Transthyretin interacts with actin regulators in a Drosophila model of familial amyloid polyneuropathy

Familial amyloid polyneuropathy (FAP) is a neurodegenerative disorder whose major hallmark is the deposition of mutated transthyretin (TTR) in the form of amyloid fibrils in the peripheral nervous system (PNS). The exposure of PNS axons to extracellular TTR deposits leads to an axonopathy that culminates in neuronal death. However, the molecular mechanisms underlying TTR-induced neurodegeneration are still unclear, despite the extensive studies in vertebrate models. In this work we used a Drosophila FAP model, based on the expression of the amyloidogenic TTR (V30M) in the fly retina, to uncover genetic interactions with cytoskeleton regulators. We show that TTR interacts with actin regulators and induces cytoskeleton alterations, leading to axonal defects. Moreover, our study pinpoints an interaction between TTRV30M and members of Rho GTPase signaling pathways, the major actin regulators. Based on these findings we propose that actin cytoskeleton alterations may mediate the axonopathy observed in FAP patients, and highlight a molecular pathway, mediated by Rho GTPases, underlying TTR-induced neurodegeneration. We expect this work to prompt novel studies and approaches towards FAP therapy.This work was supported by: FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-028336 (PTDC/MED-NEU/28336/2017), to MAL; and Norte-01-0145-FEDER-000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through FEDER, to CSL and MAL. MIOS is a FCT fellow (SFRH/ BD/118728/2016). CSL is funded by DL 57/2016/CP1355/CT0022. MAL is an FCT Investigator. Flies expressing wild-type and mutant alleles of TTR were kindly provided by Malgorzata Pokrzywa and Per Hammarström. The DCAD2, PDF and Rho1 monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242. We would like to thank the SEM facility at CEMUP (University of Porto) for technical help and Mónica M Sousa and Fernando Casares for comments on the manuscript

Neuropsychological Assessment of Children With Reading Disabilities From 8 to 10 Years Old: An Exploratory Portuguese Study

Abstract Reading disabilities are one of the most significant causes of school failure and may result from different causes and cognitive processes. A comprehensive battery of neuropsychological tests was applied to a control group of 102 children (46 girls, 56 boys) with no history of learning disabilities and 32 children (13 girls, 19 boys) with poor reading achievement (PRA) to characterize their cognitive profile. A principal component analysis of the cognitive measures was undertaken to identify cognitive domains. Age-adjusted normative data were computed from controls for verbal and visuospatial abilities, psychomotor skills, executive functions, and a total score. Significant differences were found between the 2 groups. Although single tests could not identify children with PRA, measures of oral and written language, immediate and working memory, calculation, and verbal learning discriminated the 2 groups. A logistic regression model using these factors allowed us to identify 91.2% of healthy children and 96.9% of children with PRA. PRA may result from different patterns of cognitive difficulties, and it is more common in children with oral language and working-memory deficits. Wide-range cognitive testing is necessary to identify strong and weak areas to plan personalized intervention program

O1-5 Digital tools for physical activity assessment and brief counselling in Primary Health Care: The Portuguese model

Issue/problem Implementation of national systems for patients' physical activity (PA) assessment and counselling is a cost-effective strategy recommended in the WHO Global Action Plan for PA 2018-2030. Although Primary Health Care (PHC) professionals are recognized as key agents for PA promotion, challenges remain on how to develop feasible and scalable tools to support them in promoting patients' PA. The Portuguese model could help other countries improve PA assessment and brief counselling in PHC settings. This study aims to describe the tools' development and usage. Description of the problem The Portuguese Directorate-General of Health developed two evidence-based digital tools to support PA promotion by healthcare professionals: a) PA brief assessment tool; and b) brief counselling tool. The assessment tool was incorporated within the electronic medical health record software ?SClínico? in September 2017. It includes three questions: 1) how many days per week the patient performs any kind of PA (work, commuting or leisure-time); 2) how much time per day; and 3) how many hours per day the patient spends in sedentary behaviours. The PA brief counselling tool is available through the electronic medical prescription software ?PEM? since December 2017 and consists of five inter-related self-explanatory guides that can be delivered to patients (printed or by email), according to their motivation and PA levels. They facilitate person-centered and autonomy-supportive PA counselling, targeting specific behaviour change mediators, and using validated techniques. Results From September 2017 to December 2021, 159,179 patients had their PA assessed (2235 per 100,000 users of the National Health Service) and, from these, 16133 received PA brief counselling guides (177 per 100000 residents in Portugal, ≥ 15 years old), with a six-fold and three-fold increases, respectively, between 2018 and 2019 (previous to the COVID-19 pandemic). Future actions will address cost-effectiveness of this policy. Lessons The brief assessment and brief counselling tools were well-accepted and are increasingly being used, with potential for generalized adoption within the Portuguese Health Care System. Main messages Portugal has taken a decisive action to promote PA using PHC as a priority setting. PA tools usage is increasing considerably, highlighting the importance of making available easy-to-use PA promotion tools

Two- and three-point functions in two-dimensional Landau-gauge Yang-Mills theory: Continuum results

We investigate the Dyson-Schwinger equations for the gluon and ghost propagators and the ghost-gluon vertex of Landau-gauge gluodynamics in two dimensions. While this simplifies some aspects of the calculations as compared to three and four dimensions, new complications arise due to a mixing of different momentum regimes. As a result, the solutions for the propagators are more sensitive to changes in the three-point functions and the ansaetze used for them at the leading order in a vertex a expansion. Here, we therefore go beyond this common truncation by including the ghost-gluon vertex self-consistently for the first time, while using a model for the three-gluon vertex which reproduces the known infrared asymptotics and the zeros at intermediate momenta as observed on the lattice. A separate computation of the three-gluon vertex from the results is used to confirm the stability of this behavior a posteriori. We also present further arguments for the absence of the decoupling solution in two dimensions. Finally, we show how in general the infrared exponent kappa of the scaling solutions in two, three and four dimensions can be changed by allowing an angle dependence and thus an essential singularity of the ghost-gluon vertex in the infrared.Comment: 24 pages; added references, improved choices of parameters for vertex models; identical to version published in JHE

On the gauge boson's properties in a candidate technicolor theory

The technicolor scenario replaces the Higgs sector of the standard model with a strongly interacting sector. One candidate for a realization of such a sector is two-technicolor Yang-Mills theory coupled to two degenerate flavors of adjoint, massless techniquarks. Using lattice gauge theory the properties of the technigluons in this scenario are investigated as a function of the techniquark mass towards the massless limit. For that purpose the minimal Landau gauge two-point and three-point correlation functions are determined, including a detailed systematic error analysis. The results are, within the relatively large systematic uncertainties, compatible with a behavior very similar to QCD at finite techniquark mass. However, the limit of massless techniquarks exhibits features which could be compatible with a (quasi-)conformal behavior.Comment: 27 pages, 17 figures, 1 table; v2: persistent notational error corrected, some minor modification

Towards an in-depth understanding of physical activity and eating behaviours during COVID-19 social confinement: A combined approach from a Portuguese National Survey

Rapid worldwide decreases in physical activity (PA), an increase in sedentary behaviour (SB) and poorer dietary patterns have been reported during COVID-19 confinement periods. However, as national variability has been observed, this study sought to describe PA, SB and eating patterns, and to explore their gender as well as other socio-demographic correlates and how they interrelate in a representative sample of Portuguese adults during the COVID-19 first mandatory social confinement. The survey was applied online and by telephone to 5856 adults (mean age = 45.8 years; 42.6% women). The majority reported high (46.0%) or moderate (20.5%) PA levels. Men, younger participants, those with higher education levels and a favourable perception of their financial situation reported higher PA levels, with the opposite pattern for SB. Physical fitness activities and household chores were more reported by women, with more strength training and running activities reported by men. Regarding eating behaviours, 45.1% reported changes, positive (58%) and negative (42%), with 18.2% reporting increases in consumption of fruit, vegetables, and fish and other seafood consumption, while 10.8% (most with lower educational level and less comfortable with their income) reported an increase in consumption of ready-to-eat meals, soft drinks, savoury snacks, and take-away and delivered meals. Two clustersa health-enhancing vs. risky patternemerged through multiple correspondence analysis characterized by co-occurrence of high vs. low PA levels, positive vs. negative eating changes, awareness or not of the COVID-19 PA and dietary recommendations, perceived financial situation, higher vs. lower educational level and time in social confinement. In conclusion, while in social confinement, both positive and negative PA and eating behaviours and trends were displayed, highlighting the role of key sociodemographic correlates contributing to healthy vs. risky patterns. Results may inform future health interventions and policies to be more targeted to those at risk, and also advocate the promotion of PA and healthy eating in an integrated fashion.</jats:p

Detecting a decline in serial homicide : have we banished the devil from the details?

The current research provides perspective regarding the true prevalence of serial murderers in modern society and addresses the conflict between the evidenced decline in serial homicide and the viewpoint that the phenomenon is increasing. The likelihood that serial murderers are responsible for most unresolved homicides and missing persons is examined in the context of a declining prevalence. A mixed methods approach was used, consisting of a review of a sample of unresolved homicides, a comparative analysis of the frequency of known serial homicide series and unresolved serial homicide series, and semi-structured interviews of experts. In failing to become serial killers, aspiring and probable serial killers and spree killers have impacted the rate of serial murder by not reaching their potential. The past decade contained almost half the cases (13%) that existed at the 1980s peak of serial homicide (27%). Only 282 (1.3%) strangled females made up the 22,444 unresolved homicides reviewed. Most expert respondents thought it unreasonable that any meaningful proportion of missing persons cases are victims of serial homicide. Technology, shifts in offending behavior, proactive law enforcement action, and vigilance of society have transformed serial killing and aids in viewing offenders as people impacted by societal shifts and cultural norms. The absence of narrative details inhibited some aspects of the review. An exhaustive list of known unresolved serial homicide series remained elusive as some missing persons are never reported. Future research should incorporate those intending to murder serially, but whose efforts were stalled by arrest, imprisonment, or death

Consumption patterns of sweet drinks in a population of Australian children and adolescents (2003–2008)

<p>Abstract</p> <p>Background</p> <p>Intake of sweet drinks has previously been associated with the development of overweight and obesity among children and adolescents. The present study aimed to assess the consumption pattern of sweet drinks in a population of children and adolescents in Victoria, Australia.</p> <p>Methods</p> <p>Data on 1,604 children and adolescents (4–18 years) from the comparison groups of two quasi-experimental intervention studies from Victoria, Australia were analysed<it>.</it> Sweet drink consumption (soft drink and fruit juice/cordial) was assessed as one day’s intake and typical intake over the last week or month at two time points between 2003 and 2008 (mean time between measurement: 2.2 years).</p> <p>Results</p> <p>Assessed using dietary recalls, more than 70% of the children and adolescents consumed sweet drinks, with no difference between age groups (p = 0.28). The median intake among consumers was 500 ml and almost a third consumed more than 750 ml per day. More children and adolescents consumed fruit juice/cordial (69%) than soft drink (33%) (p < 0.0001) and in larger volumes (median intake fruit juice/cordial: 500 ml and soft drink: 375 ml). Secular changes in sweet drink consumption were observed with a lower proportion of children and adolescents consuming sweet drinks at time 2 compared to time 1 (significant for age group 8 to <10 years, p = 0.001).</p> <p>Conclusion</p> <p>The proportion of Australian children and adolescents from the state of Victoria consuming sweet drinks has been stable or decreasing, although a high proportion of this sample consumed sweet drinks, especially fruit juice/cordial at both time points.</p

Invasion speeds for structured populations in fluctuating environments

We live in a time where climate models predict future increases in environmental variability and biological invasions are becoming increasingly frequent. A key to developing effective responses to biological invasions in increasingly variable environments will be estimates of their rates of spatial spread and the associated uncertainty of these estimates. Using stochastic, stage-structured, integro-difference equation models, we show analytically that invasion speeds are asymptotically normally distributed with a variance that decreases in time. We apply our methods to a simple juvenile-adult model with stochastic variation in reproduction and an illustrative example with published data for the perennial herb, \emph{Calathea ovandensis}. These examples buttressed by additional analysis reveal that increased variability in vital rates simultaneously slow down invasions yet generate greater uncertainty about rates of spatial spread. Moreover, while temporal autocorrelations in vital rates inflate variability in invasion speeds, the effect of these autocorrelations on the average invasion speed can be positive or negative depending on life history traits and how well vital rates ``remember'' the past