Host, environment, and anthropogenic factors drive landscape dynamics of an environmentally transmitted pathogen: Sarcoptic mange in the bare-nosed wombat.

Understanding the spatial dynamics and drivers of wildlife pathogens is constrained by sampling logistics, with implications for advancing the field of landscape epidemiology and targeted allocation of management resources. However, visually apparent wildlife diseases, when combined with remote-surveillance and distribution modelling technologies, present an opportunity to overcome this landscape-scale problem. Here, we investigated dynamics and drivers of landscape-scale wildlife disease, using clinical signs of sarcoptic mange (caused by Sarcoptes scabiei) in its bare-nosed wombat (BNW; Vombatus ursinus) host. We used 53,089 camera-trap observations from over 3261 locations across the 68,401 km2 area of Tasmania, Australia, combined with landscape data and ensemble species distribution modelling (SDM). We investigated: (1) landscape variables predicted to drive habitat suitability of the host; (2) host and landscape variables associated with clinical signs of disease in the host; and (3) predicted locations and environmental conditions at greatest risk of disease occurrence, including some Bass Strait islands where BNW translocations are proposed. We showed that the Tasmanian landscape, and ecosystems therein, are nearly ubiquitously suited to BNWs. Only high mean annual precipitation reduced habitat suitability for the host. In contrast, clinical signs of sarcoptic mange disease in BNWs were widespread, but heterogeneously distributed across the landscape. Mange (which is environmentally transmitted in BNWs) was most likely to be observed in areas of increased host habitat suitability, lower annual precipitation, near sources of freshwater and where topographic roughness was minimal (e.g. human modified landscapes, such as farmland and intensive land-use areas, shrub and grass lands). Thus, a confluence of host, environmental and anthropogenic variables appear to influence the risk of environmental transmission of S. scabiei. We identified that the Bass Strait Islands are highly suitable for BNWs and predicted a mix of high and low suitability for the pathogen. This study is the largest spatial assessment of sarcoptic mange in any host species, and advances understanding of the landscape epidemiology of environmentally transmitted S. scabiei. This research illustrates how host-pathogen co-suitability can be useful for allocating management resources in the landscape.

Cellular Uptake and Efflux of Palbociclib In Vitro in Single Cell and Spheroid Models.

Adequate drug distribution through tumors is essential for treatment to be effective. Palbociclib is a cyclin-dependent kinase 4/6 inhibitor approved for use in patients with hormone receptor positive, human epidermal growth factor receptor 2 negative metastatic breast cancer. It has unusual physicochemical properties, which may significantly influence its distribution in tumor tissue. We studied the penetration and distribution of palbociclib in vitro, including the use of multicellular three-dimensional models and mathematical modeling. MCF-7 and DLD-1 cell lines were grown as single cell suspensions (SCS) and spheroids; palbociclib uptake and efflux were studied using liquid chromatography-tandem mass spectrometry. Intracellular concentrations of palbociclib for MCF-7 SCS (C max 3.22 µM) and spheroids (C max 2.91 µM) were 32- and 29-fold higher and in DLD-1, 13- and 7-fold higher, respectively, than the media concentration (0.1 µM). Total palbociclib uptake was lower in DLD-1 cells than MCF-7 cells in both SCS and spheroids. Both uptake and efflux of palbociclib were slower in spheroids than SCS. These data were used to develop a mathematical model of palbociclib transport that quantifies key parameters determining drug penetration and distribution. The model reproduced qualitatively most features of the experimental data and distinguished between SCS and spheroids, providing additional support for hypotheses derived from the experimental data. Mathematical modeling has the potential for translating in vitro data into clinically relevant estimates of tumor drug concentrations. SIGNIFICANCE STATEMENT: This study explores palbociclib uptake and efflux in single cell suspension and spheroid models of cancer. Large intracellular concentrations of palbociclib are found after drug exposure. The data from this study may aid understanding of the intratumoural pharmacokinetics of palbociclib, which is useful in understanding how drug distributes within tumor tissue and optimizing drug efficacy. Biomathematical modelling has the potential to derive intratumoural drug concentrations from plasma pharmacokinetics in patients.

Physiological complexity of gait between regular and non-exercisers with Parkinson's disease.

BACKGROUND: Physiological complexity represents overall health of a system and its underlying capacity to adapt to stresses. The primary purpose of this study was to determine if physiological complexity of gait both ON and OFF anti-Parkinson medication differed between regular and non-exercisers with Parkinson's disease. METHODS: Twenty participants with idiopathic Parkinson's disease were enrolled in this cross-sectional study (regular exercisers n = 10, non-exercisers n = 10). Two data collection sessions were completed during a single visit, first after a 12-hour overnight withdrawal from anti-Parkinson medications (OFF), and again one-hour after taking anti-Parkinson medications (ON). During each session participants completed a 2-minute walking task at their preferred pace while wearing wireless inertial measurement units on each lower extremity segment (thigh, shank, foot). Multivariate multiscale entropy was calculated from the tri-axial accelerometer signals and converted to a complexity index for analysis. FINDINGS: Regular exercisers demonstrated significantly higher complexity indices ON and OFF anti-Parkinson medications compared to non-exercisers (ON F = 3.84 P = 0.02; OFF F = 3.61, P < 0.03). Regular exercisers did not significantly differ in complexity between OFF and ON states (most affected leg F = 0.15 P = 0.71; least affected leg F = 0.30 P = 0.60), but non-exercisers demonstrated significantly decreased complexity in the least affected leg OFF anti-Parkinson medications (F = 5.17 P < 0.04). INTERPRETATION: Enhanced gait complexity in the regular exercisers may indicate that ongoing exercise is a key ingredient contributing to health in persons with Parkinson's disease. Exercising on a regular basis with Parkinson's disease may augment one's ability to adapt to barriers encountered during gait regardless of medication state.

Static and dynamic stress heterogeneity in a multiscale model of the asthmatic airway wall.

Airway hyperresponsiveness (AHR) is a key characteristic of asthma that remains poorly understood. Tidal breathing and deep inspiration ordinarily cause rapid relaxation of airway smooth muscle (ASM) (as demonstrated via application of length fluctuations to tissue strips) and are therefore implicated in modulation of AHR, but in some cases (such as application of transmural pressure oscillations to isolated intact airways) this mechanism fails. Here we use a multiscale biomechanical model for intact airways that incorporates strain stiffening due to collagen recruitment and dynamic force generation by ASM cells to show that the geometry of the airway, together with interplay between dynamic active and passive forces, gives rise to large stress and compliance heterogeneities across the airway wall that are absent in tissue strips. We show further that these stress heterogeneities result in auxotonic loading conditions that are currently not replicated in tissue-strip experiments; stresses in the strip are similar to hoop stress only at the outer airway wall and are under- or overestimates of stresses at the lumen. Taken together these results suggest that a previously underappreciated factor, stress heterogeneities within the airway wall and consequent ASM cellular response to this micromechanical environment, could contribute to AHR and should be explored further both theoretically and experimentally.

What caused extinction of the Pleistocene megafauna of Sahul?

During the Pleistocene, Australia and New Guinea supported a rich assemblage of large vertebrates. Why these animals disappeared has been debated for more than a century and remains controversial. Previous synthetic reviews of this problem have typically focused heavily on particular types of evidence, such as the dating of extinction and human arrival, and have frequently ignored uncertainties and biases that can lead to misinterpretation of this evidence. Here, we review diverse evidence bearing on this issue and conclude that, although many knowledge gaps remain, multiple independent lines of evidence point to direct human impact as the most likely cause of extinction.

The role of contractile unit reorganization in force generation in airway smooth muscle.

Airway smooth muscle (ASM) cells undergo remodelling and reside in a tissue structure that is subject to heterogenous stress distributions that change dynamically during the breathing cycle. In this paper, we develop a structural model of an ASM cell that consists of contractile units (actin and myosin filaments) in series and parallel, anchored to a nonlinearly elastic cytoskeleton. We mimic a typical experimental protocol that involves isometric force generation through triggering of the contractile machinery, followed by oscillatory length fluctuation of the cell. We use the model to predict the effect of a single instance of rearrangement of the contractile machinery, combined with strain-stiffening of the cytoskeleton, on the force generated by the sarcomeres, and the total force generated by the cell. By linking intra-cellular events to whole-cell behaviour, the model reveals mechanistic relationships between structural properties and cell-level force-length loops. We show how contractile force, shortening velocity and sarcomere operating lengths vary as the internal cell architecture is altered. Additionally, we show how interactions between the internal contractile machinery and cytoskeletal structure play a role in the regulation of force generation and hysteresis of the cell.

The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer.

BACKGROUND: HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®). Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity. METHODS: In this study we examined the effect of α-TEA plus HER2/neu-specific antibody treatment on HER2/neu-expressing breast cancer cells in vitro and in a HER2/neu positive human xenograft tumor model in vivo. RESULTS: We show in vitro that α-TEA plus anti-HER2/neu antibody has an increased cytotoxic effect against murine mammary tumor cells and human breast cancer cells and that the anti-tumor effect of α-TEA is independent of HER2/neu status. More importantly, in a human breast cancer xenograft model, the combination of α-TEA plus trastuzumab resulted in faster tumor regression and more tumor-free animals than trastuzumab alone. CONCLUSION: Due to the cancer cell selectivity of α-TEA, and because α-TEA kills both HER2/neu positive and HER2/neu negative breast cancer cells, it has the potential to be effective and less toxic than existing chemotherapeutic drugs when used in combination with HER2/neu antibody.

ß-catenin dosage is a critical determinant of tracheal basal cell fate determination.

The purpose of this study was to determine whether ß-catenin regulates basal cell fate determination in the mouse trachea. Analysis of TOPGal transgene reporter activity and Wnt/ß-catenin pathway gene expression suggested a role for ß-catenin in basal cell proliferation and differentiation after naphthalene-mediated Clara-like and ciliated cell depletion. However, these basal cell activities occurred simultaneously, limiting precise determination of the role(s) played by ß-catenin. This issue was overcome by analysis of ß-catenin signaling in tracheal air-liquid interface cultures. The cultures could be divided into two phases: basal cell proliferation and basal cell differentiation. A role for ß-catenin in basal cell proliferation was indicated by activation of the TOPGal transgene on proliferation days 3 to 5 and by transient expression of Myc (alias c-myc). Another peak of TOPGal transgene activity was detected on differentiation days 2 to 10 and was associated with the expression of Axin 2. These results suggest a role for ß-catenin in basal to ciliated and basal to Clara-like cell differentiation. Genetic stabilization of ß-catenin in basal cells shortened the period of basal cell proliferation but had a minor effect on this process. Persistent ß-catenin signaling regulated basal cell fate by driving the generation of ciliated cells and preventing the production of Clara-like cells.

Tracheal Basal cells: a facultative progenitor cell pool.

Analysis of lineage relationships in the naphthalene-injured tracheal epithelium demonstrated that two multipotential keratin 14-expressing cells (K14ECs) function as progenitors for Clara and ciliated cells. These K14EC were distinguished by their self-renewal capacity and were hypothesized to reside at the stem and transit amplifying tiers of a tissue-specific stem cell hierarchy. In this study, we used gene expression and histomorphometric analysis of the steady-state and naphthalene-injured trachea to evaluate the predictions of this model. We found that the steady-state tracheal epithelium is maintained by two progenitor cell pools, secretory and basal cells, and the latter progenitor pool is further divided into two subsets, keratin 14-negative and -positive. After naphthalene-mediated depletion of the secretory and ciliated cell types, the two basal cell pools coordinate to restore the epithelium. Both basal cell types up-regulate keratin 14 and generate a broadly distributed, abundant, and highly mitotic cell pool. Furthermore, basal cell proliferation is associated with generation of differentiated Clara and ciliated cells. The uniform distribution of basal cell progenitors and of their differentiated progeny leads us to propose that the hierarchical organization of tracheal reparative cells be revised to include a facultative basal cell progenitor pool.

A biomechanical model of agonist-initiated contraction in the asthmatic airway.

This paper presents a modelling framework in which the local stress environment of airway smooth muscle (ASM) cells may be predicted and cellular responses to local stress may be investigated. We consider an elastic axisymmetric model of a layer of connective tissue and circumferential ASM fibres embedded in parenchymal tissue and model the active contractile force generated by ASM via a stress acting along the fibres. A constitutive law is proposed that accounts for active and passive material properties as well as the proportion of muscle to connective tissue. The model predicts significantly different contractile responses depending on the proportion of muscle to connective tissue in the remodelled airway. We find that radial and hoop-stress distributions in remodelled muscle layers are highly heterogenous with distinct regions of compression and tension. Such patterns of stress are likely to have important implications, from a mechano-transduction perspective, on contractility, short-term cytoskeletal adaptation and long-term airway remodelling in asthma.

A computer model of the artificially ventilated human respiratory system in adult intensive care.

A multi-technique approach to modelling artificially ventilated patients on the adult general intensive care unit (ICU) is proposed. Compartmental modelling techniques were used to describe the mechanical ventilator and the flexible hoses that connect it to the patient. 3D CFD techniques were used to model flow in the major airways and a Windkessel style balloon model was used to model the mechanical properties of the lungs. A multi-compartment model of the lung based on bifurcating tree structures representing the conducting airways and pulmonary circulation allowed lung disease to be modelled in terms of altered V/Q ratios within a lognormal distribution of values and it is from these that gas exchange was determined. A compartmental modelling tool, Bathfp, was used to integrate the different modelling techniques into a single model. The values of key parameters in the model could be obtained from measurements on patients in an ICU whilst a sensitivity analysis showed that the model was insensitive to the value of other parameters within it. Measured and modelled values for arterial blood gases and airflow parameters are compared for 46 ventilator settings obtained from 6 ventilator dependent patients. The results show correlation coefficients of 0.88 and 0.85 for the arterial partial pressures of the O(2) and CO(2), respectively (p<0.01) and of 0.99 and 0.96 for upper airway pressure and tidal volume, respectively (p<0.01). The difference between measured and modelled values was large in physiological terms, suggesting that some optimisation of the model is required.

Dynamics of range margins for metapopulations under climate change.

We link spatially explicit climate change predictions to a dynamic metapopulation model. Predictions of species' responses to climate change, incorporating metapopulation dynamics and elements of dispersal, allow us to explore the range margin dynamics for two lagomorphs of conservation concern. Although the lagomorphs have very different distribution patterns, shifts at the edge of the range were more pronounced than shifts in the overall metapopulation. For Romerolagus diazi (volcano rabbit), the lower elevation range limit shifted upslope by approximately 700 m. This reduced the area occupied by the metapopulation, as the mountain peak currently lacks suitable vegetation. For Lepus timidus (European mountain hare), we modelled the British metapopulation. Increasing the dispersive estimate caused the metapopulation to shift faster on the northern range margin (leading edge). By contrast, it caused the metapopulation to respond to climate change slower, rather than faster, on the southern range margin (trailing edge). The differential responses of the leading and trailing range margins and the relative sensitivity of range limits to climate change compared with that of the metapopulation centroid have important implications for where conservation monitoring should be targeted. Our study demonstrates the importance and possibility of moving from simple bioclimatic envelope models to second-generation models that incorporate both dynamic climate change and metapopulation dynamics.

The EuroPhysiome, STEP and a roadmap for the virtual physiological human.

Biomedical science and its allied disciplines are entering a new era in which computational methods and technologies are poised to play a prevalent role in supporting collaborative investigation of the human body. Within Europe, this has its focus in the virtual physiological human (VPH), which is an evolving entity that has emerged from the EuroPhysiome initiative and the strategy for the EuroPhysiome (STEP) consortium. The VPH is intended to be a solution to common infrastructure needs for physiome projects across the globe, providing a unifying architecture that facilitates integration and prediction, ultimately creating a framework capable of describing Homo sapiens in silico. The routine reliance of the biomedical industry, biomedical research and clinical practice on information technology (IT) highlights the importance of a tailor-made and robust IT infrastructure, but numerous challenges need to be addressed if the VPH is to become a mature technological reality. Appropriate investment will reap considerable rewards, since it is anticipated that the VPH will influence all sectors of society, with implications predominantly for improved healthcare, improved competitiveness in industry and greater understanding of (patho)physiological processes. This paper considers issues pertinent to the development of the VPH, highlighted by the work of the STEP consortium.

Quantification of lung injury using ventilation and perfusion distributions obtained from gamma scintigraphy.

This paper explores the potential of isotope V/Q lung scans to quantify lung disease. Areas of restricted perfusion in subjects with a pulmonary embolus (PE) were identified in 3D reconstructions of V/Q images achieved using anatomical data from the Visible Human Project. From these, the extent of lung damage was quantified. Significant differences in the values of both LogSD V and LogSD Q (p > 0.05) obtained from plots of V and Q against Log(V/Q) were found between normal subjects and subjects with a PE, but no correlation was found between either of these parameters and the degree of lung damage in subjects with a PE (p > 0.05). Whilst V/Q values were log normally distributed, the V/Q distributions from the subjects with a PE failed to show the bimodal distribution predicted from theoretical considerations and MIGET measurements previously reported. There was a statistically significant difference in the mean and standard deviation values of the V/Q distributions between normal subject and subjects with a PE (p < 0.05) but not in the median values (p > 0.05). There was no correlation between the mean, median and standard deviation of the distributions from the subjects with a PE and the percentage of damage present (p > 0.05).

Chondrogenic differentiation potential of human mesenchymal stem cells photoencapsulated within poly(ethylene glycol)-arginine-glycine-aspartic acid-serine thiol-methacrylate mixed-mode networks.

Chondrogenesis of human mesenchymal stem cells (hMSCs) encapsulated in poly(ethylene glycol) (PEG)-based hydrogels was studied in the presence and absence of 5 ng/mL transforming growth factor beta and chondrogenic medium to better understand the role of the gel environment on this process. The lack of any cell-polymer interactions led to decreasing cell viability, as measured using adenosine triphosphate, over a 14-day period. The extent of chondrogenic differentiation was evaluated by immunostaining, and although viability dramatically decreased, cells cultured in chondrogenic differentiation medium expressed higher levels of collagen type II. Cells cultured in hMSC control medium remained undifferentiated and continued to express CD105, a MSC marker. To increase cell survival, arginine-glycine-aspartic acid-serine (RGDS) was incorporated into gels using a novel mixed-mode thiol-ene reaction by synthesizing a cysteine-cysteine-arginine-glycine-aspartic acid-serine-cysteine-cysteine-glycine, N-terminus to C-terminus peptide sequence with pendant cysteine residues. A concentration of 5 mM RGDS incorporated into the network maintained 75% viability in control cultures. Further studies demonstrated that 5-mM RGDS chondrogenic cultures had greater gene expression for aggrecan and collagen II in conjunction with producing twice as much glycosaminoglycan as 0-mM chondrogenic cultures and 7 times that of control cultures. Incorporation of this peptide sequence not only allows for sustained viability, but also contributes to initiating chondrogenesis.

Radiological imaging as the basis for a simulation software of ventilation in the tracheo-bronchial tree.

The inhaled route is a promising new way for administering drugs to the human body. Flow and particle deposition in the human respiratory tract depends on the individual's anatomy as well as on the drug composition. A European Framework V Program supported project is currently developing a simulation tool for assessment of drug distribution and deposition. This tool relies heavily on the input of radiological data sets, which are obtained in humans. Both high temporal and spatial resolutions are required, and CT and MRI (including hyperpolarized helium-3 MRI) are applied. The radiological data are integrated into computation fluid dynamics software, which is capable of assessing air-flow profiles and compartmental behaviours. This is complemented by pharmacokinetic models, which should result in a simulation tool that will be of use for the theoretical design of new inhaled therapies. This article describes the special imaging requirements of each region of the respiratory tract and the feasibility of these sophisticated radiological techniques with a view of using these data in a simulation model of the lung.

A model for time-dependent flow in (giraffe jugular) veins: uniform tube properties.

Computations are reported for a one-dimensional model of time-dependent flow in collapsible tubes representing long mammalian veins. The tubes are taken to have uniform intrinsic properties and we concentrate on the effect of longitudinal gravity. The main application is to the jugular vein of the upright giraffe, with given inflow rate from the head, a given pressure, slightly above the external, atmospheric pressure, at the downstream (vena caval) end, and a variety of initial conditions. We show that: (i) previously calculated steady flows are the long time limits of unsteady computations, although only after a considerable time in which slowly-decaying waves and elastic jumps propagate up and down, (ii) steady flows are indeed not found when the steady-flow analysis shown them not to exist, although the consequent unsteadiness is of such small amplitude as to be practically unimportant, (iii) the time taken for the flow to become steady when the neck is raised from the horizontal or the head-down position can be several seconds longer than the neck-raising time itself (3-7s). We also find that roll-waves do not develop despite having been previously predicted for long collapsible tubes. Further application is made to the effect of postural changes on human neck and leg veins.

Predictive accuracy of population viability analysis in conservation biology.

Population viability analysis (PVA) is widely applied in conservation biology to predict extinction risks for threatened species and to compare alternative options for their management. It can also be used as a basis for listing species as endangered under World Conservation Union criteria. However, there is considerable scepticism regarding the predictive accuracy of PVA, mainly because of a lack of validation in real systems. Here we conducted a retrospective test of PVA based on 21 long-term ecological studies--the first comprehensive and replicated evaluation of the predictive powers of PVA. Parameters were estimated from the first half of each data set and the second half was used to evaluate the performance of the model. Contrary to recent criticisms, we found that PVA predictions were surprisingly accurate. The risk of population decline closely matched observed outcomes, there was no significant bias, and population size projections did not differ significantly from reality. Furthermore, the predictions of the five PVA software packages were highly concordant. We conclude that PVA is a valid and sufficiently accurate tool for categorizing and managing endangered species.