Rare events in population genetics: Stochastic tunneling in a two-locus model with recombination

We study the evolution of a population in a two-locus genotype space, in which the negative effects of two single mutations are overcompensated in a high fitness double mutant. We discuss how the interplay of finite population size, $N$, and sexual recombination at rate $r$ affects the escape times $t_\mathrm{esc}$ to the double mutant. For small populations demographic noise generates massive fluctuations in $t_\mathrm{esc}$. The mean escape time varies non-monotonically with $r$, and grows exponentially as $\ln t_{\mathrm{esc}} \sim N(r - r^\ast)^{3/2}$ beyond a critical value $r^\ast$.Comment: 4 pages, 3 figure

High concentrations of morphine sensitize and activate mouse dorsal root ganglia via TRPV1 and TRPA1 receptors.

BACKGROUND: Morphine and its derivatives are key drugs in pain control. Despite its well-known analgesic properties morphine at high concentrations may be proalgesic. Particularly, short-lasting painful sensations have been reported upon dermal application of morphine. To study a possible involvement of TRP receptors in the pro-nociceptive effects of morphine (0.3 - 10 mM), two models of nociception were employed using C57BL/6 mice and genetically related TRPV1 and TRPA1 knockout animals, which were crossed and generated double knockouts. Hindpaw skin flaps were used to investigate the release of calcitonin gene-related peptide indicative of nociceptive activation. RESULTS: Morphine induced release of calcitonin gene-related peptide and sensitized the release evoked by heat or the TRPA1 agonist acrolein. Morphine activated HEK293t cells transfected with TRPV1 or TRPA1. Activation of C57BL/6 mouse dorsal root ganglion neurons in culture was investigated with calcium imaging. Morphine induced a dose-dependent rise in intracellular calcium in neurons from wild-type animals. In neurons from TRPV1 and TRPA1 knockout animals activation by morphine was markedly reduced, in the TRPV1/A1 double knockout animals this morphine effect was abrogated. Naloxone induced an increase in calcium levels similar to morphine. The responses to both morphine and naloxone were sensitized by bradykinin. CONCLUSION: Nociceptor activation and sensitization by morphine is conveyed by TRPV1 and TRPA1

The adaptor protein PID1 regulates receptor-dependent endocytosis of postprandial triglyceride-rich lipoproteins.

ObjectiveInsulin resistance is associated with impaired receptor dependent hepatic uptake of triglyceride-rich lipoproteins (TRL), promoting hypertriglyceridemia and atherosclerosis. Next to low-density lipoprotein (LDL) receptor (LDLR) and syndecan-1, the LDLR-related protein 1 (LRP1) stimulated by insulin action contributes to the rapid clearance of TRL in the postprandial state. Here, we investigated the hypothesis that the adaptor protein phosphotyrosine interacting domain-containing protein 1 (PID1) regulates LRP1 function, thereby controlling hepatic endocytosis of postprandial lipoproteins.MethodsLocalization and interaction of PID1 and LRP1 in cultured hepatocytes was studied by confocal microscopy of fluorescent tagged proteins, by indirect immunohistochemistry of endogenous proteins, by GST-based pull down and by immunoprecipitation experiments. The in vivo relevance of PID1 was assessed using whole body as well as liver-specific Pid1-deficient mice on a wild type or Ldlr-deficient (Ldlr-/-) background. Intravital microscopy was used to study LRP1 translocation in the liver. Lipoprotein metabolism was investigated by lipoprotein profiling, gene and protein expression as well as organ-specific uptake of radiolabelled TRL.ResultsPID1 co-localized in perinuclear endosomes and was found associated with LRP1 under fasting conditions. We identified the distal NPxY motif of the intracellular C-terminal domain (ICD) of LRP1 as the site critical for the interaction with PID1. Insulin-mediated NPxY-phosphorylation caused the dissociation of PID1 from the ICD, causing LRP1 translocation to the plasma membrane. PID1 deletion resulted in higher LRP1 abundance at the cell surface, higher LDLR protein levels and, paradoxically, reduced total LRP1. The latter can be explained by higher receptor shedding, which we observed in cultured Pid1-deficient hepatocytes. Consistently, PID1 deficiency alone led to increased LDLR-dependent endocytosis of postprandial lipoproteins and lower plasma triglycerides. In contrast, hepatic PID1 deletion on an Ldlr-/- background reduced lipoprotein uptake into liver and caused plasma TRL accumulation.ConclusionsBy acting as an insulin-dependent retention adaptor, PID1 serves as a regulator of LRP1 function controlling the disposal of postprandial lipoproteins. PID1 inhibition provides a novel approach to lower plasma levels of pro-atherogenic TRL remnants by stimulating endocytic function of both LRP1 and LDLR in the liver

Ground-State and Domain-Wall Energies in the Spin-Glass Region of the 2D ±J\pm J Random-Bond Ising Model

The statistics of the ground-state and domain-wall energies for the two-dimensional random-bond Ising model on square lattices with independent, identically distributed bonds of probability $p$ of $J_{ij}= -1$ and $(1-p)$ of $J_{ij}= +1$ are studied. We are able to consider large samples of up to $320^2$ spins by using sophisticated matching algorithms. We study $L \times L$ systems, but we also consider $L \times M$ samples, for different aspect ratios $R = L / M$. We find that the scaling behavior of the ground-state energy and its sample-to-sample fluctuations inside the spin-glass region ($p_c \le p \le 1 - p_c$) are characterized by simple scaling functions. In particular, the fluctuations exhibit a cusp-like singularity at $p_c$. Inside the spin-glass region the average domain-wall energy converges to a finite nonzero value as the sample size becomes infinite, holding $R$ fixed. Here, large finite-size effects are visible, which can be explained for all $p$ by a single exponent $\omega\approx 2/3$, provided higher-order corrections to scaling are included. Finally, we confirm the validity of aspect-ratio scaling for $R \to 0$: the distribution of the domain-wall energies converges to a Gaussian for $R \to 0$, although the domain walls of neighboring subsystems of size $L \times L$ are not independent.Comment: 11 pages with 15 figures, extensively revise

Using nestedness and species-accumulation analyses to strengthen a conservation plan for littoral forest birds in south-eastern Madagascar

The littoral forests of south-eastern Madagascar are among the most threatened ecosystems on the island. A conservation plan has been developed for the region due to a proposed mining venture. Here, we provide a novel methodology to assess if the planned conservation measures would effectively conserve the bird diversity inhabiting these forests. Bird community composition within 30 littoral forest fragments was quantified with each fragment characterized by measures of fragment area, isolation, and internal habitat complexity. A nestedness and cumulative species–area analysis was conducted to ascertain the contribution of forest fragments of different sizes in capturing the overall bird species richness. Datasets representing the overall and forest-dependent bird assemblages were found to be significantly nested. The pattern of nestedness appeared to be driven by fragment size. However, cumulative species–area analyses showed that the assemblages were imperfectly nested with ten species displaying idiosyncratic distribution patterns. When a modest conservation target was set (the occurrence of a bird species in three or more fragments), the proposed conservation plan would only protect approximately half the species found in the littoral forests. We show that protecting an additional four large patches would mean that the proportion of forest-birds captured in three or more patches would increase to 70%

Reduction of Two-Dimensional Dilute Ising Spin Glasses

The recently proposed reduction method is applied to the Edwards-Anderson model on bond-diluted square lattices. This allows, in combination with a graph-theoretical matching algorithm, to calculate numerically exact ground states of large systems. Low-temperature domain-wall excitations are studied to determine the stiffness exponent y_2. A value of y_2=-0.281(3) is found, consistent with previous results obtained on undiluted lattices. This comparison demonstrates the validity of the reduction method for bond-diluted spin systems and provides strong support for similar studies proclaiming accurate results for stiffness exponents in dimensions d=3,...,7.Comment: 7 pages, RevTex4, 6 ps-figures included, for related information, see http://www.physics.emory.edu/faculty/boettcher

A deficit of ultraluminous X-ray sources in luminous infrared galaxies

We present results from a Chandra study of ultraluminous X-ray sources (ULXs) in a sample of 17 nearby (DL < 60 Mpc) luminous infrared galaxies (LIRGs), selected to have star formation rates (SFRs) in excess of 7 M⊙ yr−1 and low foreground Galactic column densities (NH ≲ 5 × 1020 cm−2). A total of 53 ULXs were detected and we confirm that this is a complete catalogue of ULXs for the LIRG sample. We examine the evolution of ULX spectra with luminosity in these galaxies by stacking the spectra of individual objects in three luminosity bins, finding a distinct change in spectral index at luminosity ∼2 × 1039 erg s−1. This may be a change in spectrum as 10 M⊙ black holes transit from an ∼ Eddington to a super-Eddington accretion regime, and is supported by a plausible detection of partially ionized absorption imprinted on the spectrum of the luminous ULX (LX ≈ 5 × 1039 erg s−1) CXOU J024238.9-000055 in NGC 1068, consistent with the highly ionized massive wind that we would expect to see driven by a super-Eddington accretion flow. This sample shows a large deficit in the number of ULXs detected per unit SFR (0.2 versus 2 ULXs, per M⊙ yr−1) compared to the detection rate in nearby (DL < 14.5 Mpc) normal star-forming galaxies. This deficit also manifests itself as a lower differential X-ray luminosity function normalization for the LIRG sample than for samples of other star-forming galaxies. We show that it is unlikely that this deficit is a purely observational effect. Part of this deficit might be attributable to the high metallicity of the LIRGs impeding the production efficiency of ULXs and/or a lag between the star formation starting and the production of ULXs; however, we argue that the evidence – including very low NULX/LFIR, and an even lower ULX incidence in the central regions of the LIRGs – shows that the main culprit for this deficit is likely to be the high column of gas and dust in these galaxies, that fuels the high SFR but also acts to obscure many ULXs from our view

Pediatric emergency medicine point-of-care ultrasound: summary of the evidence.

The utility of point-of-care ultrasound is well supported by the medical literature. Consequently, pediatric emergency medicine providers have embraced this technology in everyday practice. Recently, the American Academy of Pediatrics published a policy statement endorsing the use of point-of-care ultrasound by pediatric emergency medicine providers. To date, there is no standard guideline for the practice of point-of-care ultrasound for this specialty. This document serves as an initial step in the detailed how to and description of individual point-of-care ultrasound examinations. Pediatric emergency medicine providers should refer to this paper as reference for published research, objectives for learners, and standardized reporting guidelines