A Mathematical Framework for Predicting Lifestyles of Viral Pathogens.

Despite being similar in structure, functioning, and size, viral pathogens enjoy very different, usually well-defined ways of life. They occupy their hosts for a few days (influenza), for a few weeks (measles), or even lifelong (HCV), which manifests in acute or chronic infections. The various transmission routes (airborne, via direct physical contact, etc.), degrees of infectiousness (referring to the viral load required for transmission), antigenic variation/immune escape and virulence define further aspects of pathogenic lifestyles. To survive, pathogens must infect new hosts; the success determines their fitness. Infection happens with a certain likelihood during contact of hosts, where contact can also be mediated by vectors. Besides structural aspects of the host-contact network, three parameters appear to be key: the contact rate and the infectiousness during contact, which encode the mode of transmission, and third the immunity of susceptible hosts. On these grounds, what can be said about the reproductive success of viral pathogens? This is the biological question addressed in this paper. The answer extends earlier results of the author and makes explicit connection to another basic work on the evolution of pathogens. A mathematical framework is presented that models intra- and inter-host dynamics in a minimalistic but unified fashion covering a broad spectrum of viral pathogens, including those that cause flu-like infections, childhood diseases, and sexually transmitted infections. These pathogens turn out as local maxima of numerically simulated fitness landscapes. The models involve differential and integral equations, agent-based simulation, networks, and probability.

Follicular competition in cows: the selection of dominant follicles as a synergistic effect.

The reproductive cycle of mono-ovulatory species such as cows or humans is known to show two or more waves of follicular growth and decline between two successive ovulations. Within each wave, there is one dominant follicle escorted by subordinate follicles of varying number. Under the surge of the luteinizing hormone a growing dominant follicle ovulates. Rarely the number of ovulating follicles exceeds one. In the biological literature, the change of hormonal concentrations and individually varying numbers of follicular receptors are made responsible for the selection of exactly one dominant follicle, yet a clear cause has not been identified. In this paper, we suggest a synergistic explanation based on competition, formulated by a parsimoniously defined system of ordinary differential equations (ODEs) that quantifies the time evolution of multiple follicles and their competitive interaction during one wave. Not discriminating between follicles, growth and decline are given by fixed rates. Competition is introduced via a growth-suppressing term, equally supported by all follicles. We prove that the number of dominant follicles is determined exclusively by the ratio of follicular growth and competition. This number turns out to be independent of the number of subordinate follicles. The asymptotic behavior of the corresponding dynamical system is investigated rigorously, where we demonstrate that the [Formula: see text]-limit set only contains fixed points. When also including follicular decline, our ODEs perfectly resemble ultrasound data of bovine follicles. Implications for the involved but not explicitly modeled hormones are discussed.

Device-Embedded Cameras for Eye Tracking-Based Cognitive Assessment: Validation With Paper-Pencil and Computerized Cognitive Composites.

BACKGROUND: As eye tracking-based assessment of cognition becomes more widely used in older adults, particularly those at risk for dementia, reliable and scalable methods to collect high-quality data are required. Eye tracking-based cognitive tests that utilize device-embedded cameras have the potential to reach large numbers of people as a screening tool for preclinical cognitive decline. However, to fully validate this approach, more empirical evidence about the comparability of eyetracking-based paradigms to existing cognitive batteries is needed. OBJECTIVE: Using a population of clinically normal older adults, we examined the relationship between a 30-minute Visual Paired Comparison (VPC) recognition memory task and cognitive composite indices sensitive to a subtle decline in domains associated with Alzheimer disease. Additionally, the scoring accuracy between software used with a commercial grade eye tracking camera at 60 frames per second (FPS) and a manually scored procedure used with a laptop-embedded web camera (3 FPS) on the VPC task was compared, as well as the relationship between VPC task performance and domain-specific cognitive function. METHODS: A group of 49 clinically normal older adults completed a 30-min VPC recognition memory task with simultaneous recording of eye movements by a commercial-grade eye-tracking camera and a laptop-embedded camera. Relationships between webcam VPC performance and the Preclinical Alzheimer Cognitive Composite (PACC) and National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB) were examined. Inter-rater reliability for manually scored tests was analyzed using Krippendorff's kappa formula, and we used Spearman's Rho correlations to investigate the relationship between VPC performance scores with both cameras. We also examined the relationship between VPC performance with the device-embedded camera and domain-specific cognitive performance. RESULTS: Modest relationships were seen between mean VPC novelty preference and the PACC (r=.39, P=.007) and NIHTB-CB (r=.35, P=.03) composite scores, and additional individual neurocognitive task scores including letter fluency (r=.33, P=.02), category fluency (r=.36, P=.01), and Trail Making Test A (-.40, P=.006). Robust relationships were observed between the 60 FPS eye tracker and 3 FPS webcam on both trial-level VPC novelty preference (r=.82, P<.001) and overall mean VPC novelty preference (r=.92 P<.001). Inter-rater agreement of manually scored web camera data was high (kappa=.84). CONCLUSIONS: In a sample of clinically normal older adults, performance on a 30-minute VPC task correlated modestly with computerized and paper-pencil based cognitive composites that serve as preclinical Alzheimer disease cognitive indices. The strength of these relationships did not differ between camera devices. We suggest that using a device-embedded camera is a reliable and valid way to assess performance on VPC tasks accurately and that these tasks correlate with existing cognitive composites.

Reconstruction of disease transmission rates: Applications to measles, dengue, and influenza.

Transmission rates are key in understanding the spread of infectious diseases. Using the framework of compartmental models, we introduce a simple method to reconstruct time series of transmission rates directly from incidence or disease-related mortality data. The reconstruction employs differential equations, which model the time evolution of infective stages and strains. Being sensitive to initial values, the method produces asymptotically correct solutions. The computations are fast, with time complexity being quadratic. We apply the reconstruction to data of measles (England and Wales, 1948-1967), dengue (Thailand, 1982-1999), and influenza (U.S., 1910-1927). The Measles example offers comparison with earlier work. Here we re-investigate reporting corrections, include and exclude demographic information. The dengue example deals with the failure of vector-control measures in reducing dengue hemorrhagic fever (DHF) in Thailand. Two competing mechanisms have been held responsible: strain interaction and demographic transitions. Our reconstruction reveals that both explanations are possible, showing that the increase in DHF cases is consistent with decreasing transmission rates resulting from reduced vector counts. The flu example focuses on the 1918/1919 pandemic, examining the transmission rate evolution for an invading strain. Our analysis indicates that the pandemic strain could have circulated in the population for many months before the pandemic was initiated by an event of highly increased transmission.

Sox17 is required for normal pulmonary vascular morphogenesis.

The SRY-box containing transcription factor Sox17 is required for endoderm formation and vascular morphogenesis during embryonic development. In the lung, Sox17 is expressed in mesenchymal progenitors of the embryonic pulmonary vasculature and is restricted to vascular endothelial cells in the mature lung. Conditional deletion of Sox17 in splanchnic mesenchyme-derivatives using Dermo1-Cre resulted in substantial loss of Sox17 from developing pulmonary vascular endothelial cells and caused pulmonary vascular abnormalities before birth, including pulmonary vein varices, enlarged arteries, and decreased perfusion of the microvasculature. While survival of Dermo1-Cre;Sox17Δ/Δ mice (herein termed Sox17Δ/Δ) was unaffected at E18.5, most Sox17Δ/Δ mice died by 3 weeks of age. After birth, the density of the pulmonary microvasculature was decreased in association with alveolar simplification, biventricular cardiac hypertrophy, and valvular regurgitation. The severity of the postnatal cardiac phenotype was correlated with the severity of pulmonary vasculature abnormalities. Sox17 is required for normal formation of the pulmonary vasculature and postnatal cardiovascular homeostasis.

Different ways of looking at the force between two nanocrystals.

The potential of mean force (PMF) between two nanocrystals (NCs) represents an effective interaction potential that is essential when explaining the assembly of NCs to superstructures. For a given temperature, the PMF is obtained best from molecular dynamics simulations. Based on a density functional approach, this study proposes three methods of predicting the PMF for any given temperature based on a single molecular dynamics simulation for one temperature. The three methods construct the PMF by considering the ligands as an ideal gas, as hard-sphere chains, or as Lennard-Jones interaction sites. To apply this methodology, the density of the interaction centers must be extracted from the simulation data. For the ideal gas model, a straightforward sampling procedure with a fixed lattice in space leads to free energies that are too large in order to consistently explain the simulation data for different temperatures. Naive sampling does not account for the small momenta added to the NCs when coupled to a thermostat. A method is proposed that corrects for the unphysical steps during the simulation. The ideal gas contribution computed for the corrected density is significantly smaller than the one obtained from naive sampling and can thus explain the temperature dependence of the PMF correctly. For the hard-sphere chain model, where a weighted density is used, the correction of the particle density is not essential. However, the PMF calculated based on the corrected density confirms our approach. All three models predict PMF curves in very good agreement with simulation results, but they differ in the number of input parameters and the computational effort. Based on the modeling results, we predict the existence of an additional attractive force at small distances of the NCs - a depletion force.

NFATC1 promotes epicardium-derived cell invasion into myocardium.

Epicardium-derived cells (EPDCs) contribute to formation of coronary vessels and fibrous matrix of the mature heart. Nuclear factor of activated T-cells cytoplasmic 1 (NFATC1) is expressed in cells of the proepicardium (PE), epicardium and EPDCs in mouse and chick embryos. Conditional loss of NFATC1 expression in EPDCs in mice causes embryonic death by E18.5 with reduced coronary vessel and fibrous matrix penetration into myocardium. In osteoclasts, calcineurin-mediated activation of NFATC1 by receptor activator of NFκB ligand (RANKL) signaling induces cathepsin K (CTSK) expression for extracellular matrix degradation and cell invasion. RANKL/NFATC1 pathway components also are expressed in EPDCs, and loss of NFATC1 in EPDCs causes loss of CTSK expression in the myocardial interstitium in vivo. Likewise, RANKL treatment induces Ctsk expression in PE-derived cell cultures via a calcineurin-dependent mechanism. In chicken embryo hearts, RANKL treatment increases the distance of EPDC invasion into myocardium, and this response is calcineurin dependent. Together, these data demonstrate a crucial role for the RANKL/NFATC1 signaling pathway in promoting invasion of EPDCs into the myocardium by induction of extracellular matrix-degrading enzyme gene expression.

Inkjet printed solar cell active layers based on a novel, amorphous polymer.

Organic solar cells are a favorable alternative to their inorganic counterparts because the functional layers of these devices can be processed with printing or coating on a large scale. In this study, a novel polymer was synthesized, blended with fullerene and deposited with inkjet printing for solar cell applications. Devices with printed layers were compared to those with spin coated films in order to evaluate inkjet printing as a thin film deposition method. Efficiency values of 3.7% were found for devices with inkjet printed or spin coated layers. Inkjet printing can be used to successfully process the active layers of organic solar cells consisting of novel polymers without sacrificing device performance.

Sox2 activates cell proliferation and differentiation in the respiratory epithelium.

Sox2, a transcription factor critical for the maintenance of embryonic stem cells and induction of pluripotent stem cells, is expressed exclusively in the conducting airway epithelium of the lung, where it is required for differentiation of nonciliated, goblet, and ciliated cells. To determine the role of Sox2 in respiratory epithelial cells, Sox2 was selectively and conditionally expressed in nonciliated airway epithelial cells and in alveolar type II cells in the adult mouse. Sox2 induced epithelial cell proliferation within 3 days of expression. Epithelial cell proliferation was associated with increased Ki-67 and cyclin D1 staining. Expression of cell cycle genes, including FoxM1, Ccna2 (Cyclin A2), Ccnb2 (Cyclin B2), and Ccnd1 (Cyclin D1), was increased. Consistent with a role in cell proliferation, Sox2 activated the transcription of FoxM1 in vitro. In alveoli, Sox2 caused hyperplasia and ectopic differentiation of epithelial cells to those with morphologic and molecular characteristics of conducting airway epithelium. Sox2 induced the expression of conducting airway epithelial specific genes, including Scgb1a1, Foxj1, Tubb3, and Cyp2f2. Although prolonged expression of Sox2 caused cell proliferation and epithelial hyperplasia, Sox2 did not induce pulmonary tumors. Sox2 induces proliferation of respiratory epithelial cells and, subsequently, partially reprograms alveolar epithelial cells into cells with characteristics of the conducting airways.

Antigenic diversity, transmission mechanisms, and the evolution of pathogens.

Pathogens have evolved diverse strategies to maximize their transmission fitness. Here we investigate these strategies for directly transmitted pathogens using mathematical models of disease pathogenesis and transmission, modeling fitness as a function of within- and between-host pathogen dynamics. The within-host model includes realistic constraints on pathogen replication via resource depletion and cross-immunity between pathogen strains. We find three distinct types of infection emerge as maxima in the fitness landscape, each characterized by particular within-host dynamics, host population contact network structure, and transmission mode. These three infection types are associated with distinct non-overlapping ranges of levels of antigenic diversity, and well-defined patterns of within-host dynamics and between-host transmissibility. Fitness, quantified by the basic reproduction number, also falls within distinct ranges for each infection type. Every type is optimal for certain contact structures over a range of contact rates. Sexually transmitted infections and childhood diseases are identified as exemplar types for low and high contact rates, respectively. This work generates a plausible mechanistic hypothesis for the observed tradeoff between pathogen transmissibility and antigenic diversity, and shows how different classes of pathogens arise evolutionarily as fitness optima for different contact network structures and host contact rates.

Model-based exploration of the impact of glucose metabolism on the estrous cycle dynamics in dairy cows.

BACKGROUND: Nutrition plays a crucial role in regulating reproductive hormones and follicular development in cattle. This is visible particularly during the time of negative energy balance at the onset of milk production after calving. Here, elongated periods of anovulation have been observed, resulting from alterations in luteinizing hormone concentrations, likely caused by lower glucose and insulin concentrations in the blood. The mechanisms that result in a reduced fertility are not completely understood, although a close relationship to the glucose-insulin metabolism is widely supported. RESULTS: Following this idea, we developed a mathematical model of the hormonal network combining reproductive hormones and hormones that are coupled to the glucose compartments within the body of the cow. The model is built on ordinary differential equations and relies on previously introduced models on the bovine estrous cycle and the glucose-insulin dynamics. Necessary modifications and coupling mechanisms are thoroughly discussed. Depending on the composition and the amount of feed, in particular the glucose content in the dry matter, the model quantifies reproductive hormones and follicular development over time. Simulation results for different nutritional regimes in lactating and non-lactating dairy cows are examined and compared with experimental studies. The simulations describe realistically the effects of nutritional glucose supply on the ovulatory cycle of dairy cattle. CONCLUSIONS: The mathematical model enables the user to explore the relationship between nutrition and reproduction by running simulations and performing parameter studies. Regarding its applicability, this work is an early attempt towards developing in silico feeding strategies and may eventually help to refine and reduce animal experiments. REVIEWERS: This article was reviewed by John McNamara and Tin Pang (nominated by Martin Lercher).

Bayesian approximations and extensions: optimal decisions for small brains and possibly big ones too.

We compared the performance of Bayesian learning strategies and approximations to such strategies, which are far less computationally demanding, in a setting requiring individuals to make binary decisions based on experience. Extending Bayesian updating schemes, we compared the different strategies while allowing for various implementations of memory and knowledge about the environment. The dynamics of the observable variables was modeled through basic probability distributions and convolution. This theoretical framework was applied to the problem of male fruit flies who have to decide which females they should court. Computer simulations indicated that, for most parameter values, approximations to the Bayesian strategy performed as well as the full Bayesian one. The linear approximation, reminiscent of the linear operator, was notably successful, and, without innate knowledge, the only successful learning strategy. Besides being less demanding in computation and thus realistic for small brains, the linear approximation was also successful at limited memory, which would translate into robustness in rapidly changing environments. Knowledge about the environment boosted the performance of the various learning strategies with maximal performance at large utilization of memory. Only for limited memory capacities, intermediate knowledge was most successful. We conclude that many animals may rely on algorithms that involve approximations rather than full Bayesian calculations because such approximations achieve high levels of performance with only a fraction of the computational requirements, in particular for extensions of Bayesian updating schemes, which can represent universal and realistic environments.

Impact of FDG PET for staging of Ewing sarcomas and primitive neuroectodermal tumours.

AIM: High-grade Ewing sarcomas and Primitive neuroectodermal tumours (PNET) make up the tumours of the Ewing family. Our purpose was to evaluate the value of [18F]fluorodeoxyglucose positron emission tomography (FDG PET) in patients with Ewing tumours. PATIENTS AND METHODS: Twenty-four patients who had PET because of a suspected Ewing tumour during a 5-year period were included in this retrospective study. The images of 33 whole-body FDG PET investigations performed in primary or secondary diagnostics were analysed visually and semi-quantitatively by using standardized uptake values (SUVs). In 14 cases, PET was compared to bone scintigraphy regarding bone lesions. The final diagnosis was based on histology, imaging and follow-up. RESULTS: Histologically, the primary lesions were 10 Ewing sarcoma, 13 PNET and one osteomyelitis. The sensitivity and specificity of an examination-based analysis (presence of Ewing tumour and/or its metastases) were 96 and 78%, respectively. Altogether, 163 focal lesions were evaluated. Sensitivity and specificity regarding individual lesions were 73 and 78%. This lower sensitivity is mainly due to small lesions. In true-positive cases, the mean SUV was 4.54+/-2.79, and the SUVs in two false-positive cases were 4.66 and 1.60. True-positive and false-positive cases could not be differentiated definitively based on SUVs because of overlap and low values in true-positive lesions. In four cases, PET depicted 70 while bone scintigraphy depicted only eight bone metastases. CONCLUSION: An FDG PET investigation is a valuable method in the case of Ewing tumours. PET is superior to bone scintigraphy in the detection of bone metastases of Ewing tumours. For the depiction of small lesions, mainly represented by pulmonary metastases, PET is less sensitive than helical computed tomography. Determination of the role of whole-body FDG PET in diagnostic algorithm needs further investigation.

Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung.

The Hippo/Yap pathway is a well-conserved signaling cascade that regulates cell proliferation and differentiation to control organ size and stem/progenitor cell behavior. Following airway injury, Yap was dynamically regulated in regenerating airway epithelial cells. To determine the role of Hippo signaling in the lung, the mammalian Hippo kinases, Mst1 and Mst2, were deleted in epithelial cells of the embryonic and mature mouse lung. Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation. The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated following embryonic Mst1/2 deletion. Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation. Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion, consistent with canonical Hippo/Yap signaling. YAP potentiated cell proliferation and inhibited differentiation of human bronchial epithelial cells in vitro. Loss of Mst1/2 and expression of YAP regulated transcriptional targets controlling cell proliferation and differentiation, including Ajuba LIM protein. Ajuba was required for the effects of YAP on cell proliferation in vitro. Hippo/Yap signaling regulates Ajuba and controls proliferation and differentiation of lung epithelial progenitor cells.

Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.

The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells.

Sox2 is required for maintenance and differentiation of bronchiolar Clara, ciliated, and goblet cells.

The bronchioles of the murine lung are lined by a simple columnar epithelium composed of ciliated, Clara, and goblet cells that together mediate barrier function, mucociliary clearance and innate host defense, vital for pulmonary homeostasis. In the present work, we demonstrate that expression of Sox2 in Clara cells is required for the differentiation of ciliated, Clara, and goblet cells that line the bronchioles of the postnatal lung. The gene was selectively deleted in Clara cells utilizing Scgb1a1-Cre, causing the progressive loss of Sox2 in the bronchioles during perinatal and postnatal development. The rate of bronchiolar cell proliferation was decreased and associated with the formation of an undifferentiated, cuboidal-squamous epithelium lacking the expression of markers of Clara cells (Scgb1a1), ciliated cells (FoxJ1 and alpha-tubulin), and goblet cells (Spdef and Muc5AC). By adulthood, bronchiolar cell numbers were decreased and Sox2 was absent in extensive regions of the bronchiolar epithelium, at which time residual Sox2 expression was primarily restricted to selective niches of CGRP staining neuroepithelial cells. Allergen-induced goblet cell differentiation and mucus production was absent in the respiratory epithelium lacking Sox2. In vitro, Sox2 activated promoter-luciferase reporter constructs for differentiation markers characteristic of Clara, ciliated, and goblet cells, Scgb1a1, FoxJ1, and Agr2, respectively. Sox2 physically interacted with Smad3 and inhibited TGF-beta1/Smad3-mediated transcriptional activity in vitro, a pathway that negatively regulates proliferation. Sox2 is required for proliferation and differentiation of Clara cells that serve as the progenitor cells from which Clara, ciliated, and goblet cells are derived.

Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase.

The signaling molecule nitric oxide (NO), first described as endothelium-derived relaxing factor (EDRF), acts as physiological activator of NO-sensitive guanylyl cyclase (NO-GC) in the cardiovascular, gastrointestinal, and nervous systems. Besides NO-GC, other NO targets have been proposed; however, their particular contribution still remains unclear. Here, we generated mice deficient for the beta1 subunit of NO-GC, which resulted in complete loss of the enzyme. GC-KO mice have a life span of 3-4 weeks but then die because of intestinal dysmotility; however, they can be rescued by feeding them a fiber-free diet. Apparently, NO-GC is absolutely vital for the maintenance of normal peristalsis of the gut. GC-KO mice show a pronounced increase in blood pressure, underlining the importance of NO in the regulation of smooth muscle tone in vivo. The lack of an NO effect on aortic relaxation and platelet aggregation confirms NO-GC as the only NO target regulating these two functions, excluding cGMP-independent mechanisms. Our knockout model completely disrupts the NO/cGMP signaling cascade and provides evidence for the unique role of NO-GC as NO receptor.