Destination Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a prototypical neurodegenerative disease characterized by progressive degeneration of motor neurons both in the brain and spinal cord. The constantly evolving nature of ALS represents a fundamental dimension of individual differences that underlie this disorder, yet it involves multiple levels of functional entities that alternate in different directions and finally converge functionally to define ALS disease progression. ALS may start from a single entity and gradually becomes multifactorial. However, the functional convergence of these diverse entities in eventually defining ALS progression is poorly understood. Various hypotheses have been proposed without any consensus between the for-and-against schools of thought. The present review aims to capture explanatory hierarchy both in terms of hypotheses and mechanisms to provide better insights on how they functionally connect. We can then integrate them within a common functional frame of reference for a better understanding of ALS and defining future treatments and possible therapeutic strategies. Here, we provide a philosophical understanding of how early leads are crucial to understanding the endpoints in ALS, because invariably, all early symptomatic leads are underpinned by neurodegeneration at the cellular, molecular and genomic levels. Consolidation of these ideas could be applied to other neurodegenerative diseases (NDs) and guide further critical thinking to unveil their roadmap of destination ALS

Destination Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a prototypical neurodegenerative disease characterized by progressive degeneration of motor neurons both in the brain and spinal cord. The constantly evolving nature of ALS represents a fundamental dimension of individual differences that underlie this disorder, yet it involves multiple levels of functional entities that alternate in different directions and finally converge functionally to define ALS disease progression. ALS may start from a single entity and gradually becomes multifactorial. However, the functional convergence of these diverse entities in eventually defining ALS progression is poorly understood. Various hypotheses have been proposed without any consensus between the for-and-against schools of thought. The present review aims to capture explanatory hierarchy both in terms of hypotheses and mechanisms to provide better insights on how they functionally connect. We can then integrate them within a common functional frame of reference for a better understanding of ALS and defining future treatments and possible therapeutic strategies. Here, we provide a philosophical understanding of how early leads are crucial to understanding the endpoints in ALS, because invariably, all early symptomatic leads are underpinned by neurodegeneration at the cellular, molecular and genomic levels. Consolidation of these ideas could be applied to other neurodegenerative diseases (NDs) and guide further critical thinking to unveil their roadmap of destination ALS

Cohort profile : Oxford Pain, Activity and Lifestyle (OPAL) Study, a prospective cohort study of older adults in England

Purpose: The ‘Oxford Pain, Activity and Lifestyle’ (OPAL) Cohort is a longitudinal, prospective cohort study of adults, aged 65 years and older, living in the community which is investigating the determinants of health in later life. Our focus was on musculoskeletal pain and mobility, but the cohort is designed with flexibility to include new elements over time. This paper describes the study design, data collection and baseline characteristics of participants. We also compared the OPAL baseline characteristics with nationally representative data sources. Participants: We randomly selected eligible participants from two stratified age bands (65–74 and 75 and over years). In total, 5409 individuals (42.1% of eligible participants) from 35 general practices in England agreed to participate between 2016 and 2018. The majority of participants (n=5367) also consented for research team to access their UK National Health Service (NHS) Digital and primary healthcare records. Findings: to date Mean participant age was 74.9 years (range 65–100); 51.5% (n=2784/5409) were women. 94.9% of participants were white, and 28.8% lived alone. Over 83.0% reported pain in at least one body area in the previous 6 weeks. Musculoskeletal symptoms were more prevalent in women (86.4%). One-third of participants reported having one or more falls in the last year. Most participants were confident in their ability to walk outside. The characteristics of OPAL Cohort participants were broadly similar to the general population of the same age. Future plans: Postal follow-up of the cohort is being undertaken at annual intervals, with data collection ongoing. Linkage to NHS hospital admission data is planned. This English prospective cohort offers a large and rich resource for research on the longitudinal associations between demographic, clinical, and social factors and health trajectories and outcomes in community-dwelling older people

Clinical and genetic analysis of 29 Brazilian patients with Huntington’s disease-like phenotype

Huntington’s disease (HD) is a neurodegenerative disorder characterized by chorea, behavioral disturbances and dementia, caused by a pathological expansion of the CAG trinucleotide in the HTT gene. Several patients have been recognized with the typical HD phenotype without the expected mutation. The objective of this study was to assess the occurrence of diseases such as Huntington’s disease-like 2 (HDL2), spinocerebellar ataxia (SCA) 1, SCA2, SCA3, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA) and choreaacanthocytosis (ChAc) among 29 Brazilian patients with a HD-like phenotype. In the group analyzed, we found 3 patients with HDL2 and 2 patients with ChAc. The diagnosis was not reached in 79.3% of the patients. HDL2 was the main cause of the HD-like phenotype in the group analyzed, and is attributable to the African ancestry of this population. However, the etiology of the disease remains undetermined in the majority of the HD negative patients with HD-like phenotype. Key words: Huntington’s disease, Huntington’s disease-like, chorea-acanthocytosis, Huntington’s disease-like 2

The GOODSTEP project: General Object-Oriented Database for Software Engineering Processes

The goal of the GOODSTEP project is to enhance and improve the functionality of a fully object-oriented database management system to yield a platform suited for applications such as software development environments (SDEs). The baseline of the project is the O2 database management system (DBMS). The O2 DBMS already includes many of the features regulated by SDEs. The project has identified enhancements to O2 in order to make it a real software engineering DBMS. These enhancements are essentially upgrades of the existing O2 functionality, and hence require relatively easy extensions to the O2 system. They have been developed in the early stages of the project and are now exploited and validated by a number of software engineering tools built on top of the enhanced O2 DBMS. To ease tool construction, the GOODSTEP platform encompasses tool generation capabilities which allow for generation of integrated graphical and textual tools from high-level specifications. In addition, the GOODSTEP platform provides a software process toolset which enables modeling, analysis and enaction of software processes and is also built on top of the extended O2 database. The GOODSTEP platform is to be validated using two CASE studies carried out to develop an airline application and a business application

Wisdom of groups promotes cooperation in evolutionary social dilemmas

Whether or not to change strategy depends not only on the personal success of each individual, but also on the success of others. Using this as motivation, we study the evolution of cooperation in games that describe social dilemmas, where the propensity to adopt a different strategy depends both on individual fitness as well as on the strategies of neighbors. Regardless of whether the evolutionary process is governed by pairwise or group interactions, we show that plugging into the "wisdom of groups" strongly promotes cooperative behavior. The more the wider knowledge is taken into account the more the evolution of defectors is impaired. We explain this by revealing a dynamically decelerated invasion process, by means of which interfaces separating different domains remain smooth and defectors therefore become unable to efficiently invade cooperators. This in turn invigorates spatial reciprocity and establishes decentralized decision making as very beneficial for resolving social dilemmas.Comment: 8 two-column pages, 7 figures; accepted for publication in Scientific Report

Functional characterization of a 28-Kilobase Catabolic Island from Pseudomonas sp. Strain M1 involved in biotransformation of β-Myrcene and related plant-derived volatiles

Pseudomonas sp. strain M1 is able to mineralize highly hydrophobic and recalcitrant compounds, such as benzene, phenol, and their methylated/halogenated derivatives, as well as the backbone of several monoterpenes. The ability to use such a spectrum of compounds as the sole carbon source is, most probably, associated with a genetic background evolved under different environmental constraints. The outstanding performance of strain M1 regarding β-myrcene catabolism was elucidated in this work, with a focus on the biocatalytical potential of the β-myrcene-associated core code, comprised in a 28-kb genomic island (GI), predicted to be organized in 8 transcriptional units. Functional characterization of this locus with promoter probes and analytical approaches validated the genetic organization predictedin silicoand associated the β-myrcene-induced promoter activity to the production of β-myrcene derivatives. Notably, by using a whole-genome mutagenesis strategy, different genotypes of the 28-kb GI were generated, resulting in the identification of a novel putative β-myrcene hydroxylase, responsible for the initial oxidation of β-myrcene into myrcen-8-ol, and a sensor-like regulatory protein, whose inactivation abolished themyr + trait of M1 cells. Moreover, it was demonstrated that the range of monoterpene substrates of the M1 enzymatic repertoire, besides β-myrcene, also includes other acyclic (e.g., β-linalool) and cyclic [e.g.,R-(+)-limonene and (-)-β-pinene] molecules. Our findings are the cornerstone for following metabolic engineering approaches and hint at a major role of the 28-kb GI in the biotransformation of a broad monoterpene backbone spectrum for its future biotechnological applications.IMPORTANCEInformation regarding microbial systems able to biotransform monoterpenes, especially β-myrcene, is limited and focused mainly on nonsystematic metabolite identification. Complete and detailed knowledge at the genetic, protein, metabolite, and regulatory levels is essential in order to set a model organism or a catabolic system as a biotechnology tool. Moreover, molecular characterization of reported systems is scarce, almost nonexistent, limiting advances in the development of optimized cell factories with strategies based on the new generation of metabolic engineering platforms. This study provides new insights into the intricate molecular functionalities associated with β-myrcene catabolism inPseudomonas, envisaging the production of a molecular knowledge base about the underlying catalytic and regulatory mechanisms of plant-derived volatile catabolic pathways.Vectors from the Standard European Vector Architecture (SEVA) library and pBAM1 used in this work were kindly provided by Victor de Lorenzo (CNB-CSIC, Madrid, Spain). This work was supported by the strategic program UID/BIA/04050/2013 (POCI-01- 0145-FEDER-007569) funded by national funds through the FCT I.P. and by the ERDF through the COMPETE2020-Programa Operacional Competitividade e Internacionalização (POCI) and through a Ph.D. grant (grant SFRH/BD/76894/2011) to P.S.-C.info:eu-repo/semantics/publishedVersio

Grooming coercion and the post-conflict trading of social services in wild Barbary macaques

In animal and human societies, social services such as protection from predators are often exchanged between group members. The tactics that individuals display to obtain a service depend on its value and on differences between individuals in their capacity to aggressively obtain it. Here we analysed the exchange of valuable social services (i.e. grooming and relationship repair) in the aftermath of a conflict, in wild Barbary macaques (Macaca sylvanus). The relationship repair function of post-conflict affiliation (i.e. reconciliation) was apparent in the victim but not in the aggressor. Conversely, we found evidence for grooming coercion by the aggressor; when the victim failed to give grooming soon after a conflict they received renewed aggression from the aggressor. We argue that post-conflict affiliation between former opponents can be better described as a trading of social services rather than coercion alone, as both animals obtain some benefits (i.e. grooming for the aggressor and relationship repair for the victim). Our study is the first to test the importance of social coercion in the aftermath of a conflict. Differences in competitive abilities can affect the exchange of services and the occurrence of social coercion in animal societies. This may also help explain the variance between populations and species in their social behaviour and conflict management strategies

Mitochondrial echoes of first settlement and genetic continuity in El Salvador

Background: From Paleo-Indian times to recent historical episodes, the Mesoamerican isthmus played an important role in the distribution and patterns of variability all around the double American continent. However, the amount of genetic information currently available on Central American continental populations is very scarce. In order to shed light on the role of Mesoamerica in the peopling of the New World, the present study focuses on the analysis of the mtDNA variation in a population sample from El Salvador. Methodology/Principal Findings: We have carried out DNA sequencing of the entire control region of the mitochondrial DNA (mtDNA) genome in 90 individuals from El Salvador. We have also compiled more than 3,985 control region profiles from the public domain and the literature in order to carry out inter-population comparisons. The results reveal a predominant Native American component in this region: by far, the most prevalent mtDNA haplogroup in this country (at ~90%) is A2, in contrast with other North, Meso- and South American populations. Haplogroup A2 shows a star-like phylogeny and is very diverse with a substantial proportion of mtDNAs (45%; sequence range 16090–16365) still unobserved in other American populations. Two different Bayesian approaches used to estimate admixture proportions in El Salvador shows that the majority of the mtDNAs observed come from North America. A preliminary founder analysis indicates that the settlement of El Salvador occurred about 13,400±5,200 Y.B.P.. The founder age of A2 in El Salvador is close to the overall age of A2 in America, which suggests that the colonization of this region occurred within a few thousand years of the initial expansion into the Americas. Conclusions/Significance: As a whole, the results are compatible with the hypothesis that today's A2 variability in El Salvador represents to a large extent the indigenous component of the region. Concordant with this hypothesis is also the observation of a very limited contribution from European and African women (~5%). This implies that the Atlantic slave trade had a very small demographic impact in El Salvador in contrast to its transformation of the gene pool in neighbouring populations from the Caribbean facade