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Morphology and functionality of the epithelial lining differ along the intestinal tract, yet tissue renewal at all sites is driven by stem cells at the base of crypts 1-3 . Whether stem cell numbers and behaviour vary at different sites is unknown. Here, we show by intravital microscopy that despite similarities in the number and distribution of proliferative cells with an Lgr5 signature, small intestinal (SI) crypts contain twice as many effective stem cells as large intestinal (LI) crypts. We find that, although passively displaced by a conveyor belt-like upward movement, SI cells positioned away from the crypt base can function as long-term effective stem cells due to Wntdependent retrograde cellular movement. By contrast, the near absence of retrograde movement in the LI restricts cell repositioning, leading to a reduced effective stem cell number. Moreover, upon suppression of the retrograde movement in the SI, the number of effective stem cells is reduced, and the rate of monoclonal conversion of crypts is accelerated. Together, these results show that effective stem cell number is determined by active retrograde movement, revealing a new channel of stem cell regulation that can be experimentally and pharmacologically manipulated.

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Dopaminergic replacement has been used for Parkinson’s Disease (PD) treatment with positive effects on motor symptomatology but with low effects over disease progression and prevention. Different epidemiological studies have shown that nicotine consumption decreases PD prevalence through the activation of neuroprotective mechanisms. Nicotine-induced neuroprotection has been associated with the overstimulation of intracellular signaling pathways (SP) such as Phosphatidyl Inositol 3-kinase/Protein kinase-B (PI3K/AKT) through nicotinic acetylcholine receptors (e.g α7 nAChRs) and the over-expression of the anti-apoptotic gene Bcl-2. Considering its harmful effects (toxicity and dependency), the search for nicotine analogs with decreased secondary effects, but similar neuroprotective activity, remains a promissory field of study. In this work, a computational strategy integrating structural bioinformatics, signaling pathway (SP) manual reconstruction, and deep learning was performed to predict the potential neuroprotective activity of a series of 8 novel nicotine analogs over the behavior of PI3K/AKT. We performed a protein-ligand analysis between nicotine analogs and α7 nAChRs receptor using geometrical conformers, physicochemical characterization of the analogs and developed a manually curated neuroprotective dataset to analyze their potential activity. Additionally, we developed a predictive machine-learning model for neuroprotection in PD through the integration of Markov Chain Monte-Carlo transition matrix for the SP with synthetic training datasets of the physicochemical properties and structural dataset. Our model was able to predict the potential neuroprotective activity of seven new nicotine analogs based on the binomial Bcl-2 response regulated by the activation of PI3K/AKT. We present a new computational strategy to predict the pharmacological neuroprotective potential of nicotine analogs based on SP architecture, using deep learning and structural data. Our theoretical strategy can be further applied to the study new treatments related with SP deregulation and may ultimately offer new opportunities for therapeutic interventions in neurodegenerative diseases.Author SummaryParkinson’s disease is one of the most prevalent neurodegenerative diseases across population over age 50. Affecting controlled movements and non-motor symptoms, treatments for Parkinson prevention are indispensable to reduce patient’s population in the future. Epidemiological data provide evidence that nicotine have a neuroprotective effect decreasing Parkinson prevalence. By interacting with nicotine receptors in neurons and modulating signaling pathways expressing anti-apoptotic genes nicotine arise as a putative neuroprotective therapy. Nevertheless, toxicity and dependency prevent the use of nicotine as a suitable drug. Nicotine analogs, structurally similar compounds emerge as an alternative for Parkinson preventive treatment. In this sense we developed a quantitative strategy to predict the potential neuroprotective activity of nicotine analogs. Our model is the first approach to predict neuroprotection in the context of Parkinson and signaling pathways using machine learning and computational chemistry.

Aims:Present a novel machine learning computational strategy to predict the neuroprotection potential of nicotine analogs acting over the behavior of unpaired signaling pathways in Parkinson's disease. Background:Dopaminergic replacement has been used for Parkinson's Disease (PD) treatment with positive effects on motor symptomatology but low progression and prevention effects. Epidemiological studies have shown that nicotine consumption decreases PD prevalence through neuroprotective mechanisms activation associated with the overstimulation of signaling pathways (SP) such as PI3K/AKT through nicotinic acetylcholine receptors (e.g α7 nAChRs) and over-expression of anti-apoptotic genes such as Bcl-2. Nicotine analogs with similar neuroprotective activity but decreased secondary effects remain as a promissory field. Objective:The objective of this study is to develop an interdisciplinary computational strategy predicting the neuroprotective activity of a series of 8 novel nicotine analogs over Parkinson's disease. Methods:We present a computational strategy integrating structural bioinformatics, SP manual reconstruction, and deep learning to predict the potential neuroprotective activity of 8 novel nicotine analogs over the behavior of PI3K/AKT. We performed a protein-ligand analysis between nicotine analogs and α7 nAChRs receptor using geometrical conformers, physicochemical characterization of the analogs and developed manually curated neuroprotective datasets to analyze their potential activity. Additionally, we developed a predictive machine-learning model for neuroprotection in PD through the integration of Markov Chain Monte-Carlo transition matrix for the 2 SP with synthetic training datasets of the physicochemical properties and structural dataset. Results:Our model was able to predict the potential neuroprotective activity of seven new nicotine analogs based on the binomial Bcl-2 response regulated by the activation of PI3K/AKT. Conclusion:Hereby, we present a robust novel strategy to assess the neuroprotective potential of biomolecules based on SP architecture. Our theoretical strategy can be further applied to the study of new treatments related to SP deregulation and may ultimately offer new opportunities for therapeutic interventions in neurodegenerative diseases.

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