The transcriptional landscape of Alzheimer’s and Parkinson’s diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders worldwide. Although the aetiology, affected brain region and clinical features are particular to each of these diseases, they nevertheless share common mechanisms such as mitochondria dysfunction, neuronal loss and tau protein accumulation. The major risk factor for those disorders is ageing, the age of onset of both AD or PD being around 65 years old. Together, they account for 50 million cases worldwide, a number expected to increase due to the fact that the world population is living longer than ever. Most of AD and PD cases are sporadic and, despite all the research during the last centuries to better understand their molecular nature, current treatments are still symptomatic. Therefore, the development of effective therapies requires a better comprehension of the diseases’ aetiology and underlying mechanisms as well as finding disease-specific targets for drug discovery. A common strategy to identify biological pathways and cellular processes altered in neurodegenerative disorders is to compare gene expression profiles between age-matched diseased and non-diseased post-mortem brain tissues. However, the expression profiles derived from whole brain tissue mRNA highly reflect alterations in cellular composition, namely the well-known AD- or PD-associated loss of neurons, but not necessarily the disease-related molecular changes in brain cells. The advent of single-cell transcriptomes has made it possible to tackle this limitation, enabling the determination of reference gene expression profiles for each major brain cell type (namely neurons, astrocytes, microglia and oligodendrocytes) that can then be used to computationally estimate the cell type-specific content of bulk brain sample’s in healthy and diseased conditions, decoupling the neurodegeneration effect (i.e. the relative loss of neurons) from the intrinsic systemic or cell type-specific disease effects. This approach has already been applied in determining the effects of age and psychiatric disorders on the cellular composition of human brain, or the contribution of each cell type in shaping the pathological autism transcriptome. The same principle was applied in AD by modelling the expression of its risk genes as a function of estimated cellular composition of brain samples. For instance, APP, PSEN1, APOE and TREM2 had their expression levels associated with the relative abundance of respectively neurons, oligodendrocytes, astrocytes and microglia. Additionally, two recent studies profiled single nuclei of major brain cell types in AD and non-AD post-mortem brain samples, unveiling cell type-specific transcriptional changes. All these studies highlight the importance of charactering disease-associated cell type-specific phenotypes that can not only unveil the cellular and molecular bases of pathological mechanisms but also be therapeutically targeted. However, some of these studies still lack independent validation and have not fully dissected the nature of transcriptomic alterations in AD brains. Moreover, to our knowledge, similar approaches have not yet been applied to PD, despite increasing evidence regarding the importance of modelling cellular composition in neurodegenerative disorders. We therefore used scRNA-seq data to derive gene expression signatures for the major human brain cell types and estimate the cellular composition of idiopathic AD and PD post-mortem brain samples from their bulk transcriptomes, investigating whether neuronal loss could be confounding or masking the intrinsic disease effects on gene expression, and validating the results in independent datasets. Additionally, since AD and PD might share the same mechanisms of disease progression, we also investigated the similarities between the transcriptomic alterations induced by AD and PD in human brain tissues. This approach allowed the novel identification of genes and pathways whose activity in the brain is intrinsically altered by AD and PD in systemic and cell type-specific ways. Additionally, we pinpoint the genes that are commonly altered by these major neurodegenerative disorders as well as those specifically perturbed in each illness. Moreover, using chemical perturbagen data, we computationally identified candidate small molecules for specifically targeting the profiled AD/PD-associated molecular alterations. Thus, we unveil a set of novel candidates that can potentially be targeted in AD and PD therapeutics. Moreover, we herein demonstrate the potential of modelling cellular composition in transcriptomics analyses in the discovery of therapeutic targets for other neurodegenerative diseases

Building Conflict Resilience: It\u27s Not Just About Problem-Solving

Political polarization in the United States and internationally has increased enormously in the past decade, resulting in legislative impasse in some countries, political instability and partisan re-alignment in others, and decreased levels of communication, trust, and cooperation across partisan lines in schools, communities, and across the nation. As partisan polarization has increased, I have observed several perceptible changes in the way law school students engage each other around political differences and conflict in the classroom. From conversations with my colleagues, I am not alone in observing these trends

A measure of tripartite entanglement in bosonic and fermionic systems

We describe an efficient theoretical criterion suitable for the evaluation of the tripartite entanglement of any mixed three-boson or -fermion state, based on the notion of the entanglement of particles for bipartite systems of identical particles. Our approach allows one to quantify the accessible amount of quantum correlations in the systems without any violation of the local particle number superselection rule. A generalization of the tripartite negativity is here applied to some correlated systems including the continuous-time quantum walks of identical particles (both for bosons and fermions) and compared with other criteria recently proposed in the literature. Our results show the dependence of the entanglement dynamics upon the quantum statistics: the bosonic bunching results into a low amount of quantum correlations while Fermi-Dirac statistics allows for higher values of the entanglement.Comment: 19 pages, 3 figure

Dynamics of quantum correlations in colored environments

We address the dynamics of entanglement and quantum discord for two non interacting qubits initially prepared in a maximally entangled state and then subjected to a classical colored noise, i.e. coupled with an external environment characterized by a noise spectrum of the form $1/f^{\alpha}$. More specifically, we address systems where the Gaussian approximation fails, i.e. the sole knowledge of the spectrum is not enough to determine the dynamics of quantum correlations. We thus investigate the dynamics for two different configurations of the environment: in the first case the noise spectrum is due to the interaction of each qubit with a single bistable fluctuator with an undetermined switching rate, whereas in the second case we consider a collection of classical fluctuators with fixed switching rates. In both cases we found analytical expressions for the time dependence of entanglement and quantum discord, which may be also extended to a collection of flcutuators with random switching rates. The environmental noise is introduced by means of stochastic time-dependent terms in the Hamiltonian and this allows us to describe the effects of both separate and common environments. We show that the non-Gaussian character of the noise may lead to significant effects, e.g. environments with the same power spectrum, but different configurations, give raise to opposite behavior for the quantum correlations. In particular, depending on the characteristics of the environmental noise considered, both entanglement and discord display either a monotonic decay or the phenomena of sudden death and revivals. Our results show that the microscopic structure of environment, besides its noise spectrum, is relevant for the dynamics of quantum correlations, and may be a valid starting point for the engineering of non-Gaussian colored environments.Comment: 8 pages, 3 figure

Unraveling targetable systemic and cell-type-specific molecular phenotypes of Alzheimer’s and Parkinson’s brains with digital cytometry

Copyright © 2020 Bordone and Barbosa-Morais. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders worldwide, with age being their major risk factor. The increasing worldwide life expectancy, together with the scarcity of available treatment choices, makes it thus pressing to find the molecular basis of AD and PD so that the causing mechanisms can be targeted. To study these mechanisms, gene expression profiles have been compared between diseased and control brain tissues. However, this approach is limited by mRNA expression profiles derived for brain tissues highly reflecting their degeneration in cellular composition but not necessarily disease-related molecular states. We therefore propose to account for cell type composition when comparing transcriptomes of healthy and diseased brain samples, so that the loss of neurons can be decoupled from pathology-associated molecular effects. This approach allowed us to identify genes and pathways putatively altered systemically and in a cell-type-dependent manner in AD and PD brains. Moreover, using chemical perturbagen data, we computationally identified candidate small molecules for specifically targeting the profiled AD/PD-associated molecular alterations. Our approach therefore not only brings new insights into the disease-specific and common molecular etiologies of AD and PD but also, in these realms, foster the discovery of more specific targets for functional and therapeutic exploration.This work was supported by European Molecular Biology Organization (EMBO Installation Grant 3057 to NB-M), Fundação para a Ciência e a Tecnologia (FCT Investigator Starting Grant IF/00595/2014 and CEEC Individual Assistant Researcher contract CEECIND/00436/2018 to NB-M, Ph.D.Studentship PD/BD/105854/2014 to MB), and Genome PT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 – Operational Programme for Competitiveness and Internationalization (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020),under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by Fundação para a Ciência e a Tecnologia (FCT).info:eu-repo/semantics/publishedVersio

Mechanistic and pathological study of the genesis, growth, and rupture of abdominal aortic aneurysms

Postprint (published version

The Negotiation Within: The Impact of Internal Conflict Over Identity and Role on Across-The-Table Negotiations

This article argues that negotiators\u27 experiences of internal conflict over their identity and role - what we term the negotiation within - has a significant impact on across-the-table negotiations in the legal profession and in business. This impact has been mostly overlooked by the literature on negotiation, which focuses on strategic, structural, and psychological barriers to negotiated agreements that are divorced from the real, internal experiences of most negotiators. The article analyzes the impact and suggests a typology for naming and understanding internal conflict. It concludes with a three-stage prescription on how to manage such conflicts described as Mirror work, Chair work, and Table work

Hemodynamic on abdominal aortic aneurysm: Parametric study

El objetivo del presente estudio es determinar qué influencia tienen los parámetros geométricos con las tensiones hemodinámicas en aneurismas abdominales aórticos. Para ello los autores han creado varios modelos geométricos de aneurismas abdominales basándose en sus principales características geométricas (diámetro máximo, diámetro mínimo, longitud aneurisma y asimetría) y técnicas computacionales para calcular la presión y la tensión de corte en el saco aneurismático. Los resultados obtenidos constatan que la presión hemodinámica es la principal carga mecánica que actúa sobre la pared arterial y que la morfometría de los aneurismas podría ser utilizada como buen predictor del riesgo de rotura. Posteriormente, con el objetivo de determinar si los modelos geométricos se podrían usar como aproximación de modelos reales, se compararon varios modelos reales (patient-specific) con sus respectivos modelos geométricos obteniendo una buena aproximación.The aim of this study is to assess how the shape of the abdominal aortic aneurysms (AAA) affects the hemodynamic wall stresses. With this purpose, different AAAs are studied through simplified models based on geometrical parameters of the aneurism such as its maximum and minimum diameter, length and asymmetry. Then, a computational fluid dynamics analysis is performed on the simplified models in order to compute pressure and wall shear stresses on the aneurysm sac. The results obtained show that blood pressure is the main dynamic load acting on the artery wall, and that the morphology of the aneurysm could be a good indicator of risk of failure. Furthermore, the computational results are compared with patient-specific real models with the objective to assess the reliability of the proposed simplified approach.Peer Reviewe