Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease\u2014secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide\u2014and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future

Lorenz function of Bi2_{2}Te3_{3}/Sb2_{2}Te3_{3} superlattices

Combining first principles density functional theory and semi-classical Boltzmann transport, the anisotropic Lorenz function was studied for thermoelectric Bi$_{2}$Te$_{3}$/Sb$_{2}$Te$_{3}$ superlattices and their bulk constituents. It was found that already for the bulk materials Bi$_{2}$Te$_{3}$ and Sb$_{2}$Te$_{3}$, the Lorenz function is not a pellucid function on charge carrier concentration and temperature. For electron-doped Bi$_{2}$Te$_{3}$/Sb$_{2}$Te$_{3}$ superlattices large oscillatory deviations for the Lorenz function from the metallic limit were found even at high charge carrier concentrations. The latter can be referred to quantum well effects, which occur at distinct superlattice periods

Hamiltonian Description of Composite Fermions: Magnetoexciton Dispersions

A microscopic Hamiltonian theory of the FQHE, developed by Shankar and myself based on the fermionic Chern-Simons approach, has recently been quite successful in calculating gaps in Fractional Quantum Hall states, and in predicting approximate scaling relations between the gaps of different fractions. I now apply this formalism towards computing magnetoexciton dispersions (including spin-flip dispersions) in the $\nu=1/3$, 2/5, and 3/7 gapped fractions, and find approximate agreement with numerical results. I also analyse the evolution of these dispersions with increasing sample thickness, modelled by a potential soft at high momenta. New results are obtained for instabilities as a function of thickness for 2/5 and 3/7, and it is shown that the spin-polarized 2/5 state, in contrast to the spin-polarized 1/3 state, cannot be described as a simple quantum ferromagnet.Comment: 18 pages, 18 encapsulated ps figure

The spread of epidemic disease on networks

The study of social networks, and in particular the spread of disease on networks, has attracted considerable recent attention in the physics community. In this paper, we show that a large class of standard epidemiological models, the so-called susceptible/infective/removed (SIR) models can be solved exactly on a wide variety of networks. In addition to the standard but unrealistic case of fixed infectiveness time and fixed and uncorrelated probability of transmission between all pairs of individuals, we solve cases in which times and probabilities are non-uniform and correlated. We also consider one simple case of an epidemic in a structured population, that of a sexually transmitted disease in a population divided into men and women. We confirm the correctness of our exact solutions with numerical simulations of SIR epidemics on networks.Comment: 12 pages, 3 figure

Hamiltonian Theory of the FQHE: Conserving Approximation for Incompressible Fractions

A microscopic Hamiltonian theory of the FQHE developed by Shankar and the present author based on the fermionic Chern-Simons approach has recently been quite successful in calculating gaps and finite tempertature properties in Fractional Quantum Hall states. Initially proposed as a small-$q$ theory, it was subsequently extended by Shankar to form an algebraically consistent theory for all $q$ in the lowest Landau level. Such a theory is amenable to a conserving approximation in which the constraints have vanishing correlators and decouple from physical response functions. Properties of the incompressible fractions are explored in this conserving approximation, including the magnetoexciton dispersions and the evolution of the small-$q$ structure factor as \nu\to\half. Finally, a formalism capable of dealing with a nonuniform ground state charge density is developed and used to show how the correct fractional value of the quasiparticle charge emerges from the theory.Comment: 15 pages, 2 eps figure

Iron under Earth's core conditions: Liquid-state thermodynamics and high-pressure melting curve

{\em Ab initio} techniques based on density functional theory in the projector-augmented-wave implementation are used to calculate the free energy and a range of other thermodynamic properties of liquid iron at high pressures and temperatures relevant to the Earth's core. The {\em ab initio} free energy is obtained by using thermodynamic integration to calculate the change of free energy on going from a simple reference system to the {\em ab initio} system, with thermal averages computed by {\em ab initio} molecular dynamics simulation. The reference system consists of the inverse-power pair-potential model used in previous work. The liquid-state free energy is combined with the free energy of hexagonal close packed Fe calculated earlier using identical {\em ab initio} techniques to obtain the melting curve and volume and entropy of melting. Comparisons of the calculated melting properties with experimental measurement and with other recent {\em ab initio} predictions are presented. Experiment-theory comparisons are also presented for the pressures at which the solid and liquid Hugoniot curves cross the melting line, and the sound speed and Gr\"{u}neisen parameter along the Hugoniot. Additional comparisons are made with a commonly used equation of state for high-pressure/high-temperature Fe based on experimental data.Comment: 16 pages including 6 figures and 5 table

Spectroscopy of the first resolved strongly lensed Type Ia supernova iPTF16geu

We report the results from spectroscopic observations of the multiple images of the strongly lensed Type Ia supernova (SN Ia), iPTF16geu, obtained with ground-based telescopes and the Hubble Space Telescope (HST). From a single epoch of slitless spectroscopy with HST, we resolve spectra of individual lensed supernova images for the first time. This allows us to perform an independent measurement of the time-delay between the two brightest images, Δt = 1.4 ± 5.0 d, which is consistent with the time-delay measured from the light curves. We also present measurements of narrow emission and absorption lines characterizing the interstellar medium in the SN Ia host galaxy at z = 0.4087, as well as in the foreground lensing galaxy at z = 0.2163. We detect strong Na ID absorption in the host galaxy, indicating that iPTF16geu belongs to a subclass of SNe Ia displaying ‘anomalously’ large Na ID column densities compared to dust extinction derived from light curves. For the lens galaxy, we refine the measurement of the velocity dispersion, σ = 129 ± 4 km s⁻¹, which significantly constrains the lens model. We use ground-based spectroscopy, boosted by a factor ∼70 from lensing magnification, to study the properties of a high-z SN Ia with unprecedented signal-to-noise ratio. The spectral properties of the supernova, such as pseudo-Equivalent widths of several absorption features and velocities of the Si II-line, indicate that iPTF16geu is a normal SN Ia. We do not detect any significant deviations of the SN spectral energy distribution from microlensing of the SN photosphere by stars and compact objects in the lensing galaxy

An adverse outcome pathway for Parkinsonian motor deficits associated with mitochondrial complex I inhibition

Epidemiological studies have observed an association between pesticide exposure and the development of Parkinson\u2019s disease, but have not established causality. The concept of an adverse outcome pathway (AOP) has been developed as a framework for the organization of available information linking the modulation of a molecular target [molecular initiating event (MIE)], via a sequence of essential biological key events (KEs), with an adverse outcome (AO). Here, we present an AOP covering the toxicological pathways that link the binding of an inhibitor to mitochondrial complex I (i.e., the MIE) with the onset of parkinsonian motor de cits (i.e., the AO). This AOP was developed according to the Organisation for Economic Co-operation and Development guidelines and uploaded to the AOP database. The KEs linking complex I inhibition to parkinsonian motor de cits are mitochondrial dysfunction, impaired proteostasis, neuroin ammation, and the degeneration of dopaminergic neurons of the substantia nigra. These KEs, by convention, were linearly organized. However, there was also evidence of additional feed-forward connections and shortcuts between the KEs, possibly depending on the intensity of the insult and the model system applied. The present AOP demonstrates mechanistic plausibility for epidemiological observations on a relationship between pesticide exposure and an elevated risk for Parkinson\u2019s disease development

The MOSFIRE deep evolution field survey: implications of the lack of evolution in the dust attenuation-mass relation to z ~ 2

Galaxie

The MOSDEF-LRIS survey: connection between galactic-scale outflows and the properties of z ~ 2 star-forming galaxies

Large scale structure and cosmolog