Computing with cells: membrane systems - some complexity issues.

Membrane computing is a branch of natural computing which abstracts computing models from the structure and the functioning of the living cell. The main ingredients of membrane systems, called P systems, are (i) the membrane structure, which consists of a hierarchical arrangements of membranes which delimit compartments where (ii) multisets of symbols, called objects, evolve according to (iii) sets of rules which are localised and associated with compartments. By using the rules in a nondeterministic/deterministic maximally parallel manner, transitions between the system configurations can be obtained. A sequence of transitions is a computation of how the system is evolving. Various ways of controlling the transfer of objects from one membrane to another and applying the rules, as well as possibilities to dissolve, divide or create membranes have been studied. Membrane systems have a great potential for implementing massively concurrent systems in an efficient way that would allow us to solve currently intractable problems once future biotechnology gives way to a practical bio-realization. In this paper we survey some interesting and fundamental complexity issues such as universality vs. nonuniversality, determinism vs. nondeterminism, membrane and alphabet size hierarchies, characterizations of context-sensitive languages and other language classes and various notions of parallelism

How to Escape Local Optima in Black Box Optimisation: When Non-elitism Outperforms Elitism

Escaping local optima is one of the major obstacles to function optimisation. Using the metaphor of a fitness landscape, local optima correspond to hills separated by fitness valleys that have to be overcome. We define a class of fitness valleys of tunable difficulty by considering their length, representing the Hamming path between the two optima and their depth, the drop in fitness. For this function class we present a runtime comparison between stochastic search algorithms using different search strategies. The ((Formula presented.)) EA is a simple and well-studied evolutionary algorithm that has to jump across the valley to a point of higher fitness because it does not accept worsening moves (elitism). In contrast, the Metropolis algorithm and the Strong Selection Weak Mutation (SSWM) algorithm, a famous process in population genetics, are both able to cross the fitness valley by accepting worsening moves. We show that the runtime of the ((Formula presented.)) EA depends critically on the length of the valley while the runtimes of the non-elitist algorithms depend crucially on the depth of the valley. Moreover, we show that both SSWM and Metropolis can also efficiently optimise a rugged function consisting of consecutive valleys

Accurate Distinction of Pathogenic from Benign CNVs in Mental Retardation

Copy number variants (CNVs) have recently been recognized as a common form of genomic variation in humans. Hundreds of CNVs can be detected in any individual genome using genomic microarrays or whole genome sequencing technology, but their phenotypic consequences are still poorly understood. Rare CNVs have been reported as a frequent cause of neurological disorders such as mental retardation (MR), schizophrenia and autism, prompting widespread implementation of CNV screening in diagnostics. In previous studies we have shown that, in contrast to benign CNVs, MR-associated CNVs are significantly enriched in genes whose mouse orthologues, when disrupted, result in a nervous system phenotype. In this study we developed and validated a novel computational method for differentiating between benign and MR-associated CNVs using structural and functional genomic features to annotate each CNV. In total 13 genomic features were included in the final version of a Naïve Bayesian Tree classifier, with LINE density and mouse knock-out phenotypes contributing most to the classifier's accuracy. After demonstrating that our method (called GECCO) perfectly classifies CNVs causing known MR-associated syndromes, we show that it achieves high accuracy (94%) and negative predictive value (99%) on a blinded test set of more than 1,200 CNVs from a large cohort of individuals with MR. These results indicate that this classification method will be of value for objectively prioritizing CNVs in clinical research and diagnostics

Combined Inactivation of MYC and K-Ras Oncogenes Reverses Tumorigenesis in Lung Adenocarcinomas and Lymphomas

Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as "oncogene-addiction." However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment.To examine how the MYC and K-ras(G12D) oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-ras(G12D) to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-, K-ras(G12D)- or MYC/K-ras(G12D)-induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas K-ras(G12D)-induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-ras(G12D) resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-ras(G12D) in maintenance of lung tumors, we found that the down-stream mediators of K-ras(G12D) signaling, Stat3 and Stat5, are dephosphorylated following conditional K-ras(G12D) but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-ras(G12D). Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation.Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic pathways is more likely to be effective in the treatment of lung cancers and lymphomas

A Potential Role for Shed Soluble Major Histocompatibility Class I Molecules as Modulators of Neurite Outgrowth

The neurobiological activities of classical major histocompatibility class I (MHCI) molecules are just beginning to be explored. To further examine MHCI's actions during the formation of neuronal connections, we cultured embryonic mouse retina explants a short distance from wildtype thalamic explants, or thalami from transgenic mice (termed “NSE-Db”) whose neurons express higher levels of MHCI. While retina neurites extended to form connections with wildtype thalami, we were surprised to find that retina neurite outgrowth was very stunted in regions proximal to NSE-Db thalamic explants, suggesting that a diffusible factor from these thalami inhibited retina neurite outgrowth. It has been long known that MHCI-expressing cells release soluble forms of MHCI (sMHCI) due to the shedding of intact MHCI molecules, as well as the alternative exon splicing of its heavy chain or the action proteases which cleave off it's transmembrane anchor. We show that the diffusible inhibitory factor from the NSE-Db thalami is sMHCI. We also show that COS cells programmed to express murine MHCI release sMHCI that inhibits neurite outgrowth from nearby neurons in vitro. The neuroinhibitory effect of sMHCI could be blocked by lowering cAMP levels, suggesting that the neuronal MHCI receptor's signaling mechanism involves a cyclic nucleotide-dependent pathway. Our results suggest that MHCI may not only have neurobiological activity in its membrane-bound form, it may also influence local neurons as a soluble molecule. We discuss the involvement of complement proteins in generating sMHCI and new theoretical models of MHCI's biological activities in the nervous system

Caenorhabditis elegans Myotubularin MTM-1 Negatively Regulates the Engulfment of Apoptotic Cells

During programmed cell death, apoptotic cells are recognized and rapidly engulfed by phagocytes. Although a number of genes have been identified that promote cell corpse engulfment, it is not well understood how phagocytosis of apoptotic cells is negatively regulated. Here we have identified Caenorhabditis elegans myotubularin MTM-1 as a negative regulator of cell corpse engulfment. Myotubularins (MTMs) constitute a large, highly conserved family of lipid phosphatases. MTM gene mutations are associated with various human diseases, but the cellular functions of MTM proteins are not clearly defined. We found that inactivation of MTM-1 caused significant reduction in cell corpses in strong loss-of-function mutants of ced-1, ced-6, ced-7, and ced-2, but not in animals deficient in the ced-5, ced-12, or ced-10 genes. In contrast, overexpression of MTM-1 resulted in accumulation of cell corpses. This effect is dependent on the lipid phosphatase activity of MTM-1. We show that loss of mtm-1 function accelerates the clearance of cell corpses by promoting their internalization. Importantly, the reduction of cell corpses caused by mtm-1 RNAi not only requires the activities of CED-5, CED-12, and CED-10, but also needs the functions of the phosphatidylinositol 3-kinases (PI3Ks) VPS-34 and PIKI-1. We found that MTM-1 localizes to the plasma membrane in several known engulfing cell types and may modulate the level of phosphatidylinositol 3-phosphate (PtdIns(3)P) in vivo. We propose that MTM-1 negatively regulates cell corpse engulfment through the CED-5/CED-12/CED-10 module by dephosphorylating PtdIns(3)P on the plasma membrane

Chronic disease prevalence and care among the elderly in urban and rural Beijing, China - a 10/66 Dementia Research Group cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>Demographic ageing is occurring at an unprecedented rate in China. Chronic diseases and their disabling consequences will become much more common. Public policy has a strong urban bias, and older people living in rural areas may be especially vulnerable due to limited access to good quality healthcare, and low pension coverage. We aim to compare the sociodemographic and health characteristics, health service utilization, needs for care and informal care arrangements of representative samples of older people in two Beijing communities, urban Xicheng and rural Daxing.</p> <p>Methods</p> <p>A one-phase cross-sectional survey of all those aged 65 years and over was conducted in urban and rural catchment areas in Beijing, China. Assessments included questionnaires, a clinical interview, physical examination, and an informant interview. Prevalence of chronic diseases, self-reported impairments and risk behaviours was calculated adjusting for household clustering. Poisson working models were used to estimate the independent effect of rural versus urban residence, and to explore the predictors of health services utilization.</p> <p>Results</p> <p>We interviewed 1002 participants in rural Daxing, and 1160 in urban Xicheng. Those in Daxing were more likely to be younger, widowed, less educated, not receiving a pension, and reliant on family transfers. Chronic diseases were more common in Xicheng, when based on self-report rather than clinical assessment. Risk exposures were more common in Daxing. Rural older people were much less likely to access health services, controlling for age and health. Community health services were ineffective, particularly in Daxing, where fewer than 3% of those with hypertension were adequately controlled. In Daxing, care was provided by family, who had often given up work to do so. In Xicheng, 45% of those needing care were supported by paid caregivers. Caregiver strain was higher in Xicheng. Dementia was strongly associated with care needs and caregiver strain, but not with medical helpseeking.</p> <p>Conclusion</p> <p>Apparent better health in Daxing might be explained by under-diagnosis, under-reporting or selective mortality. Far-reaching structural reforms may be needed to improve access and strengthen rural healthcare. The impact of social and economic change is already apparent in Xicheng, with important implications for future long-term care.</p