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Is evolution predictable at the molecular level? The ambitious goal to answer this question requires an understanding of the mutational effects that govern the complex relationship between genotype and phenotype. In practice, it involves integrating systems-biology modelling, microbial laboratory evolution experiments and large-scale mutational analyses — a feat that is made possible by the recent availability of the necessary computational tools and experimental techniques. Through concentrating largely on the problem antibiotic resistance evolution, I will discuss the degree to which these promises are realistic.

In the last decade we have used different cellular automata approaches to model immune responses in infectious diseases, as for instance, HIV infection, malaria and tuberculosis. In the first part of this talk, I briefly introduce the necessary biological concepts regarding immune responses and them I review two different types of modeling focusing on the details of the question addressed, its experimental validation and its predictive aspects. In the second part of the talk I will present a very recent work in which we use the network ideas and a Boolean approach to understand the dynamics of a chronic disease caused by helminthes, very common in Brazil. This approach allow to understand the particularities of the immune response that lead to the different clinical outcomes as well as the prevalence of these different clinical stages on the population. We discuss the implications of such results from the statistical physics point of view.

Major failures in AD patients with several low molecular weight (LMW) compounds and certain immunotherapies indicate that the etiology of the disease is still elusive. Therefore future therapies should address all AD hallmarks, regardless of prime etiological culprits. In this lecture several low molecular weight (LMW) compounds and their respective target(s) are critically discussed as potential treatments for AD including, inter alia: cholinergic modulators [cholinesterase inhibitors (AChE-Is), alpha7-nicotinic agonists, M1 muscarinic agonists], alpha-secretase activators, BACE1 inhibitors, gamma-secretase inhibitors or modulators, inhibitors of beta-amyloids (Abeta) aggregation or Abeta-induced neurotoxicity, inhibitors of tau proteins hyperphosphorylation and/or tau proteins aggregation, GSK-3beta inhibitors and sigma-1 receptor (Sig1R) agonists. Comparison among these compounds is made when possible also with M1 muscarinic agonists and a new compound, AF710B. In this context the M1 muscarinic receptor (M1 mAChR) appears to be a pivotal target for treatment of AD, Parkinson's disease (PD) and Lewy body dementia (LBD). Notably the M1 muscarinic agonists AF102B, AF267B, AF292 are effective cognitive enhancers and disease modifiers with a wide safety margin. Thus - i) AF102B decreased CSF Abeta in AD patients (Nitsch et al, Ann Neurol 2000); ii) AF267B rescued cognitive deficits and decreased Abeta42 and tau pathologies in 3xTg-AD mice (Caccamo et al, Neuron, 2006); and iii) AF102B and AF267B decreased brain alpha-synuclein aggregates in transgenic mice overexpressing human alpha-synuclein (Fisher et al., ADPD 2011). However in spite of their potential in disease modification (DM) and cognitive enhancement, M1 agonists (either orthosteric or allosteric) still do not address a prime disease hallmark, e.g. mitochondrial dysfunctions, which can be ameliorated via the molecular chaperone Sig1R. In this context we have designed a novel molecule, AF710B (MW, 357.5) which shows a novel mechanism of action (MoA) of enhancing neuroprotection and cognition via Sig1R activation and M1 muscarinic allosteric modulation, but not resembling Sig1R, M1 muscarinic (allosteric or orthosteric) and dual Sig1R/M1 agonists, respectively. The effects of AF710B at low concentrations in vitro against neurodegeneration, oxidative stress, Abeta, Tau-phosphorylation and GSK-3beta activation translate into down-regulation of the apoptotic protein Bax and mitochondrial dysfunction, up-regulation of anti-apoptotic Bcl2. AF710B has an exceptional pharmacology being an excellent cognitive enhancer in rats (at 1-30 and 10-100mcg/kg, po in trihexyphenidyl- and in MK801-induced passive avoidance impairments, respectively). AF710B is devoid of side effects, having an unprecedented safety margin > 50,000 (po). Furthermore, AF710B mitigated cognitive impairments, reduced Abeta40, Abeta42 levels and tau pathology and inflammation in 3xTg-AD mice AF710B (at 10 mcg/kg, ip/daily for 2 months; Morris water maze). The unique effects of AF710B can be explained by a super-sensitization of M1 mAChR through a hypothetical heteromerization with Sig1R. Conclusions: Only some of the reviewed compounds can bridge treatment of both cognitive impairments with DM. In this context, AF710B is the 1st reported low MW CNS-penetrable mono-therapy that meets comprehensively this challenge. The unmatched potency of AF710B on cognition and on amyloid and tau pathologies, combined with its beneficial effects on inflammation and mitochondrial dysfunctions, indicates extensive therapeutic advantages for AF710B in AD and other protein-aggregation related diseases vs. a plethora of experimental and licensed treatments.
Keywords: M1 muscarinic receptor, M1 agonist, disease modifiers, beta-amyloids, sigma-1 agonist, tau proteins, alpha-synuclein