Evolution to a chronic disease niche correlates with increased sensitivity to tryptophan availability for the obligate intracellular bacterium Chlamydia pneumoniae

The chlamydiae are obligate intracellular parasites that have evolved specific interactions with their various hosts and host cell types to ensure their successful survival and consequential pathogenesis. The species Chlamydia pneumoniae is ubiquitous, with serological studies showing that most humans are infected at some stage in their lifetime. While most human infections are asymptomatic, C. pneumoniae can cause more-severe respiratory disease and pneumonia and has been linked to chronic diseases such as asthma, atherosclerosis, and even Alzheimer's disease. The widely dispersed animal-adapted C. pneumoniae strains cause an equally wide range of diseases in their hosts. It is emerging that the ability of C. pneumoniae to survive inside its target cells, including evasion of the host's immune attack mechanisms, is linked to the acquisition of key metabolites. Tryptophan and arginine are key checkpoint compounds in this host-parasite battle. Interestingly, the animal strains of C. pneumoniae have a slightly larger genome, enabling them to cope better with metabolite restrictions. It therefore appears that as the evolutionarily more ancient animal strains have evolved to infect humans, they have selectively become more "susceptible" to the levels of key metabolites, such as tryptophan. While this might initially appear to be a weakness, it allows these human C. pneumoniae strains to exquisitely sense host immune attack and respond by rapidly reverting to a persistent phase. During persistence, they reduce their metabolic levels, halting progression of their developmental cycle, waiting until the hostile external conditions have passed before they reemerge.

Increased sensitivity to tryptophan bioavailability is a positive adaptation by the human strains of Chlamydia pneumoniae

One of the most significant activities induced by interferon-gamma against intracellular pathogens is the induction of IDO (indoleamine 2,3-dioxygenase) expression, which subsequently results in the depletion of tryptophan. We tested the hypothesis that human strains of Chlamydia pneumoniae are more sensitive to tryptophan limitation than animal C. pneumoniae strains. The human strains were significantly more sensitive to IFN-γ than the animal strains in a lung epithelia cell model (BEAS-2B), with exposure to 1 U ml(-1) IFN-γ resulting in complete loss of infectious yield of human strains, compared to the animal strains where reductions in infectious progeny were around 3.5-4.0 log. Strikingly, the IFN-γ induced loss of ability to form infectious progeny production was completely rescued by removal of the IFN-γ and addition of exogenous tryptophan for the human strains, but not the animal strains. In fact, a human heart strain was more capable of entering a non-infectious, viable persistent stage when exposed to IFN-γ and was also more effectively rescued, compared to a human respiratory strain. Exquisite susceptibility to IFN-γ, specifically due to tryptophan availability appears to be a core adaptation of the human C. pneumoniae strains, which may reflect the chronic nature of their infections in this host.

The effects of exercise and adipose tissue lipolysis on plasma adiponectin concentration and adiponectin receptor expression in human skeletal muscle

Objective It has been suggested that adiponectin regulates plasma free fatty acid (FFA) clearance by stimulating FFA uptake and/or oxidation in muscle. We aimed to determine changes in plasma adiponectin concentration and adiponectin receptor 1 and 2 mRNA expression in skeletal muscle during and after prolonged exercise under normal, fasting conditions (high FFA trial; HFA) and following pharmacological inhibition of adipose tissue lipolysis (low FFA trial; LFA). Furthermore, we aimed to detect and locate adiponectin in skeletal muscle tissue. Methods Ten subjects performed two exercise trials (120 min at 50% VO2max). Indirect calorimetry was used to determine total fat oxidation rate. Plasma samples were collected at rest, during exercise and during post-exercise recovery to determine adiponectin, FFA and glycerol concentrations. Muscle biopsies were taken to determine adiponectin protein and adiponectin receptor 1 and 2 mRNA expression and to localise intramyocellular adiponectin. Results Basal plasma adiponectin concentrations averaged 6.57±0.7 and 6.63±0.8 mg/l in the HFA and LFA trials respectively, and did not change significantly during or after exercise. In the LFA trial, plasma FFA concentrations and total fat oxidation rates were substantially reduced. However, plasma adiponectin and muscle adiponectin receptor 1 and 2 mRNA expression did not differ between trials. Immunohistochemical staining of muscle cross-sections showed the presence of adiponectin in the sarcolemma of individual muscle fibres and within the interfibrillar arterioles. Conclusion Plasma adiponectin concentrations and adiponectin receptor 1 and 2 mRNA expression in muscle are not acutely regulated by changes in adipose tissue lipolysis and/or plasma FFA concentrations. Adiponectin is abundantly expressed in muscle, and, for the first time, it has been shown to be present in/on the sarcolemma of individual muscle fibres.

Three-dimensional flow-through protein platform

We have developed a new protein microarray (Immuno-Flow Protein Platform, IFPP) that utilizes a porous nitrocellulose (NC) membrane with printed spots of capture probes. The sample is pumped actively through the NC membrane, to enhance binding efficiency and introduce stringency. Compared to protein microarrays assayed with the conventional incubation-shaking method the rate of binding is enhanced on the IFPP by at least a factor of 10, so that the total assay time can be reduced drastically without compromising sensitivity. Similarly, the sensitivity can be improved. We demonstrate the detection of 1 pM of C-reactive protein (CRP) in 70 mu L of plasma within a total assay time of 7 min. The small sample and reagent volumes, combined with the speed of the assay, make our IFPP also well-suited for a point-of-care/near-patient setting. The potential clinical application of the IFPP is demonstrated by validating CRP detection both in human plasma and serum samples against standard clinical laboratory methods.

Evaluation of the potential impact of the global economic crisis on HIV epidemics in Southeast Asia

Economic conditions around the world are likely to deteriorate in the short to medium term. The potential impact of this crisis on the spread of HIV is not clear. Government revenues and aid flows from international donors may face constraints, possibly leading to reductions in funding for HIV programs. Economic conditions (leading to increases in unemployment, for example) may also have an indirect impact on HIV epidemics by affecting the behaviour of individual people. Some behavioural changes may influence the rate of HIV transmission. This report presents findings from a study that investigates the potential impact of the economic crisis on HIV epidemics through the use of mathematical modelling. The potential epidemiological impacts of changes in the economy are explored for two distinctly characterised HIV epidemics: (i) a well-defined, established, and generalised HIV epidemic (specifically Cambodia, where incidence is declining); (ii) an HIV epidemic in its early expansion phase (specifically Papua New Guinea, where incidence has not yet peaked). Country-specific data are used for both settings and the models calibrated to accurately reflect the unique HIV epidemics in each population in terms of both incidence and prevalence. Models calibrated to describe the past and present epidemics are then used to forecast epidemic trajectories over the next few years under assumptions that behavioural or program conditions may change due to economic conditions. It should be noted that there are very limited solid data on how HIV/AIDS program funds may decrease or how social determinants related to HIV risk may change due to the economic crisis. Potential changes in key relevant factors were explored, along with sensitivity ranges around these assumptions, based on extensive discussions with in-country and international experts and stakeholders. As with all mathematical models, assumptions should be reviewed critically and results interpreted cautiously.

Blast response and sensitivity analysis of segmental tunnel

This research treated the response of underground transportation tunnels to surface blast loads using advanced computer simulation techniques. The influences of important parameters, such as tunnel material, geometrical configuration of segments and surrounding soil were investigated. The findings of this research offer significant new information on the blast performance of underground tunnels and will contribute towards future civil engineering applications.

The effects of metabolic work rate and ambient environment on physiological tolerance times while wearing explosive and chemical personal protective equipment

This study evaluated the physiological tolerance times when wearing explosive and chemical (>35kg) personal protective equipment (PPE) in simulated environmental extremes across a range of differing work intensities. Twelve healthy males undertook nine trials which involved walking on a treadmill at 2.5, 4 and 5.5 km.h-1 in the following environmental conditions, 21, 30 and 37 °C wet bulb globe temperature (WBGT). Participants exercised for 60 min or until volitional fatigue, core temperature reached 39 °C, or heart rate exceeded 90% of maximum. Tolerance time, core temperature, skin temperature, mean body temperature, heart rate and body mass loss were measured. Exercise time was reduced in the higher WBGT environments (WBGT37rate exceeding 90% of their maximum. A total of eight trials (7.4%) lasted the full duration. Only nine (8.3%) trials were terminated due to volitional fatigue and six (5.6%) due to core temperatures in excess of 39 °C. These results demonstrate that physiological tolerance times are influenced by the external environment and workload, and that cardiovascular strain is the limiting factor to work tolerance when wearing this heavy multi layered PPE.

The driving visual field and a history of motor vehicle collision involvement in older drivers: A population-based examination

Purpose We designed a visual field test focused on the field utilized while driving to examine associations between field impairment and motor vehicle collision involvement in 2,000 drivers ≥70 years old. Methods The "driving visual field test" involved measuring light sensitivity for 20 targets in each eye, extending 15° superiorly, 30° inferiorly, 60° temporally and 30° nasally. The target locations were selected on the basis that they fell within the field region utilized when viewing through the windshield of a vehicle or viewing the dashboard while driving. Monocular fields were combined into a binocular field based on the more sensitive point from each eye. Severe impairment in the overall field or a region was defined as average sensitivity in the lowest quartile of sensitivity. At-fault collision involvement for five years prior to enrollment was obtained from state records. Poisson regression was used to calculate crude and adjusted rate ratios examining the association between field impairment and at-fault collision involvement. Results Drivers with severe binocular field impairment in the overall driving visual field had a 40% increased rate of at-fault collision involvement (RR 1.40, 95%CI 1.07-1.83). Impairment in the lower and left fields was associated with elevated collision rates (RR 1.40 95%CI 1.07-1.82 and RR 1.49, 95%CI 1.15-1.92, respectively), whereas impairment in the upper and right field regions was not. Conclusions Results suggest that older drivers with severe impairment in the lower or left region of the driving visual field are more likely to have a history of at-fault collision involvement.

A new ambiguity acceptance test threshold determination method with controllable failure rate

The ambiguity acceptance test is an important quality control procedure in high precision GNSS data processing. Although the ambiguity acceptance test methods have been extensively investigated, its threshold determine method is still not well understood. Currently, the threshold is determined with the empirical approach or the fixed failure rate (FF-) approach. The empirical approach is simple but lacking in theoretical basis, while the FF-approach is theoretical rigorous but computationally demanding. Hence, the key of the threshold determination problem is how to efficiently determine the threshold in a reasonable way. In this study, a new threshold determination method named threshold function method is proposed to reduce the complexity of the FF-approach. The threshold function method simplifies the FF-approach by a modeling procedure and an approximation procedure. The modeling procedure uses a rational function model to describe the relationship between the FF-difference test threshold and the integer least-squares (ILS) success rate. The approximation procedure replaces the ILS success rate with the easy-to-calculate integer bootstrapping (IB) success rate. Corresponding modeling error and approximation error are analysed with simulation data to avoid nuisance biases and unrealistic stochastic model impact. The results indicate the proposed method can greatly simplify the FF-approach without introducing significant modeling error. The threshold function method makes the fixed failure rate threshold determination method feasible for real-time applications.

A sensitivity analysis of train speed and its effect on railway capacity

Increasing train speeds is conceptually a simple and straight forward method to expand railway capacity, for example in comparison to other more extensive and elaborate alternatives. In this article an analytical capacity model has been investigated as a means of performing a sensitivity analysis of train speeds. The results of this sensitivity analysis can help improve the operation of this railway system and to help it cope with additional demands in the future. To test our approach a case study of the Rah Ahane Iran (RAI) national railway network has been selected. The absolute capacity levels for this railway network have been determined and the analysis shows that increasing trains speeds may not be entirely cost effective in all circumstances.

Age-related changes in perception of movement in driving scenes

Purpose Age-related changes in motion sensitivity have been found to relate to reductions in various indices of driving performance and safety. The aim of this study was to investigate the basis of this relationship in terms of determining which aspects of motion perception are most relevant to driving. Methods Participants included 61 regular drivers (age range 22–87 years). Visual performance was measured binocularly. Measures included visual acuity, contrast sensitivity and motion sensitivity assessed using four different approaches: (1) threshold minimum drift rate for a drifting Gabor patch, (2) Dmin from a random dot display, (3) threshold coherence from a random dot display, and (4) threshold drift rate for a second-order (contrast modulated) sinusoidal grating. Participants then completed the Hazard Perception Test (HPT) in which they were required to identify moving hazards in videos of real driving scenes, and also a Direction of Heading task (DOH) in which they identified deviations from normal lane keeping in brief videos of driving filmed from the interior of a vehicle. Results In bivariate correlation analyses, all motion sensitivity measures significantly declined with age. Motion coherence thresholds, and minimum drift rate threshold for the first-order stimulus (Gabor patch) both significantly predicted HPT performance even after controlling for age, visual acuity and contrast sensitivity. Bootstrap mediation analysis showed that individual differences in DOH accuracy partly explained these relationships, where those individuals with poorer motion sensitivity on the coherence and Gabor tests showed decreased ability to perceive deviations in motion in the driving videos, which related in turn to their ability to detect the moving hazards. Conclusions The ability to detect subtle movements in the driving environment (as determined by the DOH task) may be an important contributor to effective hazard perception, and is associated with age, and an individuals' performance on tests of motion sensitivity. The locus of the processing deficits appears to lie in first-order, rather than second-order motion pathways.