ALBERT

Description: Urban animals often show differences in aggression relative to their rural counterparts, but the ultimate and proximate origins of these differences are poorly understood. Here, we compared urban and rural song sparrows ( Melospiza melodia ), a species for which higher levels of aggression in urban populations have previously been reported. First, we confirmed elevated territorial aggression levels in urban birds relative to rural birds over multiple years. To begin to identify the environmental variables contributing to these differences, we related aggression to features of the social and physical environment, specifically population density and the availability of suitable nesting vegetation. Population distribution and the availability of suitable nest vegetation were not correlated with territorial aggression levels. Subsequently, we conducted a food supplementation experiment to determine whether potential differences in the relative availability of food between the 2 habitats might drive differences in aggression. Food supplementation increased territorial aggression significantly, particularly in rural birds. Thus, it appears that the availability of food could play a role in determining territorial aggression in song sparrows. The specific combination of these features found in urban areas may cause the increased levels of territorial aggression seen in these populations.

Description: More than 200 mutations in the skeletal muscle α-actin gene ( ACTA1 ) cause either dominant or recessive skeletal muscle disease. Currently, there are no specific therapies. Cardiac α-actin is 99% identical to skeletal muscle α-actin and the predominant actin isoform in fetal muscle. We previously showed cardiac α-actin can substitute for skeletal muscle α-actin, preventing the early postnatal death of Acta1 knock-out mice, which model recessive ACTA1 disease. Dominant ACTA1 disease is caused by the presence of ‘poison’ mutant actin protein. Experimental and anecdotal evidence nevertheless indicates that the severity of dominant ACTA1 disease is modulated by the relative amount of mutant skeletal muscle α-actin protein present. Thus, we investigated whether transgenic over-expression of cardiac α-actin in postnatal skeletal muscle could ameliorate the phenotype of mouse models of severe dominant ACTA1 disease. In one model, lethality of ACTA1 D286G . Acta1 +/– mice was reduced from ~59% before 30 days of age to ~12%. In the other model, Acta1 H40Y , in which ~80% of male mice die by 5 months of age, the cardiac α-actin transgene did not significantly improve survival. Hence cardiac α-actin over-expression is likely to be therapeutic for at least some dominant ACTA1 mutations. The reason cardiac α-actin was not effective in the Acta1 H40Y mice is uncertain. We showed that the Acta1 H40Y mice had endogenously elevated levels of cardiac α-actin in skeletal muscles, a finding not reported in dominant ACTA1 patients.

Description: Multiple congenital myopathies, including nemaline myopathy, can arise due to mutations in the ACTA1 gene encoding skeletal muscle α-actin. The main characteristics of ACTA1 null mutations (absence of skeletal muscle α-actin) are generalized skeletal muscle weakness and premature death. A mouse model ( ACTC Co /KO) mimicking these conditions has successfully been rescued by transgenic over-expression of cardiac α-actin in skeletal muscles using the ACTC gene. Nevertheless, myofibres from ACTC Co /KO animals generate less force than normal myofibres (–20 to 25%). To understand the underlying mechanisms, here we have undertaken a detailed functional study of myofibres from ACTC Co /KO rodents. Mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized myofibres showed, upon maximal Ca 2+ activation and under rigor conditions, lower stiffness and disrupted actin-layer line reflections in ACTC Co /KO when compared with age-matched wild-types. These results demonstrate that in ACTC Co /KO myofibres, the presence of cardiac α-actin instead of skeletal muscle α-actin alters actin conformational changes upon activation. This later finely modulates the strain of individual actomyosin interactions and overall lowers myofibre force production. Taken together, the present findings provide novel primordial information about actin isoforms, their functional differences and have to be considered when designing gene therapies for ACTA1 -based congenital myopathies.

Description: We present accurate, spatially resolved imaging of radio spectra at the bases of jets in eleven low-luminosity (Fanaroff–Riley I) radio galaxies, derived from Very Large Array (VLA) observations. We pay careful attention to calibration and to the effects of random and systematic errors, and we base the flux-density scale on recent measurements of VLA primary amplitude calibrators by Perley and Butler. We show images and profiles of spectral index over the frequency range 1.4–8.5 GHz, together with values integrated over fiducial regions defined by our relativistic models of the jets. We find that the spectral index α, defined in the sense I ()  –α , decreases with distance from the nucleus in all of the jets. The mean spectral indices are 0.66 ± 0.01 where the jets first brighten abruptly and 0.59 ± 0.01 after they recollimate. The mean change in spectral index between these locations, which is independent of calibration and flux-density scale errors and is therefore more accurately and robustly measured, is –0.067 ± 0.006. Our jet models associate the decrease in spectral index with a bulk deceleration of the flow from 0.8 c to 0.5 c . We suggest that the decrease is the result of a change in the characteristics of ongoing particle acceleration. One possible acceleration mechanism is the first-order Fermi process in mildly relativistic shocks: in the Bohm limit, the index of the electron energy spectrum, p  = 2α + 1, is slightly larger than 2 and decreases with velocity upstream of the shock. This possibility is consistent with our measurements, but requires shocks throughout the jet volume rather than at a few discrete locations. A second possibility is that two acceleration mechanisms operate in these jets: one (with p  = 2.32) dominant close to the galactic nucleus and associated with high flow speeds, another (with p  = 2.18) taking over at larger distances and slower flow speeds.

Description: The parasitic nematode Haemonchus contortus is an economically and clinically important pathogen of small ruminants, and a model system for understanding the mechanisms and evolution of traits such as anthelmintic resistance. Anthelmintic resistance is widespread and is a major threat to the sustainability of livestock agriculture globally; however, little is known about the genome architecture and parameters such as recombination that will ultimately influence the rate at which resistance may evolve and spread. Here, we performed a genetic cross between two divergent strains of H. contortus , and subsequently used whole-genome resequencing of a female worm and her brood to identify the distribution of genome-wide variation that characterizes these strains. Using a novel bioinformatic approach to identify variants that segregate as expected in a pseudotestcross, we characterized linkage groups and estimated genetic distances between markers to generate a chromosome-scale F 1 genetic map. We exploited this map to reveal the recombination landscape, the first for any helminth species, demonstrating extensive variation in recombination rate within and between chromosomes. Analyses of these data also revealed the extent of polyandry, whereby at least eight males were found to have contributed to the genetic variation of the progeny analyzed. Triploid offspring were also identified, which we hypothesize are the result of nondisjunction during female meiosis or polyspermy. These results expand our knowledge of the genetics of parasitic helminths and the unusual life-history of H. contortus , and enhance ongoing efforts to understand the genetic basis of resistance to the drugs used to control these worms and for related species that infect livestock and humans throughout the world. This study also demonstrates the feasibility of using whole-genome resequencing data to directly construct a genetic map in a single generation cross from a noninbred nonmodel organism with a complex lifecycle.

Description: Jets in low-luminosity radio galaxies are known to decelerate from relativistic speeds on parsec scales to mildly or subrelativistic speeds on kiloparsec scales. Several mechanisms have been proposed to explain this effect, including strong reconfinement shocks and the growth of instabilities (both leading to boundary-layer entrainment) and mass loading from stellar winds or molecular clouds. We have performed a series of axisymmetric simulations of the early evolution of jets in a realistic ambient medium to probe the effects of mass loading from stellar winds using the code ratpenat . We study the evolution of Fanaroff–Riley Class I (FR I) jets, with kinetic powers L j ~ 10 41 –10 44 erg s –1 , within the first 2 kpc of their evolution, where deceleration by stellar mass loading should be most effective. Mass entrainment rates consistent with present models of stellar mass loss in elliptical galaxies produce deceleration and effective decollimation of weak FR I jets within the first kiloparsec. However, powerful FR I jets are not decelerated significantly. In those cases where the mass loading is important, the jets show larger opening angles and decollimate at smaller distances, but the overall structure and dynamics of the bow shock are similar to those of unloaded jets with the same power and thrust. According to our results, the flaring observed on kiloparsec scales is initiated by mass loading in the weaker FR I jets and by reconfinement shocks or the growth of instabilities in the more powerful jets. The final mechanism of decollimation and deceleration is always the development of disruptive pinching modes.

Description: Streptomycetes sense and respond to the stress of phosphate starvation via the two-component PhoR–PhoP signal transduction system. To identify the in vivo targets of PhoP we have undertaken a chromatin-immunoprecipitation-on-microarray analysis of wild-type and phoP mutant cultures and, in parallel, have quantified their transcriptomes. Most (ca. 80%) of the previously in vitro characterized PhoP targets were identified in this study among several hundred other putative novel PhoP targets. In addition to activating genes for phosphate scavenging systems PhoP was shown to target two gene clusters for cell wall/extracellular polymer biosynthesis. Furthermore PhoP was found to repress an unprecedented range of pathways upon entering phosphate limitation including nitrogen assimilation, oxidative phosphorylation, nucleotide biosynthesis and glycogen catabolism. Moreover, PhoP was shown to target many key genes involved in antibiotic production and morphological differentiation, including afsS , atrA , bldA , bldC , bldD , bldK , bldM, cdaR , cdgA, cdgB and scbR-scbA . Intriguingly, in the PhoP-dependent cpk polyketide gene cluster, PhoP accumulates substantially at three specific sites within the giant polyketide synthase-encoding genes. This study suggests that, following phosphate limitation, Streptomyces coelicolor PhoP functions as a ‘master’ regulator, suppressing central metabolism, secondary metabolism and developmental pathways until sufficient phosphate is salvaged to support further growth and, ultimately, morphological development.

Description: We model the kiloparsec (kpc)-scale synchrotron emission from jets in 10 Fanaroff–Riley Class I radio galaxies for which we have sensitive, high-resolution imaging and polarimetry from the Very Large Array. We assume that the jets are intrinsically symmetrical, axisymmetric, decelerating, relativistic outflows and we infer their inclination angles and the spatial variations of their flow velocities, magnetic field structures and emissivities using a common set of fitting functions. The inferred inclinations agree well with independent indicators. The spreading rates increase rapidly, then decrease, in a flaring region. The jets then recollimate to form conical outer regions at distance r 0 from the active galactic nucleus (AGN). The flaring regions are homologous when scaled by r 0 . At 0.1 r 0 , the jets brighten abruptly at the onset of a high-emissivity region and we find an outflow speed of 0.8 c , with a uniform transverse profile. Jet deceleration first becomes detectable at 0.2 r 0 and the outflow often becomes slower at its edges than it is on-axis. Deceleration continues until 0.6 r 0 , after which the outflow speed is usually constant. The dominant magnetic-field component is longitudinal close to the AGN and toroidal after recollimation, but the field evolution is initially much slower than predicted by flux-freezing. In the flaring region, acceleration of ultrarelativistic particles is required to counterbalance the effects of adiabatic losses and account for observed X-ray synchrotron emission, but the brightness evolution of the outer jets is consistent with adiabatic losses alone. We interpret our results as effects of the interaction between the jets and their surroundings. The initial increase in brightness occurs in a rapidly falling external pressure gradient in a hot, dense, kpc-scale corona around the AGN. We interpret the high-emissivity region as the base of a transonic ‘spine’ and suggest that a subsonic shear layer starts to penetrate the flow there. Most of the resulting entrainment must occur before the jets start to recollimate.

Description: Motivation: In vitro and in vivo selection of vaccines is time consuming, expensive and the selected vaccines may not be able to provide protection against broad-spectrum viruses because of emerging antigenically novel disease strains. A powerful computational model that incorporates these protein/DNA or RNA level fluctuations can effectively predict antigenically variant strains, and can minimize the amount of resources spent on exclusive serological testing of vaccines and make wide spectrum vaccines possible for many diseases. However, in silico vaccine prediction remains a grand challenge. To address the challenge, we investigate the use of linear and non-linear regression models to predict the antigenic similarity in foot-and-mouth disease virus strains and in influenza strains, where the structure and parameters of the non-linear model are optimized using an evolutionary algorithm (EA). In addition, we examine two different scoring methods for weighting the type of amino acid substitutions in the linear and non-linear models. We also test our models with some unseen data. Results: We achieved the best prediction results on three datasets of SAT2 (Foot-and-Mouth disease), two datasets of serotype A (Foot-and-Mouth disease) and two datasets of influenza when the scoring method based on biochemical properties of amino acids is employed in combination with a non-linear regression model. Models based on substitutions in the antigenic areas performed better than those that took the entire exposed viral capsid proteins. A majority of the non-linear regression models optimi z ed with the EA performed better than the linear and non-linear models whose parameters are estimated using the least-squares method. In addition, for the best models, optimi z ed non-linear regression models consist of more terms than their linear counterparts, implying a non-linear nature of influences of amino acid substitutions. Our models were also tested on five recently generated FMDV datasets and the best model was able to achieve an 80% agreement rate. Contact: yaochu.jin@surrey.ac.uk or e.laing@surrey.ac.uk

Description: The therapeutic use of antisense and siRNA oligonucleotides has been constrained by the limited ability of these membrane-impermeable molecules to reach their intracellular sites of action. We sought to address this problem using small organic molecules to enhance the effects of oligonucleotides by modulating their intracellular trafficking and release from endosomes. A high-throughput screen of multiple small molecule libraries yielded several hits that markedly potentiated the actions of splice switching oligonucleotides in cell culture. These compounds also enhanced the effects of antisense and siRNA oligonucleotides. The hit compounds preferentially caused release of fluorescent oligonucleotides from late endosomes rather than other intracellular compartments. Studies in a transgenic mouse model indicated that these compounds could enhance the in vivo effects of a splice-switching oligonucleotide without causing significant toxicity. These observations suggest that selected small molecule enhancers may eventually be of value in oligonucleotide-based therapeutics.