Continuum approaches to understanding ion and peptide interactions with the membrane.

Experimental and computational studies have shown that cellular membranes deform to stabilize the inclusion of transmembrane (TM) proteins harboring charge. Recent analysis suggests that membrane bending helps to expose charged and polar residues to the aqueous environment and polar head groups. We previously used elasticity theory to identify membrane distortions that minimize the insertion of charged TM peptides into the membrane. Here, we extend our work by showing that it also provides a novel, computationally efficient method for exploring the energetics of ion and small peptide penetration into membranes. First, we show that the continuum method accurately reproduces energy profiles and membrane shapes generated from molecular simulations of bare ion permeation at a fraction of the computational cost. Next, we demonstrate that the dependence of the ion insertion energy on the membrane thickness arises primarily from the elastic properties of the membrane. Moreover, the continuum model readily provides a free energy decomposition into components not easily determined from molecular dynamics. Finally, we show that the energetics of membrane deformation strongly depend on membrane patch size both for ions and peptides. This dependence is particularly strong for peptides based on simulations of a known amphipathic, membrane binding peptide from the human pathogen Toxoplasma gondii. In total, we address shortcomings and advantages that arise from using a variety of computational methods in distinct biological contexts

Steering Entropy Changes as a Function of Microsleeps

This study aimed to assess steering entropy as a measure of decrements in driving performance caused by microsleeps. Microsleeps are brief, unintended episodes of loss of attention that last 3-14 seconds. These episodes, which are frequent in drivers with sleep disorders, can be long enough to impact steering performance and are particularly disruptive when driver action is imperative, as when driving around curved highway segments. Steering entropy is a driver-centered performance measure that can detect drivers’ corrective responses to situations when the vehicle state falls outside the driver’s expectations. This study tests the hypothesis that steering entropy is an indicator of increased erratic steering behavior during microsleep episodes in drivers with obstructive sleep apnea/hypopena syndrome (OSAHS). Twenty-four drivers with OSAHS were used in this study and their electroencephalography (EEG) defined microsleep (cases) and non-microsleep episodes (crossover control) were compared using a case-crossover method. The performance measure, steering entropy, was calculated from a time-series history of steering angle data. Steering entropy was compared for each microsleep in the three-second interval both immediately preceding and immediately following each microsleep. Results showed that steering entropy was higher on curves during microsleeps and post microsleeps when compared to straight road segments and the no-workload baseline condition. This suggests that steering entropy can capture erratic steering behavior, allowing us to better understand how drivers correct for previous steering errors

TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite Toxoplasma gondii

New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite's replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the "reader" module of acetylated lysines. In independent studies, we sought to determine the targets of these two compounds using forward genetics, generating resistant mutants and identifying the determinants of resistance with comparative genome sequencing. Despite the dissimilarity of the two compounds, we recovered resistant mutants with nonsynonymous mutations in the same domain of the same gene, TGGT1_254250, which we found encodes a protein that localizes to the parasite mitochondrion (designated TgPRELID after the name of said domain). We found that mutants selected with one compound were cross resistant to the other compound, suggesting a common mechanism of resistance. To further support our hypothesis that TgPRELID mutations facilitate resistance to both I-BET151 and F3215-0002, CRISPR (clustered regularly interspaced short palindromic repeat)/CAS9-mediated mutation of TgPRELID directly led to increased F3215-0002 resistance. Finally, all resistance mutations clustered in the same subdomain of TgPRELID. These findings suggest that TgPRELID may encode a multidrug resistance factor or that I-BET151 and F3215-0002 have the same target(s) despite their distinct chemical structures. IMPORTANCE We report the discovery of TgPRELID, a previously uncharacterized mitochondrial protein linked to multidrug resistance in the parasite Toxoplasma gondii. Drug resistance remains a major problem in the battle against parasitic infection, and understanding how TgPRELID mutations augment resistance to multiple, distinct compounds will reveal needed insights into the development of new therapies for toxoplasmosis and other related parasitic diseases

NGC 7582: The Prototype Narrow-Line X-ray Galaxy

NGC 7582 is a candidate prototype of the Narrow Line X-ray Galaxies (NLXGs) found in deep X-ray surveys. An ASCA observation shows the hard (> 3 keV) X-ray continuum of NGC 7582 drops 40% in ~6 ks, implying an AGN, while the soft band (< 3 keV) does not drop in concert with the hard continuum, requiring a separate component. The X-ray spectrum of NGC 7582 also shows a clear 0.5-2 keV soft (kT = 0.8 (+0.9,-0.3) keV or Gamma = 2.4 +/- 0.6; L(X) = 6 x 10**40 ergs s**-1) low--energy component, in addition to a heavily absorbed [N(H) = (6 +/- 2)\times 10**22 cm**-2 ] and variable 2-10 keV power law [Gamma = 0.7 (+0.3,-0.4); L(X) = (1.7-2.3) x 10**42 ergs s**-1]. This is one of the flattest 2-10 keV slopes in any AGN observed with ASCA. (The ROSAT HRI image of NGC 7582 further suggests extent to the SE.) These observations make it clear that the hard X-ray emission of NGC 7582, the most "narrow-line" of the NLXGs, is associated with an AGN. The strong suggestion is that all NLXGs are obscured AGNs, as hypothesized to explain the X-ray background spectral paradox. The separate soft X-ray component makes NGC 7582 (and by extension other NLXGs) detectable as a ROSAT source.Comment: text: Latex2e 10 pages, including 1 table, and 2 postscript figures via psfi

The impact of COVID-19 pandemic on vascular registries and clinical trials.

Quality improvement programs and clinical trial research experienced disruption due to the coronavirus disease 2019 (COVID-19) pandemic. Vascular registries showed an immediate impact with significant declines in second-quarter vascular procedure volumes witnessed across Europe and the United States. To better understand the magnitude and impact of the pandemic, organizations and study groups sent grass roots surveys to vascular specialists for needs assessment. Several vascular registries responded quickly by insertion of COVID-19 variables into their data collection forms. More than 80% of clinical trials have been reported delayed or not started due to factors that included loss of enrollment from patient concerns or mandated institutional shutdowns, weighing the risk of trial participation on patient safety. Preliminary data of patients undergoing vascular surgery with active COVID-19 infection show inferior outcomes (morbidity) and increased mortality. Disease-specific vascular surgery study collaboratives about COVID-19 were created for the desire to study the disease in a more focused manner than possible through registry outcomes. This review describes the pandemic effect on multiple VASCUNET registries including Germany (GermanVasc), Sweden (SwedVasc), United Kingdom (UK National Vascular Registry), Australia and New Zealand (bi-national Australasian Vascular Audit), as well as the United States (Society for Vascular Surgery Vascular Quality Initiative). We will highlight the continued collaboration of VASCUNET with the Vascular Quality Initiative in the International Consortium of Vascular Registries as part of the Medical Device Epidemiology Network coordinated registry network. Vascular registries must remain flexible and responsive to new and future real-world problems affecting vascular patients

Strain-dependent host transcriptional responses to toxoplasma infection are largely conserved in mammalian and avian hosts

Toxoplasma gondii has a remarkable ability to infect an enormous variety of mammalian and avian species. Given this, it is surprising that three strains (Types I/II/III) account for the majority of isolates from Europe/North America. The selective pressures that have driven the emergence of these particular strains, however, remain enigmatic. We hypothesized that strain selection might be partially driven by adaptation of strains for mammalian versus avian hosts. To test this, we examine in vitro, strain-dependent host responses in fibroblasts of a representative avian host, the chicken (Gallus gallus). Using gene expression profiling of infected chicken embryonic fibroblasts and pathway analysis to assess host response, we show here that chicken cells respond with distinct transcriptional profiles upon infection with Type II versus III strains that are reminiscent of profiles observed in mammalian cells. To identify the parasite drivers of these differences, chicken fibroblasts were infected with individual F1 progeny of a Type II x III cross and host gene expression was assessed for each by microarray. QTL mapping of transcriptional differences suggested, and deletion strains confirmed, that, as in mammalian cells, the polymorphic rhoptry kinase ROP16 is the major driver of strain-specific responses. We originally hypothesized that comparing avian versus mammalian host response might reveal an inversion in parasite strain-dependent phenotypes; specifically, for polymorphic effectors like ROP16, we hypothesized that the allele with most activity in mammalian cells might be less active in avian cells. Instead, we found that activity of ROP16 alleles appears to be conserved across host species; moreover, additional parasite loci that were previously mapped for strain-specific effects on mammalian response showed similar strain-specific effects in chicken cells. These results indicate that if different hosts select for different parasite genotypes, the selection operates downstream of the signaling occurring during the beginning of the host's immune response. © 2011 Ong et al

Colors of 2625 Quasars at 0<z<5 Measured in the Sloan Digital Sky Survey Photometric System

We present an empirical investigation of the colors of quasars in the Sloan Digital Sky Survey (SDSS) photometric system. The sample studied includes 2625 quasars with SDSS photometry. The quasars are distributed in a 2.5 degree wide stripe centered on the Celestial Equator covering $\sim529$ square degrees. Positions and SDSS magnitudes are given for the 898 quasars known prior to SDSS spectroscopic commissioning. New SDSS quasars represent an increase of over 200% in the number of known quasars in this area of the sky. The ensemble average of the observed colors of quasars in the SDSS passbands are well represented by a power-law continuum with $\alpha_{\nu} = -0.5$ ($f_{\nu} \propto \nu^{\alpha}$). However, the contributions of the $3000 {\rm \AA}$ bump and other strong emission lines have a significant effect upon the colors. The color-redshift relation exhibits considerable structure, which may be of use in determining photometric redshifts for quasars. The range of colors can be accounted for by a range in the optical spectral index with a distribution $\alpha_{\nu}=-0.5\pm0.65$ (95% confidence), but there is a red tail in the distribution. This tail may be a sign of internal reddening. Finally, we show that there is a continuum of properties between quasars and Seyfert galaxies and we test the validity of the traditional division between the two classes of AGN.Comment: 66 pages, 15 figures (3 color), accepted by A

Composite genome map and recombination parameters derived from three archetypal lineages of Toxoplasma gondii

Toxoplasma gondii is a highly successful protozoan parasite in the phylum Apicomplexa, which contains numerous animal and human pathogens. T.gondii is amenable to cellular, biochemical, molecular and genetic studies, making it a model for the biology of this important group of parasites. To facilitate forward genetic analysis, we have developed a high-resolution genetic linkage map for T.gondii. The genetic map was used to assemble the scaffolds from a 10X shotgun whole genome sequence, thus defining 14 chromosomes with markers spaced at ∼300 kb intervals across the genome. Fourteen chromosomes were identified comprising a total genetic size of ∼592 cM and an average map unit of ∼104 kb/cM. Analysis of the genetic parameters in T.gondii revealed a high frequency of closely adjacent, apparent double crossover events that may represent gene conversions. In addition, we detected large regions of genetic homogeneity among the archetypal clonal lineages, reflecting the relatively few genetic outbreeding events that have occurred since their recent origin. Despite these unusual features, linkage analysis proved to be effective in mapping the loci determining several drug resistances. The resulting genome map provides a framework for analysis of complex traits such as virulence and transmission, and for comparative population genetic studies

HD 20329b: An ultra-short-period planet around a solar-type star found by TESS

We used TESS light curves and HARPS-N spectrograph radial velocity measurements to establish the physical properties of the transiting exoplanet candidate found around the star HD 20329 (TOI-4524). We performed a joint fit of the light curves and radial velocity time series to measure the mass, radius, and orbital parameters of the candidate. We confirm and characterize HD 20329b, an ultra-short-period (USP) planet transiting a solar-type star. The host star (HD 20329, $V = 8.74$ mag, $J = 7.5$ mag) is characterized by its G5 spectral type with $\mathrm{M}_\star= 0.90 \pm 0.05$ M$_\odot$, $\mathrm{R}_\star = 1.13 \pm 0.02$ R$_\odot$, and $\mathrm{T}_{\mathrm{eff}} = 5596 \pm 50$ K; it is located at a distance $d= 63.68 \pm 0.29$ pc. By jointly fitting the available TESS transit light curves and follow-up radial velocity measurements, we find an orbital period of $0.9261 \pm (0.5\times 10^{-4})$ days, a planetary radius of $1.72 \pm 0.07$ $\mathrm{R}_\oplus$, and a mass of $7.42 \pm 1.09$ $\mathrm{M}_\oplus$, implying a mean density of $\rho_\mathrm{p} = 8.06 \pm 1.53$ g cm$^{-3}$. HD 20329b joins the $\sim$30 currently known USP planets with radius and Doppler mass measurements.Comment: Accepted for publication in A&A, 26 page