Model identification for DNA sequence-structure relationships

We investigate the use of algebraic state-space models for the sequence dependent properties of DNA. By considering the DNA sequence as an input signal, rather than using an all atom physical model, computational efficiency is achieved. A challenge in deriving this type of model is obtaining its structure and estimating its parameters. Here we present two candidate model structures for the sequence dependent structural property Slide and a method of encoding the models so that a recursive least squares algorithm can be applied for parameter estimation. These models are based on the assumption that the value of Slide at a base-step is determined by the surrounding tetranucleotide sequence. The first model takes the four bases individually as inputs and has a median root mean square deviation of 0.90 A. The second model takes the four bases pairwise and has a median root mean square deviation of 0.88 A. These values indicate that the accuracy of these models is within the useful range for structure prediction. Performance is comparable to published predictions of a more physically derived model, at significantly less computational cost.     

The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition

Nogo receptor (NgR)-mediated control of axon growth relies on the central nervous system-specific type I transmembrane protein Lingo-1. Interactions between Lingo-1 and NgR, along with a complementary co-receptor, result in neurite and axonal collapse. In addition, the inhibitory role of Lingo-1 is particularly important in regulation of oligodendrocyte differentiation and myelination, suggesting that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies. Here we report on the crystal structure of the ligand-binding ectodomain of human Lingo-1 and show it has a bimodular, kinked structure composed of leucine-rich repeat (LRR) and immunoglobulin (Ig)-like modules. The structure, together with biophysical analysis of its solution properties, reveals that in the crystals and in solution Lingo-1 persistently associates with itself to form a stable tetramer and that it is its LRR-Ig-composite fold that drives such assembly. Specifically, in the crystal structure protomers of Lingo-1 associate in a ring-shaped tetramer, with each LRR domain filling an open cleft in an adjacent protomer. The tetramer buries a large surface area (9,200 A2) and may serve as an efficient scaffold to simultaneously bind and assemble the NgR complex components during activation on a membrane. Potential functional binding sites that can be identified on the ectodomain surface, including the site of self-recognition, suggest a model for protein assembly on the membrane.     

Diverse viscerotropic isolates of Leishmania all express a highly conserved secretory nuclease during human infections

Previously, we characterized a gene encoding the unique nuclease (LdNuc(s)) from a Sudanese isolate of the human pathogen Leishmania donovani. This parasite secretory enzyme is involved in the salvage of host-derived purines and is constitutively expressed by both developmental forms of the parasite. Currently, we assessed whether an LdNuc(s)-like nuclease was conserved among other geographically disparate isolates of L. donovani and whether this enzyme was produced by intracellular amastigotes during human infections. Using RT-PCR and Southern blotting, we showed that LdNuc(s) gene homologs were present in each of the viscerotropic Leishmania tested (i.e., L. donovani isolates from the Sudan, Ethiopia and India as well as L. infantum). Further results of in situ enzyme activity gel analyses showed that each of these parasite isolates also expressed a released/secreted LdNuc(s)-like nuclease activity. In Western blots, our anti-LdNuc(s) (Sudan) peptide-specific antibody reacted with only a single ~35 kDa protein in each of the viscerotropic Leishmania isolates. Further, the ~35 kDa nuclease secreted by each of these isolates was specifically immunoprecipitated by the anti-LdNuc(s) antibody above. In situ gel analyses showed that each of these immunoprecipitates had LdNuc(s)-like nuclease activity. Moreover, sera from acute visceral leishmaniasis patients from India, Sudan and Brazil all immunoprecipitated an LdNuc(s)-HA expressed nuclease demonstrating, that these patients possessed antibodies against this parasite secretory enzyme. Cumulatively, these results showed that the LdNuc(s) homologs were functionally conserved among geographically disparate visceral Leishmania spp. and that amastigotes of these parasites must produce this nuclease enzyme during the course of human disease.     

Triazolbenzo[d]thiazoles: Efficient synthesis and biological evaluation as neuroprotective agents

A number of (1H-1,2,3-triazol-1-yl)benzo[d]thiazoles were synthesized utilizing a versatile Cu-catalyzed azide-alkyne click reaction (CuAAC) on tautomeric benzo[4,5]thiazolo[3,2-d]tetrazole (1) and 2-azidobenzo[d]thiazole (2) starting materials. Moreover, one of the resulting products of this investigation, triazolbenzo[d]thiazole 22, was found to possess significant neuroprotective activity in human neuroblastoma (SH-SY5Y) cells.     

Global positioning system data analysis: velocity ranges and a new definition of sprinting for field sport athletes

Global positioning system (GPS) technology has improved the speed, accuracy, and ease of time-motion analyses of field sport athletes. The large volume of numerical data generated by GPS technology is usually summarized by reporting the distance traveled and time spent in various locomotor categories (e.g., walking, jogging, and running). There are a variety of definitions used in the literature to represent these categories, which makes it nearly impossible to compare findings among studies. The purpose of this work was to propose standard definitions (velocity ranges) that were determined by an objective analysis of time-motion data. In addition, we discuss the limitations of the existing definition of a sprint and present a new definition of sprinting for field sport athletes. Twenty-five GPS data files collected from 5 different sports (men's and women's field hockey, men's and women's soccer, and Australian Rules Football) were analyzed to identify the average velocity distribution. A curve fitting process was then used to determine the optimal placement of 4 Gaussian curves representing the typical locomotor categories. Based on the findings of these analyses, we make recommendations about sport-specific velocity ranges to be used in future time-motion studies of field sport athletes. We also suggest that a sprint be defined as any movement that reaches or exceeds the sprint threshold velocity for at least 1 second and any movement with an acceleration that occurs within the highest 5% of accelerations found in the corresponding velocity range. From a practical perspective, these analyses provide conditioning coaches with information on the high-intensity sprinting demands of field sport athletes, while also providing a novel method of capturing maximal effort, short-duration sprints.     

Fertilization Is Not a New Beginning: The Relationship between Sperm Longevity and Offspring Performance

Sperm are the most diverse cell type known: varying not only among- and within- species, but also among- and within-ejaculates of a single male. Recently, the causes and consequences of variability in sperm phenotypes have received much attention, but the importance of within-ejaculate variability remains largely unknown. Correlative evidence suggests that reduced within-ejaculate variation in sperm phenotype increases a male’s fertilization success in competitive conditions; but the transgenerational consequences of within-ejaculate variation in sperm phenotype remain relatively unexplored. Here we examine the relationship between sperm longevity and offspring performance in a marine invertebrate with external fertilization, Styela plicata. Offspring sired by longer-lived sperm had higher performance compared to offspring sired by freshly-extracted sperm of the same ejaculate, both in the laboratory and the field. This indicates that within-ejaculate differences in sperm longevity can influence offspring fitness – a source of variability in offspring phenotypes that has not previously been considered. Links between sperm phenotype and offspring performance may constrain responses to selection on either sperm or offspring traits, with broad ecological and evolutionary implications.     

Treating and Preventing Influenza in Aged Care Facilities: A Cluster Randomised Controlled Trial

Background

Influenza is an important cause of morbidity and mortality for frail older people. Whilst the antiviral drug oseltamivir (a neuraminidase inhibitor) is approved for treatment and prophylaxis of influenza during outbreaks, there have been no trials comparing treatment only (T) versus treatment and prophylaxis (T&P) in Aged Care Facilities (ACFs). Our objective was to compare a policy of T versus T&P for influenza outbreaks in ACFs.

Methods and Findings

We performed a cluster randomised controlled trial in 16 ACFs, that followed a policy of either “T”—oseltamivir treatment (75 mg twice a day for 5 days)—or “T&P”—treatment and prophylaxis (75 mg once a day for 10 days) for influenza outbreaks over three years, in addition to enhanced surveillance. The primary outcome measure was the attack rate of influenza. Secondary outcomes measures were deaths, hospitalisation, pneumonia and adverse events. Laboratory testing was performed to identify the viral cause of influenza-like illness (ILI) outbreaks. The study period 30 June 2006 to 23 December 2008 included three southern hemisphere winters. During that time, influenza was confirmed as the cause of nine of the 23 ILI outbreaks that occurred amongst the 16 ACFs. The policy of T&P resulted in a significant reduction in the influenza attack rate amongst residents: 93/255 (36%) in residents in T facilities versus 91/397 (23%) in T&P facilities (p = 0.002). We observed a non-significant reduction in staff: 46/216 (21%) in T facilities versus 47/350 (13%) in T&P facilities (p = 0.5). There was a significant reduction in mean duration of outbreaks (T = 24 days, T&P = 11 days, p = 0.04). Deaths, hospitalisations and pneumonia were non-significantly reduced in the T&P allocated facilities. Drug adverse events were common but tolerated.

Conclusion

Our trial lacked power but these results provide some support for a policy of “treatment and prophylaxis” with oseltamivir in controlling influenza outbreaks in ACFs.

Trail Registration

Australian Clinical Trials Registry ACTRN12606000278538     

Theories of Nomadic Movement: A New Theoretical Approach for Understanding the Movement Decisions of Nenets and Komi Reindeer Herders

It is known that the relationship between humans and their animals is important for understanding many aspects of nomadic pastoralist systems, including nomadic movement. However, to date, these complex human–animal relations have not been analyzed in a way that has led to an explanatory model of nomadic movement capable of producing testable hypotheses. Based on ethnographic material collected amongst Komi and Nenets nomadic reindeer herders of the Russian Arctic, we argue that nomadic movements can be best understood as a product of the interplay that exists between animal behaviour and the herders’ skilful actions to (a) maintain herd cohesion and (b) avoid hazards, whilst deploying the minimum amount of resources (i.e., human/animal effort and use of equipment) on rounding up the herd, stopping and turning it. Ecological factors affect movement through their influence on animal behaviour, whereas non-ecological factors do so by influencing the herders’ skilful actions. We demonstrate that, based on these assumptions, it is possible to build a testable model explaining the movement of some nomadic groups.

Physical activity and healthy weight maintenance from childhood to adulthood

The objective of this study was to determine whether change in physical activity was associated with maintaining a healthy weight from childhood to adulthood. This prospective cohort study examined 1,594 young Australian adults (48.9% female) aged 27-36 years who were first examined at age 9-15 years as part of a national health and fitness survey. BMI was calculated from measured height and weight, and physical activity was self-reported at both time points; pedometers were also used at follow-up. Change in physical activity was characterized by calculating the difference between baseline and follow-up z-scores. Change scores were categorized as decreasing (large, moderate), stable, or increasing (large, moderate). Healthy weight was defined in childhood as a BMI less than international overweight cutoff points, and in adulthood as BMI<25 kg/m(2). Healthy weight maintainers were healthy weight at both time points. Compared with those who demonstrated large relative decreases in physical activity, females in all other groups were 25-37% more likely to be healthy weight maintainers, although associations differed according to the physical activity measure used at follow-up and few reached statistical significance. Although younger males whose relative physical activity moderately or largely increased were 27-34% more likely to be healthy weight maintainers than those whose relative physical activity largely decreased, differences were not statistically significant. In conclusion, relatively increasing and stable physical activity from childhood to adulthood was only weakly associated with healthy weight maintenance. Examining personal, social, and environmental factors associated with healthy weight maintenance will be an important next step in understanding why some groups avoid becoming overweight.