Networked buffering: a basic mechanism for distributed robustness in complex adaptive systems

A generic mechanism - networked buffering - is proposed for the generation of robust traits in complex systems. It requires two basic conditions to be satisfied: 1) agents are versatile enough to perform more than one single functional role within a system and 2) agents are degenerate, i.e. there exists partial overlap in the functional capabilities of agents. Given these prerequisites, degenerate systems can readily produce a distributed systemic response to local perturbations. Reciprocally, excess resources related to a single function can indirectly support multiple unrelated functions within a degenerate system. In models of genome:proteome mappings for which localized decision-making and modularity of genetic functions are assumed, we verify that such distributed compensatory effects cause enhanced robustness of system traits. The conditions needed for networked buffering to occur are neither demanding nor rare, supporting the conjecture that degeneracy may fundamentally underpin distributed robustness within several biotic and abiotic systems. For instance, networked buffering offers new insights into systems engineering and planning activities that occur under high uncertainty. It may also help explain recent developments in understanding the origins of resilience within complex ecosystems. \ud \u

Poloxomer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function

Duchenne muscular dystrophy (DMD) is an X-linked, fatal muscle wasting disease for which there is currently no cure and limited palliative treatments. Poloxomer 188 (P188) is a tri-block copolymer that has been proposed as a potential treatment for cardiomyopathy in DMD patients. Despite the reported beneficial effects of P188 on dystrophic cardiac muscle function, the effects of P188 on dystrophic skeletal muscle function are relatively unknown. Mdx mice were injected intraperitoneally with 460 mg/kg or 30 mg/kg P188 dissolved in saline, or saline alone (control). The effect of single-dose and 2-week daily treatment was assessed using a muscle function test on the Tibialis Anterior (TA) muscle in situ in anaesthetised mice. The test comprises a warm up, measurement of the force-frequency relationship and a series of eccentric contractions with a 10% stretch that have previously been shown to cause a drop in maximum force in mdx mice. After 2 weeks of P188 treatment at either 30 or 460 mg/kg/day the drop in maximum force produced following eccentric contractions was significantly greater than that seen in saline treated control mice (P = 0.0001). Two week P188 treatment at either dose did not significantly change the force-frequency relationship or maximum isometric specific force produced by the TA muscle. In conclusion P188 treatment increases susceptibility to contraction-induced injury following eccentric contractions in dystrophic skeletal muscle and hence its suitability as a potential therapeutic for DMD should be reconsidered

Pyrite-induced hydroxyl radical formation and its effect on nucleic acids

BACKGROUND: Pyrite, the most abundant metal sulphide on Earth, is known to spontaneously form hydrogen peroxide when exposed to water. In this study the hypothesis that pyrite-induced hydrogen peroxide is transformed to hydroxyl radicals is tested. RESULTS: Using a combination of electron spin resonance (ESR) spin-trapping techniques and scavenging reactions involving nucleic acids, the formation of hydroxyl radicals in pyrite/aqueous suspensions is demonstrated. The addition of EDTA to pyrite slurries inhibits the hydrogen peroxide-to-hydroxyl radical conversion, but does not inhibit the formation of hydrogen peroxide. Given the stability of EDTA chelation with both ferrous and ferric iron, this suggests that the addition of the EDTA prevents the transformation by chelation of dissolved iron species. CONCLUSION: While the exact mechanism or mechanisms of the hydrogen peroxide-to-hydroxyl radical conversion cannot be resolved on the basis of the experiments reported in this study, it is clear that the pyrite surface promotes the reaction. The formation of hydroxyl radicals is significant because they react nearly instantaneously with most organic molecules. This suggests that the presence of pyrite in natural, engineered, or physiological aqueous systems may induce the transformation of a wide range of organic molecules. This finding has implications for the role pyrite may play in aquatic environments and raises the question whether inhalation of pyrite dust contributes to the development of lung diseases

Two Nuclear Localization Signals in USP1 Mediate Nuclear Import of the USP1/UAF1 Complex

The human deubiquitinase USP1 plays important roles in cancer-related processes, such as the DNA damage response, and the maintenance of the undifferentiated state of osteosarcoma cells. USP1 deubiquitinase activity is critically regulated by its interaction with the WD40 repeat-containing protein UAF1. Inhibiting the function of the USP1/UAF1 complex sensitizes cancer cells to chemotherapy, suggesting that this complex is a relevant anticancer target. Intriguingly, whereas UAF1 has been reported to locate in the cytoplasm, USP1 is a nuclear protein, although the sequence motifs that mediate its nuclear import have not been functionally characterized. Here, we identify two nuclear localization signals (NLSs) in USP1 and show that these NLSs mediate the nuclear import of the USP1/UAF1 complex. Using a cellular relocation assay based on these results, we map the UAF1-binding site to a highly conserved 100 amino acid motif in USP1. Our data support a model in which USP1 and UAF1 form a complex in the cytoplasm that subsequently translocates to the nucleus through import mediated by USP1 NLSs. Importantly, our findings have practical implications for the development of USP1-directed therapies. First, the UAF1-interacting region of USP1 identified here might be targeted to disrupt the USP1/UAF1 interaction with therapeutic purposes. On the other hand, we describe a cellular relocation assay that can be easily implemented in a high throughput setting to search for drugs that may dissociate the USP1/UAF1 complex

Molecular evolution of HoxA13 and the multiple origins of limbless morphologies in amphibians and reptiles

Developmental processes and their results, morphological characters, are inherited through transmission of genes regulating development. While there is ample evidence that cis-regulatory elements tend to be modular, with sequence segments dedicated to different roles, the situation for proteins is less clear, being particularly complex for transcription factors with multiple functions. Some motifs mediating protein-protein interactions may be exclusive to particular developmental roles, but it is also possible that motifs are mostly shared among different processes. Here we focus on HoxA13, a protein essential for limb development. We asked whether the HoxA13 amino acid sequence evolved similarly in three limbless clades: Gymnophiona, Amphisbaenia and Serpentes. We explored variation in ω (dN/dS) using a maximum-likelihood framework and HoxA13sequences from 47 species. Comparisons of evolutionary models provided low ω global values and no evidence that HoxA13 experienced relaxed selection in limbless clades. Branch-site models failed to detect evidence for positive selection acting on any site along branches of Amphisbaena and Gymnophiona, while three sites were identified in Serpentes. Examination of alignments did not reveal consistent sequence differences between limbed and limbless species. We conclude that HoxA13 has no modules exclusive to limb development, which may be explained by its involvement in multiple developmental processes

Is informed consent related to success in exercise and diet intervention as evaluated at 12 months? DR's EXTRA study

<p>Abstract</p> <p>Background</p> <p>There is a permanent need to evaluate and develop the ethical quality of scientific research and to widen knowledge about the effects of ethical issues. Therefore we evaluated whether informed consent is related to implementation and success in a lifestyle intervention study with older research participants. There is little empirical research into this topic.</p> <p>Methods</p> <p>The subjects (n = 597) are a subgroup of a random population sample of 1410 men and women aged 57-78 years who are participating in a 4-year randomized controlled intervention trial on the effects of physical exercise and diet on atherosclerosis, endothelial function and cognition. Data were collected in two steps: A questionnaire about informed consent was given to all willing participants (n = 1324) three months after the randomization. Data on implementation and success in the exercise and diet interventions were evaluated at 12 months by intervention-group personnel. The main purpose of the analysis procedure performed in this study was to identify and examine potential correlates for the chosen dependent variables and to generate future hypotheses for testing and confirming the independent determinants for implementation and success. The nature of the analysis protocol is exploratory at this stage.</p> <p>Results</p> <p>About half of the participants (54%) had achieved good results in the intervention. Nearly half of the participants (47%) had added to or improved their own activity in some sector of exercise or diet. Significant associations were found between performance in the interventions and participants' knowledge of the purpose of the study (p < 0.001), and between success in interventions and working status (p = 0.02), and the participants' knowledge of the purpose of the study (p = 0.04).</p> <p>Conclusion</p> <p>The main finding of this study was that those participants who were most aware or had understood the purpose of the study at an early stage had also attained better results at their 12-month intervention evaluation. Therefore, implementation and success in intervention is related to whether subjects receive a sufficient amount and are able to comprehend the information provided i.e. the core principles of informed consent.</p> <p>Trial Registration</p> <p>(ISRCTN 45977199)</p