Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation

Insights into the genomic adaptive traits of Treponema pallidum, the causative bacterium of syphilis, have long been hampered due to the absence of in vitro culture models and the constraints associated with its propagation in rabbits. Here, we have bypassed the culture bottleneck by means of a targeted strategy never applied to uncultivable bacterial human pathogens to directly capture whole-genome T. pallidum data in the context of human infection. This strategy has unveiled a scenario of discreet T. pallidum interstrain single-nucleotide-polymorphism-based microevolution, contrasting with a rampant within-patient genetic heterogeneity mainly targeting multiple phase-variable loci and a major antigen-coding gene (tprK). TprK demonstrated remarkable variability and redundancy, intra- and interpatient, suggesting ongoing parallel adaptive diversification during human infection. Some bacterial functions (for example, flagella- and chemotaxis-associated) were systematically targeted by both inter- and intrastrain single nucleotide polymorphisms, as well as by ongoing within-patient phase variation events. Finally, patient-derived genomes possess mutations targeting a penicillin-binding protein coding gene (mrcA) that had never been reported, unveiling it as a candidate target to investigate the impact on the susceptibility to penicillin. Our findings decode the major genetic mechanisms by which T. pallidum promotes immune evasion and survival, and demonstrate the exceptional power of characterizing evolving pathogen subpopulations during human infection.

The socioeconomic gradient in health: The role of intra-household resource allocation

This paper aims to analyse the impact of different household financial regimes on the health status of males and females in a number of European countries. Using the EU-SILC 2010 on intra-household sharing of resources, we find that each member of the couple is worse off if his/her partner has most decision-making responsibilities. Additionally, the presence of children in the household plays a role in the effect that household financial regimens exert on individual self-assessed health, especially among females. We conclude that family arrangements regarding resource allocation and decision-making have important consequences and should be given some attention in the task of identifying individuals predisposed to health problems.

Economic growth and individual satisfaction in an agent-based economy

Macro and micro-economic perspectives are combined in an eco- nomic growth model. An agent-based modeling approach is used to develop an overlapping generation framework where endogenous growth is supported by work- ers that decide to study depending on their relative (skilled and unskilled) indi- vidual satisfaction. The micro perspective is based on individual satisfaction: an utility function computed from the variation of the relative income in both space and time. The macro perspective emerges from micro decisions, and, as in other growth models of this type, concerns an important allocative social decision the share of the working population that is engaged in producing ideas (skilled work- ers). Simulations show that production and satisfaction levels are higher when the evolution of income measured in both space and time are equally weighted.

Office workers' objectively assessed total and prolonged sitting time: individual-level correlates and worksite variations

Sedentary behavior is highly prevalent in office-based workplaces; however, few studies have assessed the attributes associated with this health risk factor in the workplace setting. This study aimed to identify the correlates of office workers' objectively-assessed total and prolonged (≥ 30 min bouts) workplace sitting time. Participants were 231 Australian office workers recruited from 14 sites of a single government employer in 2012-13. Potential socio-demographic, work-related, health-related and cognitive-social correlates were measured through a self-administered survey and anthropometric measurements. Associations with total and prolonged workplace sitting time (measured with the activPAL3) were tested using linear mixed models. Worksites varied significantly in total workplace sitting time (overall mean [SD]: 79% [10%] of work hours) and prolonged workplace sitting time (42% [19%]), after adjusting for socio-demographic and work-related characteristics. Organisational tenure of 3-5 years (compared to tenure > 5 years) was associated with more time spent in total and prolonged workplace sitting time, while having a BMI categorised as obese (compared to a healthy BMI) was associated with less time spent in total and prolonged workplace sitting time. Significant variations in sitting time were observed across different worksites of the same employer and the variation remained after adjusting for individual-level factors. Only BMI and organisational tenure were identified as correlates of total and prolonged workplace sitting time. Additional studies are needed to confirm the present findings across diverse organisations and occupations.

Can the direct medical cost of chronic disease be transferred across different countries? Using cost-of-illness studies on type 2 diabetes, epilepsy and schizophrenia as examples

OBJECTIVES: To systematically review cost of illness studies for schizophrenia (SC), epilepsy (EP) and type 2 diabetes mellitus (T2DM) and explore the transferability of direct medical cost across countries.

METHODS: A comprehensive literature search was performed to yield studies that estimated direct medical costs. A generalized linear model (GLM) with gamma distribution and log link was utilized to explore the variation in costs that accounted by the included factors. Both parametric (Random-effects model) and non-parametric (Boot-strapping) meta-analyses were performed to pool the converted raw cost data (expressed as percentage of GDP/capita of the country where the study was conducted).

RESULTS: In total, 93 articles were included (40 studies were for T2DM, 34 studies for EP and 19 studies for SC). Significant variances were detected inter- and intra-disease classes for the direct medical costs. Multivariate analysis identified that GDP/capita (p<0.05) was a significant factor contributing to the large variance in the cost results. Bootstrapping meta-analysis generated more conservative estimations with slightly wider 95% confidence intervals (CI) than the parametric meta-analysis, yielding a mean (95%CI) of 16.43% (11.32, 21.54) for T2DM, 36.17% (22.34, 50.00) for SC and 10.49% (7.86, 13.41) for EP.

CONCLUSIONS: Converting the raw cost data into percentage of GDP/capita of individual country was demonstrated to be a feasible approach to transfer the direct medical cost across countries. The approach from our study to obtain an estimated direct cost value along with the size of specific disease population from each jurisdiction could be used for a quick check on the economic burden of particular disease for countries without such data.

Hampered performance of migratory swans: intra- and inter-seasonal effects of avian influenza virus

The extent to which animal migrations shape parasite transmission networks is critically dependent on a migrant's ability to tolerate infection and migrate successfully. Yet, sub-lethal effects of parasites can be intensified through periods of increased physiological stress. Long-distance migrants may, therefore, be especially susceptible to negative effects of parasitic infection. Although a handful of studies have investigated the short-term, transmission-relevant behaviors of wild birds infected with low-pathogenic avian influenza viruses (LPAIV), the ecological consequences of LPAIV for the hosts themselves remain largely unknown. Here, we assessed the potential effects of naturally-acquired LPAIV infections in Bewick's swans, a long-distance migratory species that experiences relatively low incidence of LPAIV infection during early winter. We monitored both foraging and movement behavior in the winter of infection, as well as subsequent breeding behavior and inter-annual resighting probability over 3 years. Incorporating data on infection history we hypothesized that any effects would be most apparent in naïve individuals experiencing their first LPAIV infection. Indeed, significant effects of infection were only seen in birds that were infected but lacked antibodies indicative of prior infection. Swans that were infected but had survived a previous infection were indistinguishable from uninfected birds in each of the ecological performance metrics. Despite showing reduced foraging rates, individuals in the naïve-infected category had similar accumulated body stores to re-infected and uninfected individuals prior to departure on spring migration, possibly as a result of having higher scaled mass at the time of infection. And yet individuals in the naïve-infected category were unlikely to be resighted 1 year after infection, with 6 out of 7 individuals that never resighted again compared to 20 out of 63 uninfected individuals and 5 out of 12 individuals in the re-infected category. Collectively, our findings indicate that acute and superficially harmless infection with LPAIV may have indirect effects on individual performance and recruitment in migratory Bewick's swans. Our results also highlight the potential for infection history to play an important role in shaping ecological constraints throughout the annual cycle.

Theoretical investigation of intra- and inter-cellular spatiotemporal calcium patterns in microcirculation

Microcirculatory vessels are lined by endothelial cells (ECs) which are surrounded by a single or multiple layer of smooth muscle cells (SMCs). Spontaneous and agonist induced spatiotemporal calcium (Ca2+) events are generated in ECs and SMCs, and regulated by complex bi-directional signaling between the two layers which ultimately determines the vessel tone. The contractile state of microcirculatory vessels is an important factor in the determination of vascular resistance, blood flow and blood pressure. This dissertation presents theoretical insights into some of the important and currently unresolved phenomena in microvascular tone regulation. Compartmental and continuum models of isolated EC and SMC, coupled EC-SMC and a multi-cellular vessel segment with deterministic and stochastic descriptions of the cellular components were developed, and the intra- and inter-cellular spatiotemporal Ca2+ mobilization was examined.^ Coupled EC-SMC model simulations captured the experimentally observed localized subcellular EC Ca2+ events arising from the opening of EC transient receptor vanilloid 4 (TRPV4) channels and inositol triphosphate receptors (IP3Rs). These localized EC Ca2+ events result in endothelium-derived hyperpolarization (EDH) and Nitric Oxide (NO) production which transmit to the adjacent SMCs to ultimately result in vasodilation. The model examined the effect of heterogeneous distribution of cellular components and channel gating kinetics in determination of the amplitude and spread of the Ca2+ events. The simulations suggested the necessity of co-localization of certain cellular components for modulation of EDH and NO responses. Isolated EC and SMC models captured intracellular Ca2+ wave like activity and predicted the necessity of non-uniform distribution of cellular components for the generation of Ca2+ waves. The simulations also suggested the role of membrane potential dynamics in regulating Ca2+ wave velocity. The multi-cellular vessel segment model examined the underlying mechanisms for the intercellular synchronization of spontaneous oscillatory Ca2+ waves in individual SMC. ^ From local subcellular events to integrated macro-scale behavior at the vessel level, the developed multi-scale models captured basic features of vascular Ca2+ signaling and provide insights for their physiological relevance. The models provide a theoretical framework for assisting investigations on the regulation of vascular tone in health and disease.^

Individual boldness traits influenced by temperature in male Siamese fighting fish.

Temperature has profound effects on physiology of ectothermic animals. However, the effects on temperature variation on behavioral traits are poorly studied in contrast to physiological endpoints. This may be important as even small differences in temperatures have large effects on physiological rates including overall metabolism, and behavior is known to be linked to metabolism at least in part. The primary aim of this study was to determine the effects of ambient temperature on boldness responses of a species of fish commonly used in behavioral experiments, the Siamese fighting fish (Betta splendens). At 26°C, subjects were first examined for baseline behaviors over three days, using three different (but complementary) 'open field' type assays tested in a fixed order. Those same fish were next exposed to either the same temperature (26°C) or a higher temperature (30°C) for 10days, and then the same behavioral assays were repeated. Those individuals exposed to increased temperatures reduced their latency to leave the release area (area I), spent more time in area III (farthest from release area), and were more active overall; together we infer these behaviors to reflect an increase in general 'boldness' with increased temperature. Our results add to a limited number of studies of temperature effects on behavioral tendencies in ectotherms that are evident even after some considerable acclimation. From a methodological perspective, our results indicate careful temperature control is needed when studying behavior in this and other species of fish.

Drivers and fitness consequences of individual and sexual foraging specialisation in fur seals

What did you eat today? Yesterday? Do you think the person on your right had similar meals? Probably not! Similar variability exists in wild animals. During my PhD, I studied variation in feeding strategies among individuals of a same population, focusing on the main drivers and consequences in fur seals.

Geographic variation in seasonality and its influence on the dynamics of an infectious disease

Seasonal changes in environmental drivers - such as temperature, rainfall, and resource availability - have the potential to shape infection dynamics through their reverberating effects on biological processes including host abundance and susceptibility to infection. However, seasonality varies geographically. We therefore expect marked differences in infection dynamics between regions with different seasonal patterns. By pairing extensive Avian Influenza Virus (AIV) surveillance data - 65 358 individual bird samples from 12 species of dabbling ducks sampled at 174 locations across North America - with quantification of seasonality using remote sensed data indicative for primary productivity (normalised differenced vegetation index, NDVI), we provide evidence that seasonal dynamics influence infection dynamics across a continent. More pronounced epidemics were seen to occur in regions experiencing a higher degree of seasonality, and epidemics of lower amplitude and longer duration occurred in regions with a more protracted and lower seasonal amplitude. These results demonstrate the potential importance of geographic variation in seasonality for explaining geographic variation in the dynamics of infectious diseases in wildlife.

Regional variation and change in the history of English strong verbs

This thesis investigates how the strong verb system inherited from Old English evolved in the regional dialects of Middle English (ca. 1100-1500). Old English texts preserve a relatively complex system of strong verbs, in which traditionally seven different ablaut classes are distinguished. This system becomes seriously disrupted from the Late Old English and Early Middle English periods onwards. As a result, many strong verbs die out, or have their ablaut patterns affected by sound change and morphological analogy, or transfer to the weak conjugation. In my thesis, I study the beginnings of two of these developments in two strong verb classes to find out what the evidence from Middle English regional dialects can tell us about their origins and diffusion. Chapter 2 concentrates on the strong-to-weak shift in Class III verbs, and investigates to what extent strong, mixed and weak past tense and participle forms vary in Middle English dialects, and whether the variation is more pronounced in the paradigms of specific verbs or sub-classes. Chapter 3 analyses the regional distribution of ablaut levelling in strong Class IV verbs throughout the Middle English period. The Class III and IV data for the Early Middle English period are drawn from A Linguistic Atlas of Early Middle English, and the data for the Late Middle English period from a sub-corpus of files from The Penn-Helsinki Parsed Corpus of Middle English and The Middle English Grammar Corpus. Furthermore, The English Dialect Dictionary and Grammar are consulted as an additional reference point to find out to what extent the Middle English developments are reflected in Late Modern English dialects. Finally, referring to modern insights into language variation and change and linguistic interference, Chapter 4 discusses to what extent intra- and extra-linguistc factors, such as token and type frequency, stem structure and language contact, might correlate with the strong-to-weak shift and ablaut levelling in Class III and IV verbs in the Middle English period. The thesis is accompanied by six appendices that contain further information about my distinction of Middle English dialect areas (Appendix A), historical Class III and IV verbs (B and C) and the text samples and linguistic data from the Middle English text corpora (D, E and F).

Variation in myogenic differentiation 1 mRNA abundance is associated with beef tenderness in Nelore cattle.

The myogenic differentiation 1 gene (MYOD1) has a key role in skeletal muscle differentiation and composition through its regulation of the expression of several muscle-specific genes. We first used a general linear mixed model approach to evaluate the association of MYOD1 expression levels on individual beef tenderness phenotypes. MYOD1 mRNA levels measured by quantitative polymerase chain reactions in 136 Nelore steers were significantly associated (P ? 0.01) with Warner?Bratzler shear force, measured on the longissimus dorsi muscle after 7 and 14 days of beef aging. Transcript abundance for the muscle regulatory gene MYOD1 was lower in animals with more tender beef. We also performed a coexpression network analysis using whole transcriptome sequence data generated from 30 samples of longissimus muscle tissue to identify genes that are potentially regulated by MYOD1. The effect of MYOD1 gene expression on beef tenderness may emerge from its function as an activator of muscle-specific gene transcription such as for the serum response factor (C-fos serum response element-binding transcription factor) gene (SRF), which determines muscle tissue development, composition, growth and maturation.

Geographic Variation of Notified Ross River Virus Infections in Queensland, Australia, 1985-1996

The spatial and temporal variations of Ross River virus infections reported in Queensland, Australia, between 1985 and 1996 were studied by using the Geographic Information System. The notified cases of Ross River virus infection came from 489 localities between 1985 and 1988, 805 between 1989 and 1992, and 1,157 between 1993 and 1996 (chi2(df = 2) = 680.9; P < 0.001). There was a marked increase in the number of localities where the cases were reported by 65 percent for the period of 1989-1992 and 137 percent for 1993-1996, compared with that for 1985-1988. The geographic distribution of the notified Ross River virus cases has expanded in Queensland over recent years. As Ross River virus disease has impacted considerably on tourism and industry, as well as on residents of affected areas, more research is required to explore the causes of the geographic expansion of the notified Ross River virus infections.