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The performance of integrated biological systems can often be described by the behavior of component subunits: the proportion of subunits performing an activity, and the rate of recruitment to the activity, can be relevant to system performance. We develop a model for activation of subunits (receivers) to a task when activation requires repeated signals (iterative communication). The model predicts how system performance will be affected by the parameters of iterative communication. Receiver activation is influenced by the frequency of stimulation, by forgetting about past interactions, and by the number of stimuli needed to activate the receivers. These parameters, along with the probability of activated receivers returning to a de-activated state, modulate the system-wide time course of activation and the steady-state proportion of activated receivers. Parameters can interact to affect system-wide activation, and multiple parameter combinations can yield similar patterns of activation. Group performance is less variable at higher stimulation frequencies and in systems with greater numbers of receivers. Biological constraints on iterative communication, such as time and energy costs, may limit the parameter values that are feasible for a given system. Iterative communication parameters may be subject to natural selection at the system (group) level because they affect system performance., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The microbiome can significantly impact host phenotypes and serve as an additional source of heritable genetic variation. While patterns across eukaryotes are consistent with a role for symbiotic microbes in host macroevolution, few studies have examined symbiont-driven host evolution or the ecological implications of a dynamic microbiome across temporal, spatial or ecological scales. The pea aphid, Acyrthosiphon pisum, and its eight heritable bacterial endosymbionts have served as a model for studies on symbiosis and its potential contributions to host ecology and evolution. But we know little about the natural dynamics or ecological impacts of the heritable microbiome of this cosmopolitan insect pest. Here we report seasonal shifts in the frequencies of heritable defensive bacteria from natural pea aphid populations across two host races and geographic regions. Microbiome dynamics were consistent with symbiont responses to host-level selection and findings from one population suggested symbiont-driven adaptation to seasonally changing parasitoid pressures. Conversely, symbiont levels were negatively correlated with enemy-driven mortality when measured across host races, suggesting important ecological impacts of host race microbiome divergence. Rapid drops in symbiont frequencies following seasonal peaks suggest microbiome instability in several populations, with potentially large costs of 'superinfection' under certain environmental conditions. In summary, the realization of several laboratory-derived, a priori expectations suggests important natural impacts of defensive symbionts in host-enemy eco-evolutionary feedbacks. Yet negative findings and unanticipated correlations suggest complexities within this system may limit or obscure symbiont-driven contemporary evolution, a finding of broad significance given the widespread nature of defensive microbes across plants and animals., (© 2015 John Wiley & Sons Ltd.)

A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC₅₀ values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC₅₀ values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC₅₀ values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC₅₀ values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC₅₀ values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC₅₀ determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided.

The purpose of this study was to examine the effect of short-term high fat feeding on the inflammatory response in polymicrobial sepsis. Male C57BL/6 mice at 6 weeks of age were randomized to a high-fat diet (HFD) (60% kcal fat) or control diet (CD) (16% kcal fat) for 3 weeks. After 3 weeks of feeding, sepsis was induced by cecal ligation and puncture (CLP) and animals were monitored for survival. In a separate experiment, after 3 weeks of feeding mice underwent CLP and were sacrificed at various time points thereafter. Tissue was collected for biochemical studies. Mice fed a HFD gained more weight and had a greater fat mass compared to CD-fed mice. Mice on a HFD had a lower probability of survival and more severe lung injury compared with CD-fed mice following sepsis. Myeloperoxidase (MPO) activity, an indicator of neutrophil infiltration, was increased in the lung and liver after CLP in HFD-fed mice compared with CD (P < 0.05). The plasma cytokines tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were increased in both groups after CLP, however, TNF-α and IL-6 levels were lower in HFD mice at 3 h after CLP compared with CD and consistent with lung, but not liver, messenger RNA (mRNA) expression. Leptin levels were higher in HFD-fed mice at 18 h after sepsis compared to baseline levels (P < 0.05). Polymicrobial sepsis increased hepatic nuclear factor-κB (NF-κB) activation in HFD-fed mice after CLP vs. CD-fed mice. Short duration high fat feeding increases mortality and organ injury following polymicrobial sepsis. These effects correspond to changes in NF-κB.

Background: The authors administered surveys to develop an operational definition of oral neglect in institutionalized elderly (ONiIE) in the United States., Methods: The authors administered a Delphi technique survey involving three rounds to a panel of 19 geriatric dental experts in 1995 to arrive at a definition of ONiIE. The authors validated the 1995 ONiIE definition by administering a Delphi technique survey involving four rounds to a subset of eight experts from the 1995 panel., Results: The panelists in the 2009 survey validated the 28 oral diseases or conditions that were part of the 1995 ONiIE definition and added one new oral condition-bleeding. They also reached consensus agreement for each of the 29 listed oral diseases and conditions regarding both the diagnostic stage at which those diseases and conditions should be included in a definition (mild, moderate, or severe) and the specified time period required to constitute neglect (that is, total "time to qualify as neglect" was eight days for acute conditions and 35 days for chronic conditions)., Conclusions: An expert-driven consensus ONiIE definition was established. It consists of 29 oral diseases and conditions, each of which has been associated with a diagnostic stage and a specified time period required to constitute neglect., Clinical Implications: Since federal legislation that funds payments to nursing homes for the care and housing of their residents requires that there shall be no oral neglect, this validated consensus ONiIE definition provides a utilitarian means to enforce that legislative expectation.

Power scaling relationships between body mass and organismal traits are fundamental to biology. Compilations of mammalian masses and basal metabolic rates date back over a century and are used both to support and to assail the universal quarter-power scaling invoked by the metabolic theory of ecology. However, the slope of this interspecific allometry is typically estimated without accounting for intraspecific variation in body mass or phylogenetic constraints on metabolism. We returned to the original literature and culled nearly all unique measurements of body mass and basal metabolism for 695 mammal species and (1) phylogenetically corrected the data using the fullest available phylogeny, (2) applied several different regression analyses, (3) resampled regressions by drawing randomly selected species from each of the polytomies in the phylogenetic hypothesis at each iteration, and (4) ran these same analyses independently on separate clades. Overall, 95% confidence intervals of slope estimates frequently did not include 0.75, and clade-specific slopes varied from 0.5 to 0.85, depending on the clade and regression model. Our approach reveals that the choice of analytical model has a systematic influence on the estimated allometry, but irrespective of the model applied, we find little support for a universal metabolic rate-body mass scaling relationship.

Historically, the olive ridley arribada at Playa Nancite, Costa Rica, was one of the largest olive ridley arribadas in the eastern Pacific with 70,000 nesting females in a year. Recently the Nancite arribada drastically declined. We hypothesized that the population decline at Playa Nancite could have been due to low hatching success as a result of the high density of nests on the beach, such that recruitment to the population was insufficient to balance losses. To test this hypothesis, we examined density-dependent effects on hatching success and their underlying mechanisms by experimentally manipulating nest densities in experimental plots on the nesting beach. We set up four nest-density treatments in five experimental blocks. We measured effects of density on hatching success, CO(2) and O(2) concentrations and temperature both within nests and in sand adjacent to nests frequently during incubation. Experimental nest densities affected hatching success with the highest density having the lowest hatching success. Higher nest density led to lower O(2) levels and higher CO(2) levels in the nest with greater changes in the latter part of the incubation. Highest temperatures occurred in high-density areas. Temperatures were lower in sand surrounding the nest than in the nest. Effects of density on temperature, CO(2) and O(2) were confirmed at a naturally high-density nesting beach, Playa La Flor, Nicaragua. Long-term failure in production of hatchlings due to historic high densities may have contributed to the decline of arribadas on Playa Nancite. Thus, density-dependent population control would have operated at the embryonic life stage in this population of olive ridley turtles.

A robust screen for compound interaction with P-glycoprotein (P-gp) has some obvious requirements, such as a cell line expressing P-gp and a probe substrate that is transported solely by P-gp and passive permeability. It is actually difficult to prove that a particular probe substrate interacts only with P-gp in the chosen cell line. Using a confluent monolayer of MDCKII-hMDR1 cells, we have determined the elementary rate constants for the P-gp efflux of amprenavir, digoxin, loperamide, and quinidine. For amprenavir and quinidine, transport was fitted with just P-gp and passive permeability. For digoxin and loperamide, fitting required a basolateral transporter (p < 0.01), which was inhibited by the P-gp inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). This means that when digoxin is used as a probe substrate and a compound is shown to inhibit digoxin flux, it could be that the inhibition occurs at the basolateral transporter rather than at P-gp. Digoxin basolateral>apical efflux also required an apical importer (p < 0.05). We propose that amprenavir and quinidine are robust probe substrates for assessing P-gp interactions using the MDCKII-hMDR1 confluent cell monolayer. Usage of another cell line, e.g., LLC-hMDR1 or Caco-2, would require the same kinetic validation to ensure that the probe substrate interacts only with P-gp. Attempts to identify the additional digoxin and loperamide transporters using a wide range of substrates/inhibitors of known epithelial transporters (organic cation transporters, organic anion transporters, organic ion-transporting polypeptide, uric acid transporter, or multidrug resistance-associated protein) failed to inhibit the digoxin or loperamide transport through their basolateral transporter.

Physiological and ecological allometries often pose linear regression problems characterized by (1) noncausal, phylogenetically autocorrelated independent (x) and dependent (y) variables (characters); (2) random variation in both variables; and (3) a focus on regression slopes (allometric exponents). Remedies for the phylogenetic autocorrelation of species values (phylogenetically independent contrasts) and variance structure of the data (reduced major axis [RMA] regression) have been developed, but most functional allometries are reported as ordinary least squares (OLS) regression without use of phylogenetically independent contrasts. We simulated Brownian diffusive evolution of functionally related characters and examined the importance of regression methodologies and phylogenetic contrasts in estimating regression slopes for phylogenetically constrained data. Simulations showed that both OLS and RMA regressions exhibit serious bias in estimated regression slopes under different circumstances but that a modified orthogonal (least squares variance-oriented residual [LSVOR]) regression was less biased than either OLS or RMA regressions. For strongly phylogenetically structured data, failure to use phylogenetic contrasts as regression data resulted in overestimation of the strength of the regression relationship and a significant increase in the variance of the slope estimate. Censoring of data sets by simulated extinction of taxa did not affect the importance of appropriate regression models or the use of phylogenetic contrasts.

We present an approach to delineating physiological effects on population level processes by modeling the activity and resource budgets of animals. Physiology and its environmental forcing functions are assumed to affect both the total time available for activity and foraging and the resource budgets by affecting resource acquisition, costs, and handling. We extend the earlier model of Dunham and others (1989) and translate it into a computational algorithm. To satisfy conservation needs for accuracy, wide applicability, and rapid deployment, the model is relatively simple, uses as much data on the focal organism as possible, is mechanistically driven, and can be adapted to new organisms by using data for the new species, or the best available approximations to those data. We present 2 applications of the modeling approach. First, we consider a system with substantial information available, canyon lizards (Sceloporus merriami) studied by Dunham and colleagues in west Texas. In this case the focus is on integration of numerous inputs and the ability of the model to produce predictions that approximate counterintuitive empirical patterns. By using the wealth of specific data available, the model outperforms previous attempts at explanation of those patterns. Next, we consider a system with much less available information (forest-dwelling semi-fossorial frogs). The question here is how hydric conditions can become limiting. A model of evaporation from frogs buried in leaf litter was incorporated and it demonstrates how rainfall patterns can both supply water and put the frogs at risk of critical dehydration.

Studies have focused on control of expression and the relative importance of basic fibroblast growth factor (bFGF) in a purported autocrine/paracrine regulatory network functioning in the modulation of cartilage metabolic and structural homeostasis. Preformed and newly synthesized bFGF and concurrent antagonist activity could be identified by bioassay in cell/pericellular matrix extracts of normal bovine articular chondrocytes maintained in suspension culture. Specificity was determined using antibody neutralization. Prostanoids (PGE(1), PGE(2)) enhanced chondrocyte expression of the putative inhibitor. The antagonist, recognized in the presence of suboptimally triggered bFGF receptors, was active against both endogenously produced and recombinant bFGF. Chondrocyte expression of bFGF was significantly altered following exposure to conditioned medium obtained from explant cultures of osteoarthritic synovial tissue. Response pattern, that is, an upregulation or downregulation of growth factor expression, was dependent on medium concentration and the duration of chondrocyte exposure. Synovium-conditioned medium generated in the presence of PGE(1) appeared to attenuate suppressive responses seen with naive conditioned medium. Promotion of expression of bFGF inhibitory activity within the milieu of the diseased joint may negate potential detrimental pathophysiologic effects of this competence factor on cartilage, synovial tissue, and bone metabolism and repair.