Phage Capsids as Gated, Long-Persistence, Uniform Drug Delivery Vehicles

Over the last 25 years, cancer therapies have improved survivorship. Yet, metastatic cancers remain deadly. Therapies are limited by inadequate targeting. Our goal is to develop a new drug delivery vehicle (DDV)-based strategy that improves targeting of drug delivery to solid tumors. We begin with a capsid nanoparticle derived from bacteriophage (phage) T3, a phage that naturally has high persistence in murine blood. This capsid has gating capacity. For rapidly detecting loading in this capsid, here, we describe procedures of native agarose gel electrophoresis, coupled with fluorescence-based detection of loaded molecules. We observe the loading of two fluorescent compounds: the dye, GelStar, and the anticancer drug, bleomycin. The optimal emission filters were found to be orange and green, respectively. The results constitute a first milestone in developing a drug-loaded DDV that does not leak when in blood, but unloads its cargo when in a tumor

Evidence for bacteriophage T7 tail extension during DNA injection

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

On the detectability of star-planet interaction

Magnetic (or tidal) interactions between "hot Jupiters" and their host stars can potentially enhance chromospheric and coronal activity. An ideal testbed for investigating this effect is provided by the extreme WASP-18 system, which features a massive (~10 times Jupiter) close-in (~1 day period) transiting planet orbiting a young F6 star. Optical and X-ray observations of WASP-18 were conducted in November 2011. The high-resolution echelle spectrograph MIKE was used on the 6.5m Magellan Clay telescope to obtain 13 spectra spanning planetary orbital phases of 0.7-1.4, while the X-ray Telescope on Swift provided contemporaneous monitoring with a stacked exposure of ~50 ks. The cores of the Ca II H and K lines do not show significant variability over multiple orbits spanning ~8 d, in contrast to the expectation of phase-dependent chromospheric activity enhancements for efficient star-planet interaction. The star is also X-ray faint, with log Lx < 27.6 erg/s (0.3-2 keV), indicating that coronal activity is likewise low. The lack of detectable star-planet interaction in this extreme system requires that any such effect must here be transient, if indeed present. We demonstrate that searches for Ca II H and K variability can potentially mistake a stellar hotspot, if observed over a short segment of the rotation period, for planet-induced activity. Taken together, these results suggest that the utility of star-planet interaction as a robust method of estimating exoplanet magnetic field strengths may be limited.Comment: Accepted to ApJ; 9 pages emulateapj, 5 figures, 1 table (v2: corrected fn15, typos, refs

Predicting evolution and visualizing high-dimensional fitness landscapes

The tempo and mode of an adaptive process is strongly determined by the structure of the fitness landscape that underlies it. In order to be able to predict evolutionary outcomes (even on the short term), we must know more about the nature of realistic fitness landscapes than we do today. For example, in order to know whether evolution is predominantly taking paths that move upwards in fitness and along neutral ridges, or else entails a significant number of valley crossings, we need to be able to visualize these landscapes: we must determine whether there are peaks in the landscape, where these peaks are located with respect to one another, and whether evolutionary paths can connect them. This is a difficult task because genetic fitness landscapes (as opposed to those based on traits) are high-dimensional, and tools for visualizing such landscapes are lacking. In this contribution, we focus on the predictability of evolution on rugged genetic fitness landscapes, and determine that peaks in such landscapes are highly clustered: high peaks are predominantly close to other high peaks. As a consequence, the valleys separating such peaks are shallow and narrow, such that evolutionary trajectories towards the highest peak in the landscape can be achieved via a series of valley crossingsComment: 12 pages, 7 figures. To appear in "Recent Advances in the Theory and Application of Fitness Landscapes" (A. Engelbrecht and H. Richter, eds.). Springer Series in Emergence, Complexity, and Computation, 201

Red Queen Coevolution on Fitness Landscapes

Species do not merely evolve, they also coevolve with other organisms. Coevolution is a major force driving interacting species to continuously evolve ex- ploring their fitness landscapes. Coevolution involves the coupling of species fit- ness landscapes, linking species genetic changes with their inter-specific ecological interactions. Here we first introduce the Red Queen hypothesis of evolution com- menting on some theoretical aspects and empirical evidences. As an introduction to the fitness landscape concept, we review key issues on evolution on simple and rugged fitness landscapes. Then we present key modeling examples of coevolution on different fitness landscapes at different scales, from RNA viruses to complex ecosystems and macroevolution.Comment: 40 pages, 12 figures. To appear in "Recent Advances in the Theory and Application of Fitness Landscapes" (H. Richter and A. Engelbrecht, eds.). Springer Series in Emergence, Complexity, and Computation, 201

Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom.

PURPOSE: In a large cohort of molecularly characterized inherited retinal disease (IRD) families, we investigated proportions with disease attributable to causative variants in each gene. DESIGN: Retrospective study of electronic patient records. PARTICIPANTS: Patients and relatives managed in the Genetics Service of Moorfields Eye Hospital in whom a molecular diagnosis had been identified. METHODS: Genetic screening used a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. For this study, genes listed in the Retinal Information Network online resource (https://sph.uth.edu/retnet/) were included. Transcript length was extracted for each gene (Ensembl, release 94). MAIN OUTCOME MEASURES: We calculated proportions of families with IRD attributable to variants in each gene in the entire cohort, a cohort younger than 18 years, and a current cohort (at least 1 patient encounter between January 1, 2017, and August 2, 2019). Additionally, we explored correlation between numbers of families and gene transcript length. RESULTS: We identified 3195 families with a molecular diagnosis (variants in 135 genes), including 4236 affected individuals. The pediatric cohort comprised 452 individuals from 411 families (66 genes). The current cohort comprised 2614 families (131 genes; 3130 affected individuals). The 20 most frequently implicated genes overall (with prevalence rates per families) were as follows: ABCA4 (20.8%), USH2A (9.1%), RPGR (5.1%), PRPH2 (4.6%), BEST1 (3.9%), RS1 (3.5%), RP1 (3.3%), RHO (3.3%), CHM (2.7%), CRB1 (2.1%), PRPF31 (1.8%), MY07A (1.7%), OPA1 (1.6%), CNGB3 (1.4%), RPE65 (1.2%), EYS (1.2%), GUCY2D (1.2%), PROM1 (1.2%), CNGA3 (1.1%), and RDH12 (1.1%). These accounted for 71.8% of all molecularly diagnosed families. Spearman coefficients for correlation between numbers of families and transcript length were 0.20 (P = 0.025) overall and 0.27 (P = 0.017), -0.17 (P = 0.46), and 0.71 (P = 0.047) for genes in which variants exclusively cause recessive, dominant, or X-linked disease, respectively. CONCLUSIONS: Our findings help to quantify the burden of IRD attributable to each gene. More than 70% of families showed pathogenic variants in 1 of 20 genes. Transcript length (relevant to gene delivery strategies) correlated significantly with numbers of affected families (but not for dominant disease)

Ammonite Faunal Dynamics Across Bio-Events During the Mid-and Late Cretaceous Along the Russian Pacific Coast

Jagt−Yazykova, E.A. 2012. Ammonite faunal dynamics across bio−events during the mid − and Late Cretaceous along th

Massive Stars In The W33 Giant Molecular Complex

Rich in H II regions, giant molecular clouds are natural laboratories to study massive stars and sequential star formation. The Galactic star-forming complex W33 is located at = ∼ ◦ l 12.8 and at a distance of 2.4 kpc and has a size of ≈10 pc and a total mass of ≈(0.8−8.0) × 105 M⊙. The integrated radio and IR luminosity of W33—when combined with the direct detection of methanol masers, the protostellar object W33A, and the protocluster embedded within the radio source W33 main—mark the region as a site of vigorous ongoing star formation. In order to assess the long-term star formation history, we performed an infrared spectroscopic search for massive stars, detecting for the first time 14 early-type stars, including one WN6 star and four O4–7 stars. The distribution of spectral types suggests that this population formed during the past ∼2–4 Myr, while the absence of red supergiants precludes extensive star formation at ages 6–30 Myr. This activity appears distributed throughout the region and does not appear to have yielded the dense stellar clusters that characterize other star-forming complexes such as Carina and G305. Instead, we anticipate that W33 will eventually evolve into a loose stellar aggregate, with Cyg OB2 serving as a useful, albeit richer and more massive, comparator. Given recent distance estimates, and despite a remarkably similar stellar population, the rich cluster Cl 1813–178 located on the northwest edge of W33 does not appear to be physically associated with W33

Ears of the Armadillo: Global Health Research and Neglected Diseases in Texas

Neglected tropical diseases (NTDs) have\ud been recently identified as significant public\ud health problems in Texas and elsewhere in\ud the American South. A one-day forum on the\ud landscape of research and development and\ud the hidden burden of NTDs in Texas\ud explored the next steps to coordinate advocacy,\ud public health, and research into a\ud cogent health policy framework for the\ud American NTDs. It also highlighted how\ud U.S.-funded global health research can serve\ud to combat these health disparities in the\ud United States, in addition to benefiting\ud communities abroad