Environmental regulation can arise under minimal assumptions.

Models that demonstrate environmental regulation as a consequence of organism and environment coupling all require a number of core assumptions. Many previous models, such as Daisyworld, require that certain environment-altering traits have a selective advantage when those traits also contribute towards global regulation. We present a model that results in the regulation of a global environmental resource through niche construction without employing this and other common assumptions. There is no predetermined environmental optimum towards which regulation should proceed assumed or coded into the model. Nevertheless, polymorphic stable states that resist perturbation emerge from the simulated co-evolution of organisms and environment. In any single simulation a series of different stable states are realised, punctuated by rapid transitions. Regulation is achieved through two main subpopulations that are adapted to slightly different resource values, which force the environmental resource in opposing directions. This maintains the resource within a comparatively narrow band over a wide range of external perturbations. Population driven oscillations in the resource appear to be instrumental in protecting the regulation against mutations that would otherwise destroy it. Sensitivity analysis shows that the regulation is robust to mutation and to a wide range of parameter settings. Given the minimal assumptions employed, the results could reveal a mechanism capable of environmental regulation through the by-products of organisms.

Spatially embedded random networks.

Many real-world networks analyzed in modern network theory have a natural spatial element; e.g., the Internet, social networks, neural networks, etc. Yet, aside from a comparatively small number of somewhat specialized and domain-specific studies, the spatial element is mostly ignored and, in particular, its relation to network structure disregarded. In this paper we introduce a model framework to analyze the mediation of network structure by spatial embedding; specifically, we model connectivity as dependent on the distance between network nodes. Our spatially embedded random networks construction is not primarily intended as an accurate model of any specific class of real-world networks, but rather to gain intuition for the effects of spatial embedding on network structure; nevertheless we are able to demonstrate, in a quite general setting, some constraints of spatial embedding on connectivity such as the effects of spatial symmetry, conditions for scale free degree distributions and the existence of small-world spatial networks. We also derive some standard structural statistics for spatially embedded networks and illustrate the application of our model framework with concrete examples.

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington's disease.

In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyte-neuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD.

Contribution of the second transmembrane helix of the secretin receptor to the positioning of secretin.

The secretin amino-terminal residues are essential for high affinity binding to its cognate receptor and for its biological activity. Mutation of the [Asp3] residue of secretin to [Asn3] decreased the ligand's affinity for the rat wild-type receptor 100-300-fold. Receptor mutations in the transmembrane 2 domain and the beginning of the first extracellular loop allowed the identification of three residues involved in recognition of the [Asp3] residue: D174, K173 and R166. Mutation of K173 and D174 not only reduced the secretin and [Asn3]secretin affinities, but also changed the receptor's selectivity as judged by a decreased secretin and [Asn3]secretin potency ratio. The most striking effect was observed when R166 was mutated to Q, D or L. This led to receptors with a very low affinity for secretin but an up to 10-fold higher affinity than the wild-type receptor for [Asn3]secretin. This suggested that R166, highly conserved in that subgroup of receptor, is a major determinant for the recognition of the [Asp3] of the ligand.

Role of charged amino acids conserved in the vasoactive intestinal polypeptide/secretin family of receptors on the secretin receptor functionality.

The secretin receptor is a member of a large family of G-protein-coupled receptors that recognize polypeptide hormone and/or neuropeptides. Charged, conserved residues might play a key role in their function, either by interacting with the ligand or by stabilizing the receptor structure. Of the four charged amino acids that are conserved in the whole secretin receptor family, D49 and R83 (in the N-terminal domain) were probably important for the secretin receptor structure: replacement of D49 by H or R and of R83 by D severely reduced both the maximal response to secretin and its potency. No functional secretin receptor could be detected after replacement of R83 by L. Mutation of D49 to E, A, or N had no effect or reduced 5-fold the potency of secretin. The highly conserved positive charges found at the extracellular ends of TM III (K194) and IV (R255) were important for the secretin receptor function, as K194 mutation to A or Q and R255 mutation to Q or D decreased the secretin's affinity 15- to 1000-fold, respectively. Six extracellular charged residues are conserved in closely related receptors but not in the whole family. K121 (TM I) and R277 (TM V) were not important for functional secretin receptor expression. D174 (TM II) was necessary to stabilize the active receptor structure: the D174N mutant receptors were unable to stimulate normally the adenylate cyclase in response to secretin, and functional D174A receptors could not be found. Mutation of R255, E259 (second extracellular loop), and E351 (third extracellular loop) to uncharged residues reduced only 10- to 100-fold the secretin potency without changing its efficacy: these residues either stabilized the active receptor conformation or formed hydrogen rather than ionic bonds with secretin. Mutation of K121 (TM I) to Q or L and of R277 (TM V) to E or Q did not affect the receptor functional properties.

Properties of the VIP-PACAP type II receptor stably expressed in CHO cells.

The VIP receptor cloned from rat lung (VIP1 receptor from the group of the PACAP-VIP type II receptors) was inserted into a mammalian expression vector and stably transfected into Chinese hamster ovary cells (CHO). Two clones were selected, expressing respectively a high (850 +/- 50 fmol/mg protein, for clone 3) and a low (100 +/- 30 fmol/mg protein for clone 16) number of receptors. Both clones had the same apparent Kd value of binding for VIP and related peptides. The receptor expressed had the same binding properties as the natural VIP receptor, judged from the relative potency of VIP and PACAP analogues and fragments. The EC50 value of adenylate cyclase activation were 3 to 10 fold lower in clone 3 than in 16. The values observed in clone 16 were closer to the binding Kd values. The differences between the two clones were explained by the existence of spare receptors in clone 3, since: (a) the relative efficacy of some fragments were lower in clone 16 than in clone 3; (b) pretreatment of the cells with VIP reduced the number of receptors in both clones and increased the EC50 value for VIP in clone 3 but decreased peptide efficacy in clone 16 without significant change of the EC50 value.

Pharmacological properties of two recombinant splice variants of the PACAP type I receptor, transfected and stably expressed in CHO cells.

Two splice variants of the pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor (PACAP receptor and PACAP/HOP receptor isoform) were stably expressed in Chinese hamster ovary (CHO) cells that did not express constitutively receptors for this family of peptides. The PACAP/HOP receptor protein had a 28 amino acid extension in the C-terminal part of the third intracellular loop. The two cell lines studied, CHO 2-10 (PACAP receptor) and CHO 4-12 (PACAP/HOP receptor) expressed a receptor density of 4.6 +/- 0.3 and 2.6 +/- 0.2 pmol/mg protein, respectively, with corresponding Kd values of 14.2 +/- 2.0 and 8.2 +/- 1.0 nM for [Ac-His1]PACAP-27 used as a tracer. Tracer binding was slightly decreased by GTP in both clones. The Kd values of PACAP-27, PACAP-38, vasoactive intestinal peptide (VIP), PACAP-27 fragments and analogues evaluated by binding competition curves, were higher in CHO 2-10 than in CHO 4-12, whereas the Kd for PACAP-38 fragments did not differ. The receptors were coupled to adenylate cyclase and the EC50 values were lower than the Kd values in both cell lines, suggesting an amplification process due to the existence of spare receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Properties of a recombinant human secretin receptor: a comparison with the rat and rabbit receptors.

A secretin receptor was cloned from a commercial human pancreatic complementary DNA (cDNA) bank. The amino acid sequence deduced from the nucleotide sequence differed slightly from the three different sequences previously published, suggesting a genetic polymorphism of the human receptor. The binding properties of the receptor were evaluated by testing natural secretin, related peptides, and synthetic analogs or fragments on membranes of Chinese hamster ovary (CHO) cells expressing the receptor after transfection. The second-messenger coupling was evaluated by adenylate cyclase measurement. The human secretin receptor was compared with the rat and the rabbit receptors. In the three animals species, rat and human secretin were equipotent; rabbit secretin was equipotent on human and rabbit secretin receptors and less potent on the rat receptor. Similar data were obtained for the [Arg16]-secretin analog. Deletion of histidine 1 and replacement of aspartate 3 reduced the affinity of the peptides for the three receptors; however, the reduction was more pronounced on rat than on human and rabbit secretin receptors. Finally, the low affinity of the rat and human receptors for vasoactive intestinal peptide (VIP) was identical; the rabbit receptor, however, had a 20-fold higher affinity. Thus the human secretin receptor shows properties of both rat and rabbit receptors. Evaluation of the properties of chimeric receptors will be useful to fit the ligand on the receptors.

Rhythmic and non-rhythmic attractors in asynchronous random Boolean networks.

In multi-component, discrete systems, such as Boolean networks and cellular automata, the scheme of updating of the individual elements plays a crucial role in determining their dynamic properties and their suitability as models of complex phenomena. Many interesting properties of these systems rely heavily on the use of synchronous updating of the individual elements. Considerations of parsimony have motivated the claim that, if the natural systems being modelled lack any clear evidence of synchronously driven elements, then random asynchronous updating should be used by default. The introduction of a random element precludes the possibility of strictly cyclic behaviour. In principle, this poses the question of whether asynchronously driven Boolean networks, cellular automata, etc., are inherently bad choices at the time of modelling rhythmic phenomena. This paper focuses on this subsidiary issue for the case of Asynchronous Random Boolean Networks (ARBNs). It defines measures of pseudo-periodicity between states and sufficiently relaxed statistical constraints. These measures are used to guide a genetic algorithm to find appropriate examples. Success in this search for a number of cases, and the subsequent statistical analysis lead to the conclusion that ARBNs can indeed be used as models of co-ordinated rhythmic phenomena, which may be stronger precisely because of their in-built asynchrony. The same technique is used to find non-stationary attractors that show no rhythm. Evidence suggests that the latter are more abundant than rhythmic attractor. The methodology is flexible, and allows for more demanding statistical conditions for defining pseudo-periodicity, and constraining the evolutionary search.

[Food intake and nutritional status in a group of healthy elderly residing in a nursing home]. / Valutazione dello stato di nutrizione e degli intake alimentari in un gruppo di anziani autosufficienti residenti in una residenza sanitaria assistenziale.

BACKGROUND: Aging is accompanied by a variety of economic, psychologic, and social changes that can compromise the nutritional status. Nutrition is an important aspect of healthful behaviour and a major component of general wellbeing of individuals throughout their life cycle. Nutritional intake appears to be an important factor contributing to aging. So, the purpose of this project was to evaluate diet and nutritional status. METHODS: Fifty-one healthy elderly subjects aged 70 years and older (31 F and 20 M), residing in a nursing home have been studied. Nutrient intake was assessed using 24-hour recalls; nutritional status was assessed using anthropometric measurements. The nutrient intakes for individuals were compared with the Italian Recommended Dietary Allowances (RDAs). RESULTS: Mean energy intake was 1,625 kcal; the average percentages of carbohydrate, protein, and fat were 54%, 16%, and 30%, respectively. The mean vitamin and mineral intake for participants met the RDAs except for calcium and selenium intakes. The mean fibre intake was low. The analysis of food products intake indicated that the above mentioned inadequacy in nutrient intake was the result of low consumption of milk and milk products containing calcium and a low consumption of integral foods or fruits containing fibre. CONCLUSIONS: The significance of sound nutrition education and the adverse impact of consumer misinformation about the benefits of these food choices becomes clear with the recognition that nutritional status influences the rate of physiologic and functional declines with age. This approach will require new efforts in consumer education sensitive to the needs and beliefs of older people.

PHA-stimulated cellular immune function and T-lymphocyte subsets in major depressive disorders.

We measured some immunological parameters in 20 hospitalized patients with major depression and 20 age- and sex-matched healthy controls. Both enumeration of immune cells, including T-lymphocyte subpopulations, and assay of T-cell function were studied. White blood cells were evaluated with an automated cell counter, T-cell subsets with an immunobead technique, and T-cell function with a phytohemagglutinin-induced proliferation in vitro assay. We found that T-lymphocyte responses to the mitogen were significantly lower in depressed patients than in controls. All the other parameters were normal. These findings suggest that functional but not numerical changes in T-lymphocytes characterize major depressive disorders.

Evolving neural models of path integration.

We use a genetic algorithm to evolve neural models of path integration, with particular emphasis on reproducing the homing behaviour of Cataglyphis fortis ants. This is done within the context of a complete model system, including an explicit representation of the animal's movements within its environment. We show that it is possible to produce a neural network without imposing a priori any particular system for the internal representation of the animal's home vector. The best evolved network obtained is analysed in detail and is found to resemble the bicomponent model of Mittelstaedt. Because of the presence of leaky integration, the model can reproduce the systematic navigation errors found in desert ants. The model also naturally mimics the searching behaviour that ants perform once they have reached their estimate of the nest location. The results support possible roles for leaky integration and cosine-shaped compass response functions in path integration.

Ecological symmetry breaking can favour the evolution of altruism in an action-response game.

The evolution of altruistic behaviour is studied in a simple action-response game with a tunable degree of conflict of interest. It is shown that for the continuous, mixed-medium approach no stable polymorphism favours altruism. Ecological dynamics are explored with the addition of a spatial dimension and a local energy variable. A continuous spatial model with finite local range does not introduce any substantial difference in the results with respect to the level of altruism. However, the model illustrates how ecological coupling may lead to the formation of stable spatial patterns in the form of discrete and isolated clusters of players as a consequence of inverse density dependence. A discrete, individual-based model is built in which local interactions are also modelled as occurring within a finite neighbourhood of each individual and spatial positions are not restricted as in lattice models. This model shows substantially different results. A high level of altruism is observed for low (but positive) degrees of conflict and this level decreases linearly for higher degrees of conflict. The evolution of altruism is explained by studying the broken symmetries introduced by the spatial clusters themselves, mainly between their central and peripheral regions which, in combination with the discrete and the stochastic nature of the model, result in the stabilization of strategies in which players behave altruistically towards the same type. As a consequence of the activity of the players, energy resources at the centre of an altruistic cluster are very depleted; so much so that, for low conflict, fitter non-altruistic mutants may initially invade only to become locally extinct due to their less efficient use of energy as their numbers increase. In peripheral regions invader may subsist; however, for geometrical reasons long-lasting genealogies tend to originate only at the centre of a cluster.