a subset of samples, technical reproducibility was evaluated by analyzing consecutive tissue sections from the same tumor block and biological variation was accessed among adjacent tumor regions in the same tissue section. RESULTS: Wild-type RAS protein was measured in 32 clinical non-small cell lung cancer tumors (622-2525 amol/µg) as measured by FAIMS-PRM mass spectrometry. Tumors with a known KRASG12C mutation (n = 17) expressed a wide range of RASG12C mutant protein (127-2012 amol/µg). The variation in wild-type RAS and RASG12C measurements ranged 0-18% CV across consecutive tissue sections and 5-20% CV among adjacent tissue regions. Quantitative target engagement was then demonstrated in FFPE tissues from 2 xenograft models (MIA PaCa-2 and NCI-H2122) treated with a RASG12C inhibitor (AZD4625). CONCLUSIONS: This work illustrates the potential to expand mass spectrometry-based proteomics in preclinical and clinical oncology drug development through analysis of FFPE tumor biopsies.

Top-down mass spectrometry for characterizing the low molecular weight proteome of canine osteosarcoma cell phenotypes.

Osteosarcoma (OS) is the most common primary malignant tumor of bone, which occupying about 20% of all bone cancers. To increase understanding of the biology of OS, we developed and evaluated a top-down mass spectrometry approach to detect, identify and quantify low molecular weight (MW) proteins (i.e., 1 kDa < MW < 30 kDa) in osteosarcoma cells. Top-down proteomic (TDP) data was acquired using reversed phase nano-liquid chromatography in conjunction with high-resolution mass spectrometry and resulted in the assignment of 328 proteins and 820 proteoforms or degradation products with high confidence. Eight post-translational modifications (PTMs) were identified in the present study, including N-terminal acetylation, lysine acetylation, succinylation, malonylation, serine/tyrosine phosphorylation, histidine methylation and N-acetylleucine. We confirmed that a truncated N-terminal proteoform lost 73 Da of mass through removal of the N-terminal Met (-131 Da), acetylation of the second amino acid (+42 Da), and Met oxidation (+16 Da). The results showed that the levels of proteoforms/biodegradable peptides correlated with the metastatic phenotypes of osteosarcoma cell lines. This study demonstrates the benefits of TDP for the characterization and relative quantification of proteoforms with relevance to OS biology and the potential of small molecular weight proteoforms to serve as a still underappreciated source of biomarkers.

Prediction of boridenes as high-performance anodes for alkaline metal and alkaline Earth metal ion batteries.

We conducted a comprehensive density functional theory investigation using the r2SCAN-rVV10 functional on the structural stability and electrochemical properties of boridenes for their use as anode materials in rechargeable alkaline (earth) metal-ion batteries (Li+, Na+, K+, Mg2+ and Ca2+). According to first-principles molecular dynamics simulations and reaction thermodynamic calculations, Mo4/3B2(OH)2 and Mo4/3B2F2 are unstable in the presence of alkaline (earth) metal ions due to the surface-conversion reactions between the surface terminations and adsorbates. Meanwhile, the bare Mo4/3B2 and Mo4/3B2O2 monolayers not only can accommodate alkaline (earth) metal ions, but also form stable multi-layer adsorption structures for most of the studied metal ions (Li+, Na+, K+, Mg2+ and Ca2+). The predicted gravimetric capacities of the bare Mo4/3B2 monolayer (Mo4/3B2O2) are 625.9 mA h g-1 (357.3 mA h g-1), 247.20 mA h g-1 (392.1 mA h g-1), 101.8 mA h g-1 (206.4 mA h g-1), 667.0 mA h g-1, and 413.0 mA h g-1 (485.4 mA h g-1) for Li+, Na+, K+, Mg2+ and Ca2+ ions, respectively. The bare Mo4/3B2 exhibits lower onset charging open circuit voltages for alkaline (earth) metal ions than that of Mo4/3B2O2. The diffusivities of the metal ions were revealed to be high on the boridene monolayer especially for the outer fully stable adsorption layers, where the migration energy barriers were found to be less than 0.10 eV. Similar to that of MXenes, the negative electron cloud (NEC) also plays a vital role in stabilizing the observed multi-layer adsorption structures for various metal ions on either the bare Mo4/3B2 or Mo4/3B2O2 monolayer.

First Indirect Drive Experiment Using a Six-Cylinder-Port Hohlraum.

The new hohlraum experimental platform and the quasi-3D simulation model are developed to enable the study of the indirect drive experiment using the six-cylinder-port hohlraum for the first time. It is also the first implosion experiment for the six laser-entrance-hole hohlraum to effectively use all the laser beams of the laser facility that is primarily designed for the cylindrical hohlraum. The experiments performed at the 100 kJ Laser Facility produce a peak hohlraum radiation temperature of ∼222 eV for ∼80 kJ and 2 ns square laser pulse. The inferred x-ray conversion efficiency η∼87% is similar to the cylindrical hohlraum and higher than the octahedral spherical hohlraum at the same laser facility, while the low laser backscatter is similar to the outer cone of the cylindrical hohlraum. The hohlraum radiation temperature and M-band (>1.6 keV) flux can be well reproduced by the quasi-3D simulation. The variations of the yield-over-clean and the hot spot shape can also be semiquantitatively explained by the calculated major radiation asymmetry of the quasi-3D simulation. Our work demonstrates the capability for the study of the indirect drive with the six-cylinder-port hohlraum at the cylindrically configured laser facility, which is essential for numerically assessing the laser energy required by the ignition-scale six-cylinder-port hohlraum.

First Inertial Confinement Fusion Implosion Experiment in Octahedral Spherical Hohlraum.

In inertial confinement approaches to fusion, the asymmetry of target implosion is a major obstacle to achieving high gain in the laboratory. A recently proposed octahedral spherical hohlraum makes it possible to naturally create spherical target irradiation without supplementary symmetry control. Before any decision is made to pursue an ignition-scale laser system based on the octahedral hohlraum, one needs to test the concept with the existing facilities. Here, we report a proof-of-concept experiment for the novel octahedral hohlraum geometry on the cylindrically configured SGIII laser facility without a symmetry control. All polar and equatorial self-emission images of the compressed target show a near round shape of convergence ratio 15 under both square and shaped laser pulses. The observed implosion performances agree well with the ideal spherical implosion simulation. It also shows limitations with using the existing facilities and adds further weight to the need to move to a spherical port geometry for future ignition laser facilities.

Plasma Lipidomic Patterns in Patients with Symptomatic Coronary Microvascular Dysfunction.

Coronary microvascular dysfunction (MVD) is a syndrome of abnormal regulation of vascular tone, particularly during increased metabolic demand. While there are several risk factors for MVD, some of which are similar to those for coronary artery disease (CAD), the cause of MVD is not understood. We hypothesized that MVD in symptomatic non-elderly subjects would be characterized by specific lipidomic profiles. Subjects (n = 20) aged 35-60 years and referred for computed tomography coronary angiography (CTA) for chest pain but who lacked obstructive CAD (>50% stenosis), underwent quantitative regadenoson stress-rest myocardial contrast echocardiography (MCE) perfusion imaging for MVD assessment. The presence of MVD defined by kinetic analysis of MCE data was correlated with lipidomic profiles in plasma measured by liquid chromatography and high-resolution mass spectrometry. Nine of twenty subjects had evidence of MVD, defined by reduced hyperemic perfusion versus other subjects (beta-value 1.62 ± 0.44 vs. 2.63 ± 0.99 s-1, p = 0.009). Neither the presence of high-risk but non-obstructive CAD on CTA, nor CAD risk factors were different for those with versus without MVD. Lipidomic analysis revealed that patients with MVD had lower concentrations of long-carbon chain triacylglycerols and diacylglycerols, and higher concentrations of short-chain triacylglycerols. The diacylglycerol containing stearic and linoleic acid classified all participants correctly. We conclude that specific lipidomic plasma profiles occur in MVD involving saturated long-chain fatty acid-containing acylglycerols that are distinctly different from those in non-obstructive CAD. These patterns could be used to better characterize the pathobiology and potential treatments for this condition.

A neutron time-of-flight system for inertial confinement fusion.

A neutron time-of-flight (nTOF) system has been implemented at the largest laser facility in China. The nTOF system is used to measure neutron spectra in inertial confinement fusion experiments. The nTOF system consists of 11 fast plastic scintillation detectors. The detectors employed three designs to measure neutron yield, ion temperature, and neutron bang time. The nTOF system is capable of measuring the primary neutron yield from 107 to 1013, secondary DT neutron yield from 106 to 108, and ion temperature and neutron bang time yields from 108 to 1013. The accuracies of the nTOF system are about 10% for neutron yield and ion temperature measurements and better than 60 ps for neutron bang time measurements. The nTOF system has become one of the most important diagnostics for implosions, and it is used for more than 200 shots per year.

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities.

Osteosarcoma (OS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. The proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined. To link metastatic propensity to a hypoxia-induced proteotype, we compared the protein profiles of two isogenic canine OS cell lines, POS (low metastatic) and HMPOS (highly metastatic), under normoxia and hypoxia. Label-free shotgun proteomics was applied to comprehensively characterize the hypoxia-responsive proteome profiles in the OS cell phenotypes. Hypothesis-driven parallel reaction monitoring was used to validate the differential proteins observed in the shotgun data and to monitor proteins of which we expected to exhibit hypoxia responsiveness, but which were absent in the label-free shotgun data. We established a "distance" score (|zHMPOS - zPOS|), and "sensitivity" score (|zHypoxia - zNormoxia) to quantitatively evaluate the proteome shifts exhibited by OS cells in response to hypoxia. Evaluation of the sensitivity scores for the proteome shifts observed and principal component analysis of the hypoxia-responsive proteins indicated that both cell types acquire a proteome that supports a Warburg phenotype with enhanced cell migration and proliferation characteristics. Cell migration and glucose uptake assays combined with protein function inhibitor studies provided further support that hypoxia-driven adaption of pathways associated with glycolytic metabolism, collagen biosynthesis and remodeling, redox regulation and immunomodulatory proteins typify a proteotype associated with an aggressive cancer cell phenotype. Our findings further suggest that proteins involved in collagen remodeling and immune editing may warrant further evaluation as potential targets for anti-metastatic treatment strategies in osteosarcoma.

Ion temperature measurements of indirect-drive implosions with the neutron time-of-flight detector on SG-III laser facility.

The accuracy of the determination of the burn-averaged ion temperature of inertial confinement fusion implosions depends on the unfold process, including deconvolution and convolution methods, and the function, i.e., the detector response, used to fit the signals measured by neutron time-of-flight (nToF) detectors. The function given by Murphy et al. [Rev. Sci. Instrum. 68(1), 610-613 (1997)] has been widely used in Nova, Omega, and NIF. There are two components, i.e., fast and slow, and the contribution of scattered neutrons has not been dedicatedly considered. In this work, a new function, based on Murphy's function has been employed to unfold nToF signals. The contribution of scattered neutrons is easily included by the convolution of a Gaussian response function and an exponential decay. The ion temperature is measured by nToF with the new function. Good agreement with the ion temperature determined by the deconvolution method has been achieved.

Coaxial CVD diamond detector for neutron diagnostics at ShenGuang III laser facility.

A coaxial, high performance diamond detector has been developed for neutron diagnostics of inertial confinement fusion at ShenGuangIII laser facility. A Φ10 mm × 1 mm "optical grade" chemical-vapor deposition diamond wafer is assembled in coaxial-designing housing, and the signal is linked to a SubMiniature A connector by the cathode cone. The coaxial diamond detector performs excellently for neutron measurement with the full width at half maximum of response time to be 444 ps for a 50 Ω measurement system. The average sensitivity is 0.677 µV ns/n for 14 MeV (DT fusion) neutrons at an electric field of 1000 V/mm, and the linear dynamic range is beyond three orders of magnitude. The ion temperature results fluctuate widely from the neutron time-of-flight scintillator detector results because of the short flight length. These characteristics of small size, large linear dynamic range, and insensitive to x-ray make the diamond detector suitable to measure the neutron yield, ion temperature, and neutron emission time.

Note: neutron bang time diagnostic system on Shenguang-III prototype.

A neutron bang time (NBT) diagnostic system has been implemented on Shenguang-III prototype. The bang time diagnostic system is based on a sensitive fusion neutron detector, which consists of a plastic scintillator and a micro-channel plate photomultiplier tube (PMT). An optical fiber bundle is used to couple the scintillator and the PMT. The bang time system is able to measure bang time above a neutron yield of 10(7). Bang times and start time of laser were related by probing x-ray pulses produced by 200 ps laser irradiating golden targets. Timing accuracy of the NBT is better than 60 ps.

Dual matrix-based immobilized trypsin for complementary proteolytic digestion and fast proteomics analysis with higher protein sequence coverage.

In an age of whole-genome analysis, the mass spectrometry-based bottom-up strategy is now considered to be the most powerful method for in-depth proteomics analysis. As part of this strategy, highly efficient and complete proteolytic digestion of proteins into peptides is crucial for successful proteome profiling with deep coverage. To achieve this goal, prolonged digestion time and the use of multiple proteases have been adopted. The long digestion time required and tedious sample treatment steps severely limit the sample processing throughput. Though utilization of immobilized protease greatly reduces the digestion time, highly efficient proteolysis of extremely complex proteomic samples remains a challenging task. Here, we propose a dual matrix-based complementary digestion method using two types of immobilized trypsin with opposite matrix hydrophobicity prepared by attaching trypsin on hydrophobic or hydrophilic polymer-brush-modified nanoparticles. The polymer brushes on the nanoparticles serve as three-dimensional supports for a large amount of trypsin immobilization and lead to ultrafast and highly efficient protein digestion. More importantly, the two types of immobilized trypsin show high complementarity in protein digestion with only ∼60% overlap in peptide identification for yeast and membrane protein of mouse liver. Complementary digestion by applying these two types of immobilized trypsin together leads to obviously enhanced protein and peptide identification. Furthermore, the dual matrix-based complementary digestion shows particular advantage in the digestion of membrane proteins, as twice the number of identified peptides is obtained compared with solution digestion using free proteases, demonstrating its potential as a promising alternative to promote proteomics analysis with higher protein sequence coverage.

[A novel immobilized trypsin on hydrophilic polymer modified Silica beads for proteome characterization].

A new type of immobilized trypsin was prepared using hydrophilic polymer modified silica microparticles (HPMSM) synthesized by atom transfer radical polymerization (ATRP) as the substrate material. ATRP modification led to densely packed hydrophilic polymer chains grafted on the microparticles surface which resulted in largely increased trypsin loading amount and minimized the nonspecific adsorption of proteins and peptides. Therefore, ultra-fast and highly efficient protein digestion was achieved with minimized sample loss. For standard protein bovine serum albumin (BSA), 1 min digestion led to the identification of 93 peptides, which covered 91% amino acid sequence of the protein. This immobilized trypsin was further successfully applied to the digestion of complex protein samples from yeast and 666 proteins were identified after 3 min digestion, which exceeded the number of identified proteins after 12 h solution digestion.

[Trypsin immobilization on silica beads modified by squamous polymer for ultra fast and highly efficient proteome digestion].

Currently, the shotgun based strategy has been widely applied in proteomic research. In this strategy, protein identification relied on the identification of the corresponding proteolytic peptides. Therefore, rapid and efficient protein digestion is crucial for accurate protein identification and characterization. Even though traditional free protein digestion in solution has been widely adopted, it had a few inherent disadvantages including long incubation time, incomplete digestion and non-reusability of the protease. In this work, we developed a new type of trypsin immobilized on squamous polymer modified silica bead (SPMSB) for ultra fast and highly efficient protein digestion. The squamous polymer coated silica beads were prepared by surface initiated atom transfer radical polymerization (SI-ATRP), which leaded to surface confined growth of non-crosslinked polymer chains on the sufface of the silica beads for trypsin immobilization. The digestion efficiency of the obtained SPMSB-trypsin was evaluated using both standard proteins and complex protein extracts obtained from E. coil. Highly efficient digestion was achieved in only 1 - 2 mm digestion. Furthermore, the SPMSB-Trypsin exhibited both good stability and excellent recovery, therefore can be applied in proteomic research in the future.

Trypsin immobilization on hairy polymer chains hybrid magnetic nanoparticles for ultra fast, highly efficient proteome digestion, facile 18O labeling and absolute protein quantification.

In recent years, quantitative proteomic research attracts great attention because of the urgent needs in biological and clinical research, such as biomarker discovery and verification. Currently, mass spectrometry (MS) based bottom up strategy has become the method of choice for proteomic quantification. In this strategy, the amount of proteins is determined by quantifying the corresponding proteolytic peptides of the proteins, therefore highly efficient and complete protein digestion is crucial for achieving accurate quantification results. However, the digestion efficiency and completeness obtained using conventional free protease digestion is not satisfactory for highly complex proteomic samples. In this work, we developed a new type of immobilized trypsin using hairy noncross-linked polymer chains hybrid magnetic nanoparticle as the matrix aiming at ultra fast, highly efficient proteomic digestion and facile (18)O labeling for absolution protein quantification. The hybrid nanoparticle is synthesized by in situ growth of hairy polymer chains from the magnetic nanoparticle surface using surface initiated atom transfer radical polymerization technique. The flexible noncross-linked polymer chains not only provide large amount of binding sites but also work as scaffolds to support three-dimensional trypsin immobilization which leads to increased loading amount and improved accessibility of the immobilized trypsin. For complex proteomic samples, obviously increased digestion efficiency and completeness was demonstrated by 27.2% and 40.8% increase in the number of identified proteins and peptides as well as remarkably reduced undigested proteins residues compared with that obtained using conventional free trypsin digestion. The successful application in absolute protein quantification of enolase from Thermoanaerobacter tengcongensis protein extracts using (18)O labeling and MRM strategy further demonstrated the potential of this hybrid nanoparticle immobilized trypsin for high throughput proteome quantification.

Study on boron-film thermal neutron converter prepared by pulsed laser deposition.

The boron film converter used in the position-sensitive thermal neutron detector is discussed and the method of preparing this converter layer via Pulsed Laser Deposition (PLD) is introduced. The morphology and the composition were studied by Scanning Electron Microscopy (SEM) and X-ray Photoelectron Spectroscopy (XPS). Both boron and boride existed on the layer surface. It was shown that the energy intensity of laser beam and the substrate temperature both had an important influence on the surface morphology of the film.