Sparse balance: Excitatory-inhibitory networks with small bias currents and broadly distributed synaptic weights

Cortical circuits generate excitatory currents that must be cancelled by strong inhibition to assure stability. The resulting excitatory-inhibitory (E-I) balance can generate spontaneous irregular activity but, in standard balanced E-I models, this requires that an extremely strong feedforward bias current be included along with the recurrent excitation and inhibition. The absence of experimental evidence for such large bias currents inspired us to examine an alternative regime that exhibits asynchronous activity without requiring unrealistically large feedforward input. In these networks, irregular spontaneous activity is supported by a continually changing sparse set of neurons. To support this activity, synaptic strengths must be drawn from high-variance distributions. Unlike standard balanced networks, these sparse balance networks exhibit robust nonlinear responses to uniform inputs and non-Gaussian input statistics. Interestingly, the speed, not the size, of synaptic fluctuations dictates the degree of sparsity in the model. In addition to simulations, we provide a mean-field analysis to illustrate the properties of these networks.     

Evaluation of adverse effects in tamoxifen exposed healthy female dogs

Background

Hypertension and proteinuria are medical complications associated with the multisystemic effects of long-term hypercortisolism in dogs with hyperadrenocorticism (HAC).

Methods

This study investigated the relationships among adrenocorticotropic hormone (ACTH)-stimulation test results, systemic blood pressure, and microalbuminuria in clinically-healthy dogs (n = 100), in dogs affected with naturally occurring pituitary-dependent (PDH; n = 40), or adrenal-dependent hyperadrenocorticism (ADH; n = 30).

Results

Mean systemic blood pressure was similar between clinically healthy dogs and dogs with HAC (p = 0.803). However the incidence of hypertension was highest in dogs with ADH (p = 0.017), followed by dogs with PDH, with the lowest levels in clinically healthy dogs (p = 0.019). Presence of microalbuminuria and albuminuria in clinically healthy dogs and dogs affected with HAC was significantly different (p < 0.001); incidences of albuminuria followed the same pattern of hypertension; highest incidence in dogs with ADH, and lowest level in clinically healthy dogs; but microalbuminuria showed a different pattern: clinically healthy dogs had highest incidences and dogs with ADH had lowest incidence. The presence of albuminuria was not associated with blood pressure values, regardless of whether dogs were clinically healthy or affected with ADH or PDH (p = 0.306).

Conclusions

Higher incidence of hypertension and albuminuria, not microalbuminuria was seen in dogs affected with HAC compared to clinically healthy dogs; incidence of hypertension and albuminuria was significantly higher in dogs affected with ADH compared to PDH. However, presence of albuminuria was not correlated with systemic blood pressure.     

Murine embryonic expression of the gene for the UV-responsive protein p15(PAF)

In a screen for genes expressed in the embryonic mouse facial primordia, we identified the gene sequence annotated as KIAA0101, which has previously been shown to encode a novel proliferating cell nuclear antigen (PCNA)-interacting protein named p15(PAF). We have since demonstrated that this protein also interacts in a complex with the tumour suppressor product p33ING1b, and that overexpression results in a decrease in UV-induced cell death. Although available data suggest widespread or ubiquitous expression in the adult, here we report highly restricted expression of the p15(PAF) gene in a spatio-temporal manner during mouse embryogenesis. Major sites of expression include the facial prominences, limbs, somites, brain, spinal cord and hair follicles. Based on the nature of its interacting partners, p15(PAF) is proposed to play a role in tumorigenesis. Our data also suggest a role in embryonic development, consistent with findings that a wide range of tumours result from aberrant activity of key developmental pathways.     

Weight loss is not mandatory for exercise-induced effects on health indices in females with metabolic syndrome

The aim of this study was to investigate the impact of moderate aerobic training on functional, anthropometric, biochemical, and health-related quality of life (HRQOL) parameters on women with metabolic syndrome (MS). Fifteen untrained women with MS performed moderate aerobic training for 15 weeks, without modifications of dietary behaviours. Functional, anthropometric, biochemical, control diet record and HRQOL parameters were assessed before and after the training. Despite body weight maintenance, the patients presented decreases in waist circumference (P = 0.001), number of MS components (P = 0.014), total cholesterol (P = 0.049), HDL cholesterol (P = 0.004), LDL cholesterol (P = 0.027), myeloperoxidase activity (P = 0.002) and thiobarbituric acid-reactive substances levels (P = 0.006). There were no differences in total energy, carbohydrate, protein and lipid intake pre- and post-training. Furthermore, improvements in the HRQOL subscales of physical functioning (P = 0.03), role-physical (P = 0.039), bodily pain (P = 0.048), general health (P = 0.046) and social functioning scoring (P = 0.011) were reported. Despite the absence of weight loss, aerobic training induced beneficial effects on functional, anthropometric, biochemical and HRQOL parameters in women with MS.     

Persistent Activation of Mitogen-Activated Protein Kinases p42 and p44 and ets-2 Phosphorylation in Response to Colony-Stimulating Factor 1/c-fms Signaling

An antibody that specifically recognized phosphothreonine 72 in ets-2 was used to determine the phosphorylation status of endogenous ets-2 in response to colony-stimulating factor 1 (CSF-1)/c-fms signaling. Phosphorylation of ets-2 was detected in primary macrophages, cells that normally express c-fms, and in fibroblasts engineered to express human c-fms. In the former cells, ets-2 was a CSF-1 immediate-early response gene, and phosphorylated ets-2 was detected after 2 to 4 h, coincident with expression of ets-2 protein. In fibroblasts, ets-2 was constitutively expressed and rapidly became phosphorylated in response to CSF-1. In both cell systems, ets-2 phosphorylation was persistent, with maximal phosphorylation detected 8 to 24 h after CSF-1 stimulation, and was correlated with activation of the CSF-1 target urokinase plasminogen activator (uPA) gene. Kinase assays that used recombinant ets-2 protein as a substrate demonstrated that mitogen-activated protein (MAP) kinases p42 and p44 were constitutively activated in both cell types in response to CSF-1. Immune depletion experiments and the use of the MAP kinase kinase inhibitor PD98059 indicate that these two MAP kinases are the major ets-2 kinases activated in response to CSF-1/c-fms signaling. In the macrophage cell line RAW264, conditional expression of raf kinase induced ets-2 expression and phosphorylation, as well as uPA mRNA expression. Transient assays mapped ets/AP-1 response elements as critical for basal and CSF-1-stimulated uPA reporter gene activity. These results indicate that persistent activation of the raf/MAP kinase pathway by CSF-1 is necessary for both ets-2 expression and posttranslational activation in macrophages.     

The effects of tin (Sn) additions on the growth of spinach plants

An increase in bioavailable tin in the environment could result in bioaccumulation thereof in agricultural crops, and therefore, have adverse health consequences on humans that eat these crops. The aims of the current study were thus to assess the uptake of Sn by spinach plants, and the subsequent effects this will have on the uptake of Na, Zn, K, Ca, and Mg as well as the growth of spinach plants. Spinach plants were grown in sand culture and received tin at concentrations of 0.02, 0.2, 2 and 20 mg/L along with a nutrient solution. The uptake of tin at detectible concentrations only occurred at the highest concentrations (2 and 20 mg/L), and it was mostly retained in the roots of the plants. Tin additions also resulted in no visual toxicity symptoms, and might be beneficial to biomass production. Further field trials are needed to ensure that these experimental results remain true under field conditions.     

Phenotypic variations of TRAIL sensitivity in cloned populations of prostate cancer cells

Factors that regulate the induction of apoptosis of tumour cells are potential candidates for therapeutic intervention for the majority of cancers. Studying modifiers of apoptotic responses, such as members of the tumour necrosis factor receptor superfamily, may give clues as to how induction of apoptosis in tumours could be maximized to enhance the benefit of treatment regimes. Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is a promising anti‐tumour molecule since its activity is specific for tumour cell populations. TRAIL binds to death receptors, inducing apoptosis in susceptible cells. The mechanisms which determine whether tumour cells are susceptible to TRAIL are unclear, and several mechanisms have been proposed, including expression of osteoprotegerin (OPG), decoy receptors, and factors that affect intracellular signalling of pro‐apoptotic molecules, such as c‐FLIP. Here we show that experiments to modulate the activity of one of these factors, OPG, by over‐expression and also by stable knockdown of OPG expression, alters the TRAIL sensitivity of PC3 prostate cancer cells. However we show that some observed effects, which appear to support the hypothesis that OPG prevents TRAIL‐induced apoptosis of tumour cells, may be due to variation of the TRAIL response of sub‐clones of tumour cells, even within a cloned population. These results highlight potential limitations of experiments designed to test contribution of factors affecting intrinsic apoptosis susceptibility using cloned tumour cell populations. J. Cell. Biochem. 104: 1452–1464, 2008. © 2008 Wiley‐Liss, Inc.     

Mapping the Habitat Quality of Patch Networks for the Marsh Fritillary Euphydryas aurinia (Rottemburg, 1775) (Lepidoptera, Nymphalidae) in Wales

The marsh fritillary is widely distributed in Wales, with over 200 populations identified in the past 15 years. However, agricultural improvement, habitat fragmentation and changes in agricultural practices continue to impact on status and a decline in range of 23.5% was recorded over a 10-year period. Solutions must be applied at the landscape scale to improve metapopulation viability and, since 2000, surveys of habitat extent and quality have been carried out on 116,373 ha of grassland surrounding 111 populations. Analysis of the results for standard ‘core landscapes’ (based on circles of 1 km radius around known populations) shows that overall cover of suitable breeding habitat is 3.44%. However, only 11.85% of the grassland that was suitable for marsh fritillaries was classified as being in Good Condition. The remainder was regarded as having sub-optimal vegetation structure and/or the foodplant was at low density; 33% of the habitat resource that was not in Good Condition was regarded as inappropriately or excessively managed and 67% was suffering from neglect. An Index of Landscape Quality is used to rank landscapes for evaluation. Thirty-five ‘core landscapes’ (incorporating 98 marsh fritillary populations) were assessed and just four exceeded a threshold value deemed to represent viable landscape configurations. The results have demonstrated that most marsh fritillary populations in Wales exist within depauperate patch networks that lack sufficient breeding habitat of the right quality for long-term persistence. Without targeted conservation action the marsh fritillary will continue to decline in Wales. This paper reports on efforts to collect information on the quality of breeding habitat for marsh fritillaries across Wales in order to identify priorities for conservation action.