httk: R Package for High-Throughput Toxicokinetics

Thousands of chemicals have been profiled by high-throughput screening programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics. Toxicokinetic models aid in predicting tissue concentrations resulting from chemical exposure, and a "reverse dosimetry" approach can be used to predict exposure doses sufficient to cause tissue concentrations that have been identified as bioactive by high-throughput screening. We have created four toxicokinetic models within the R software package httk. These models are designed to be parameterized using high-throughput in vitro data (plasma protein binding and hepatic clearance), as well as structure-derived physicochemical properties and species-specific physiological data. The package contains tools for Monte Carlo sampling and reverse dosimetry along with functions for the analysis of concentration vs. time simulations. The package can currently use human in vitro data to make predictions for 553 chemicals in humans, rats, mice, dogs, and rabbits, including 94 pharmaceuticals and 415 ToxCast chemicals. For 67 of these chemicals, the package includes rat-specific in vitro data. This package is structured to be augmented with additional chemical data as they become available. Package httk enables the inclusion of toxicokinetics in the statistical analysis of chemicals undergoing high-throughput screening

m-Azipropofol (AziPm) a Photoactive Analogue of the Intravenous General Anesthetic Propofol

Propofol is the most commonly used sedative-hypnotic drug for noxious procedures, yet the molecular targets underlying either its beneficial or toxic effects remain uncertain. In order to determine targets and thereby mechanisms of propofol, we have synthesized a photoactivateable analogue by substituting an alkyldiazirinyl moiety for one of the isopropyl arms but in the meta position. m-Azipropofol retains the physical, biochemical, GABAA receptor modulatory, and in vivo activity of propofol and photoadducts to amino acid residues in known propofol binding sites in natural proteins. Using either mass spectrometry or radiolabeling, this reagent may be used to reveal sites and targets that underlie the mechanism of both the desirable and undesirable actions of this important clinical compound

The baryon fraction of LambdaCDM haloes

We investigate the baryon fraction in dark matter haloes formed in non-radiative gas-dynamical simulations of the LambdaCDM cosmogony. By combining a realisation of the Millennium Simulation (Springel et al.) with a simulation of a smaller volume focussing on dwarf haloes, our study spans five decades in halo mass, from 10^10 Msun/h to 10^15 Msun/h. We find that the baryon fraction within the halo virial radius is typically 90% of the cosmic mean, with an rms scatter of 6%, independently of redshift and of halo mass down to the smallest resolved haloes. Our results show that, contrary to the proposal of Mo et al. (2005), pre-virialisation gravitational heating is unable to prevent the collapse of gas within galactic and proto-galactic haloes, and confirm the need for non-gravitational feedback in order to reduce the efficiency of gas cooling and star formation in dwarf galaxy haloes. Simulations including a simple photoheating model (where a gas temperature floor of T_{floor} = 2x10^4 K is imposed from z=11) confirm earlier suggestions that photoheating can only prevent the collapse of baryons in systems with virial temperatures T_{200} < ~2.2 T_{floor} ~ 4.4x10^4 K (corresponding to a virial mass of M_{200} ~ 10^10 Msun/h and a circular velocity of V_{200} ~ 35 km/s). Photoheating may thus help regulate the formation of dwarf spheroidals and other galaxies at the extreme faint-end of the luminosity function, but it cannot, on its own, reconcile the abundance of sub-L* galaxies with the vast number of dwarf haloes expected in the LambdaCDM cosmogony. The lack of evolution or mass dependence seen in the baryon fraction augurs well for X-ray cluster studies that assume a universal and non-evolving baryon fraction to place constraints on cosmological parameters.Comment: 9 pages, 5 figures (Figs 1. and 2 reduced in quality), 1 table, submitted to MNRAS. Version with high-resolution figures can be obtained from http://star-www.dur.ac.uk/~rcrain/baryonfractions

Religious Identity, Religious Attendance, and Parental Control

Using a national sample of adolescents aged 10–18 years and their parents (N = 5,117), this article examines whether parental religious identity and religious participation are associated with the ways in which parents control their children. We hypothesize that both religious orthodoxy and weekly religious attendance are related to heightened levels of three elements of parental control: monitoring activities, normative regulations, and network closure. Results indicate that an orthodox religious identity for Catholic and Protestant parents and higher levels of religious attendance for parents as a whole are associated with increases in monitoring activities and normative regulations of American adolescents

Prenatal Vitamin D Supplementation and Child Respiratory Health: A Randomised Controlled Trial

PMCID: PMC3691177This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Reaction mechanism for the replacement of calcite by dolomite and siderite: Implications for geochemistry, microstructure and porosity evolution during hydrothermal mineralisation

Carbonate reactions are common in mineral deposits due to CO2-rich mineralising fluids. This study presents the first in-depth, integrated analysis of microstructure and microchemistry of fluid-mediated carbonate reaction textures at hydrothermal conditions. In doing so, we describe the mechanisms by which carbonate phases replace one another, and the implications for the evolution of geochemistry, rock microstructures and porosity. The sample from the 1.95 Moz Junction gold deposit, Western Australia, contains calcite derived from carbonation of a metamorphic amphibole—plagioclase assemblage that has further altered to siderite and dolomite. The calcite is porous and contains iron-rich calcite blebs interpreted to have resulted from fluid-mediated replacement of compositionally heterogeneous amphiboles. The siderite is polycrystalline but nucleates topotactically on the calcite. As a result, the boundaries between adjacent grains are low-angle boundaries (<10°), which are geometrically similar to those formed by crystal–plastic deformation and recovery. Growth zoning within individual siderite grains shows that the low-angle boundaries are growth features and not due to deformation. Low-angle boundaries develop due to the propagation of defects at grain faces and zone boundaries and by impingement of grains that nucleated with small misorientations relative to each other during grain growth.The cores of siderite grains are aligned with the twin planes in the parent calcite crystal showing that the reactant Fe entered the crystal along the twin boundaries. Dolomite grains, many of which appear to in-fill space generated by the siderite replacement, also show alignment of cores along the calcite twin planes, suggesting that they did not grow into space but replaced the calcite. Where dolomite is seen directly replacing calcite, it nucleates on the Fe-rich calcite due to the increased compatibility of the Fe-bearing calcite lattice relative to the pure calcite. Both reactions are interpreted as fluid-mediated replacement reactions which use the crystallography and elemental chemistry of the calcite. Experiments of fluid-mediated replacement reactions show that they proceed much faster than diffusion-based reactions. This is important when considering the rates of reactions relative to fluid flow in mineralising systems

Conformational Change in the Chromatin Remodelling Protein MENT

Chromatin condensation to heterochromatin is a mechanism essential for widespread suppression of gene transcription, and the means by which a chromatin-associated protein, MENT, induces a terminally differentiated state in cells. MENT, a protease inhibitor of the serpin superfamily, is able to undergo conformational change in order to effect enzyme inhibition. Here, we sought to investigate whether conformational change in MENT is ‘fine-tuned’ in the presence of a bound ligand in an analogous manner to other serpins, such as antithrombin where such movements are reflected by a change in intrinsic tryptophan fluorescence. Using this technique, MENT was found to undergo structural shifts in the presence of DNA packaged into nucleosomes, but not naked DNA. The contribution of the four Trp residues of MENT to the fluorescence change was mapped using deconvolution analysis of variants containing single Trp to Phe mutations. The analysis indicated that the overall emission spectra is dominated by a helix-H tryptophan, but this residue did not dominate the conformational change in the presence of chromatin, suggesting that other Trp residues contained in the A-sheet and RCL regions contribute to the conformational change. Mutagenesis revealed that the conformational change requires the presence of the DNA-binding ‘M-loop’ and D-helix of MENT, but is independent of the protease specificity determining ‘reactive centre loop’. The D-helix mutant of MENT, which is unable to condense chromatin, does not undergo a conformational change, despite being able to bind chromatin, indicating that the conformational change may contribute to chromatin condensation by the serpin

Thunderclap: Exploring Vulnerabilities in Operating System IOMMU Protection via DMA from Untrustworthy Peripherals

Direct Memory Access (DMA) attacks have been known for many years: DMA-enabled I/O peripherals have complete access to the state of a computer and can fully compromise it including reading and writing all of system memory. With the popularity of Thunderbolt 3 over USB Type-C and smart internal devices, opportunities for these attacks to be performed casually with only seconds of physical access to a computer have greatly broadened. In response, commodity hardware and operating-system (OS) vendors have incorporated support for Input-Output Memory Management Units (IOMMUs), which impose memory protection on DMA, and are widely believed to protect against DMA attacks. We investigate the state-of-the-art in IOMMU protection across OSes using a novel I/O security research platform, and find that current protections fall short when faced with a functional network peripheral that uses its complex interactions with the OS for ill intent, and demonstrate compromises against macOS, FreeBSD, and Linux, which notionally utilize IOMMUs to protect against DMA attackers. Windows only uses the IOMMU in limited cases and remains vulnerable. Using Thunderclap, an open-source FPGA research platform we built, we explore a number of novel exploit techniques to expose new classes of OS vulnerability. The complex vulnerability space for IOMMU-exposed shared memory available to DMA-enabled peripherals allows attackers to extract private data (sniffing cleartext VPN traffic) and hijack kernel control flow (launching a root shell) in seconds using devices such as USB-C projectors or power adapters. We have worked closely with OS vendors to remedy these vulnerability classes, and they have now shipped substantial feature improvements and mitigations as a result of our work.DARPA I2O FA8750-10-C-0237 ("CTSRD") DARPA MTO HR0011- 18-C-0016 ("ECATS") Arm Ltd Google Inc This work was also supported by EPSRC EP/R012458/1 (“IOSEC”)