The ‘ForensOMICS’ approach for postmortem interval estimation from human bone by integrating metabolomics, lipidomics, and proteomics

The combined use of multiple omics allows to study complex interrelated biological processes in their entirety. We applied a combination of metabolomics, lipidomics and proteomics to human bones to investigate their combined potential to estimate time elapsed since death (i.e., the postmortem interval [PMI]). This 'ForensOMICS' approach has the potential to improve accuracy and precision of PMI estimation of skeletonized human remains, thereby helping forensic investigators to establish the timeline of events surrounding death. Anterior midshaft tibial bone was collected from four female body donors before their placement at the Forensic Anthropology Research Facility owned by the Forensic Anthropological Center at Texas State (FACTS). Bone samples were again collected at selected PMIs (219-790-834-872days). Liquid chromatography mass spectrometry (LC-MS) was used to obtain untargeted metabolomic, lipidomic, and proteomic profiles from the pre- and post-placement bone samples. The three omics blocks were investigated independently by univariate and multivariate analyses, followed by Data Integration Analysis for Biomarker discovery using Latent variable approaches for Omics studies (DIABLO), to identify the reduced number of markers describing postmortem changes and discriminating the individuals based on their PMI. The resulting model showed that pre-placement metabolome, lipidome and proteome profiles were clearly distinguishable from post-placement ones. Metabolites in the pre-placement samples suggested an extinction of the energetic metabolism and a switch towards another source of fuelling (e.g., structural proteins). We were able to identify certain biomolecules with an excellent potential for PMI estimation, predominantly the biomolecules from the metabolomics block. Our findings suggest that, by targeting a combination of compounds with different postmortem stability, in the future we could be able to estimate both short PMIs, by using metabolites and lipids, and longer PMIs, by using proteins

Investigation of initiation of gigantic jets connecting thunderclouds to the ionosphere

The initiation of giant electrical discharges called as "gigantic jets" connecting thunderclouds to the ionosphere is investigated by numerical simulation method in this paper. Using similarity relations, the triggering conditions of streamer formation in laboratory situations are extended to form a criterion of initiation of gigantic jets. The energy source causing a gigantic jet is considered due to the quasi-electrostatic field generated by thunderclouds. The electron dynamics from ionization threshold to streamer initiation are simulated by the Monte Carlo technique. It is found that gigantic jets are initiated at a height of ~18-24 km. This is in agreement with the observations. The method presented in this paper could be also applied to the analysis of the initiation of other discharges such as blue jets and red sprites.Comment: 12th International Congress on Plasma Physics, 25-29 October 2004, Nice (France

Convection and electrodynamic signatures in the vicinity of a Sun-aligned arc: Results from the Polar Acceleration Regions and Convection Study (Polar ARCS)

An experimental campaign designed to study high-latitude auroral arcs was conducted in Sondre Stromfjord, Greenland, on February 26, 1987. The Polar Acceleration Regions and Convection Study (Polar ARCS) consisted of a coordinated set of ground-based, airborne, and sounding rocket measurements of a weak, sun-aligned arc system within the duskside polar cap. A rocket-borne barium release experiment, two DMSP satellite overflights, all-sky photography, and incoherent scatter radar measurements provided information on the large-scale plasma convection over the polar cap region while a second rocket instrumented with a DC magnetometer, Langmuir and electric field probes, and an electron spectrometer provided measurements of small-scale electrodynamics. The large-scale data indicate that small, sun-aligned precipitation events formed within a region of antisunward convection between the duskside auroral oval and a large sun-aligned arc further poleward. This convection signature, used to assess the relationship of the sun-aligned arc to the large-scale magnetospheric configuration, is found to be consistent with either a model in which the arc formed on open field lines on the dusk side of a bifurcated polar cap or on closed field lines threading an expanded low-latitude boundary layer, but not a model in which the polar cap arc field lines map to an expanded plasma sheet. The antisunward convection signature may also be explained by a model in which the polar cap arc formed on long field lines recently reconnected through a highly skewed plasma sheet. The small-scale measurements indicate the rocket passed through three narrow (less than 20 km) regions of low-energy (less than 100 eV) electron precipitation in which the electric and magnetic field perturbations were well correlated. These precipitation events are shown to be associated with regions of downward Poynting flux and small-scale upward and downward field-aligned currents of 1-2 micro-A/sq m. The paired field-aligned currents are associated with velocity shears (higher and lower speed streams) embedded in the region of antisunward flow

First E region observations of mesoscale neutral wind interaction with auroral arcs

We report the first observations of E region neutral wind fields and their interaction with auroral arcs at mesoscale spatial resolution during geomagnetically quiet conditions at Mawson, Antarctica. This was achieved by using a scanning Doppler imager, which can observe thermospheric neutral line-of-sight winds and temperatures simultaneously over a wide field of view. In two cases, the background E region wind field was perpendicular to an auroral arc, which when it appeared caused the wind direction within ∼50 km of the arc to rotate parallel along the arc, reverting to the background flow direction when the arc disappeared. This was observed under both westward and eastward plasma convection. The wind rotations occurred within 7–16 min. In one case, as an auroral arc propagated from the horizon toward the local zenith, the background E region wind field became significantly weaker but remained unaffected where the arc had not passed through. We demonstrate through modeling that these effects cannot be explained by height changes in the emission layer. The most likely explanation seems to be the greatly enhanced ion drag associated with the increased plasma density and localized ionospheric electric field associated with auroral arcs. In all cases, the F region neutral wind appeared less affected by the auroral arc, although its presence is clear in the data

Integral cross sections for electron scattering by ground state Ba atoms

We have used the convergent close-coupling method and a unitarized first-order many-body theory to calculate integral cross sections for elastic scattering and momentum transfer, for excitation of the 5d^2 ^1S, 6s6p^1P_1, 6s7p^1P_1, 6s8p^1P_1, 6s5d^1D_2, 5d^2^1D_2, 6s6d^1D_2, 6p5d^1F_3, 6s4f^1F_3, 6p5d^1D_2, 6s6p^3P_{0,1,2}, 6s5d^3D_{1,2,3}, and 6p5d^3D_2 states, for ionization and for total scattering by electron impact on the ground state of barium at incident electron energies from 1 to 1000 eV. These results and all available experimental data have been combined to produce a recommended set of integral cross sections.Comment: 47 pages, 8 tables, 25 figure

Belle II Technical Design Report

The Belle detector at the KEKB electron-positron collider has collected almost 1 billion Y(4S) events in its decade of operation. Super-KEKB, an upgrade of KEKB is under construction, to increase the luminosity by two orders of magnitude during a three-year shutdown, with an ultimate goal of 8E35 /cm^2 /s luminosity. To exploit the increased luminosity, an upgrade of the Belle detector has been proposed. A new international collaboration Belle-II, is being formed. The Technical Design Report presents physics motivation, basic methods of the accelerator upgrade, as well as key improvements of the detector.Comment: Edited by: Z. Dole\v{z}al and S. Un

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer

Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target

Matrix-assisted laser desorption ionization hydrogen/deuterium exchange studies to probe peptide conformational changes

AbstractHydrogen/deuterium (H/D) exchange chemistry monitored by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry is used to study solution phase conformational changes of bradykinin, α-melanocyte stimulating hormone, and melittin as water is added to methanol-d4, acetonitrile, and isopropanol-d8 solutions. The results are interpreted in terms of a preference for the peptides to acquire more compact conformations in organic solvents as compared to the random conformations. Our interpretation is supported by circular dichroism spectra of the peptides in the same solvent systems and by previously published structural data for the peptides. These results demonstrate the utility of MALDI-TOF as a method to monitor the H/D exchange chemistry of peptides and investigations of solution-phase conformations of biomolecules

Institutions for Asian Connectivity

To make Asia more economically sustainable and resilient against external shocks, regional economies need to be rebalanced toward regional demand- and trade-driven growth through increased regional connectivity. The effectiveness of connectivity depends on the quality of hard and soft infrastructure. Of particular importance in terms of soft infrastructure which makes hard infrastructure work are the facilitating institutions that support connectivity through appropriate policies, reforms, systems, and procedures and through promoting effective coordination and cooperation. Asia has many overlapping subregional institutions involved in national and regional energy, transport, and telecommunications infrastructure connectivity. However, these institutions are characterized as being less effective, informal, and lacking a clear and binding system of rules and policies. This paper draws linkages between connectivity, growth and development, governance, and institutions. It details the benefits the region could achieve by addressing needed connectivity enhancements and the connectivity and financing challenges it faces. In addition, it presents various institutional options for regional infrastructure financing. To build seamless Asian connectivity, Asia needs an effective, formal, and rules-based institutional framework. The paper presents a new institutional framework together with the organizational structures of two new regional institutional mechanisms, namely the Pan-Asian Infrastructure Forum and the Asian Infrastructure Fund

Predicting Spatial Patterns of Plant Recruitment Using Animal-Displacement Kernels

For plants dispersed by frugivores, spatial patterns of recruitment are primarily influenced by the spatial arrangement and characteristics of parent plants, the digestive characteristics, feeding behaviour and movement patterns of animal dispersers, and the structure of the habitat matrix. We used an individual-based, spatially-explicit framework to characterize seed dispersal and seedling fate in an endangered, insular plant-disperser system: the endemic shrub Daphne rodriguezii and its exclusive disperser, the endemic lizard Podarcis lilfordi. Plant recruitment kernels were chiefly determined by the disperser's patterns of space utilization (i.e. the lizard's displacement kernels), the position of the various plant individuals in relation to them, and habitat structure (vegetation cover vs. bare soil). In contrast to our expectations, seed gut-passage rate and its effects on germination, and lizard speed-of-movement, habitat choice and activity rhythm were of minor importance. Predicted plant recruitment kernels were strongly anisotropic and fine-grained, preventing their description using one-dimensional, frequency-distance curves. We found a general trade-off between recruitment probability and dispersal distance; however, optimal recruitment sites were not necessarily associated to sites of maximal adult-plant density. Conservation efforts aimed at enhancing the regeneration of endangered plant-disperser systems may gain in efficacy by manipulating the spatial distribution of dispersers (e.g. through the creation of refuges and feeding sites) to create areas favourable to plant recruitment