Oral Treatment with Iododiflunisal Delays Hippocampal Amyloid-β Formation in a Transgenic Mouse Model of Alzheimer's Disease: A Longitudinal in vivo Molecular Imaging Study

Transthyretin (TTR) is a tetrameric, amyloid-β (Aβ)-binding protein, which reduces Aβ toxicity. The TTR/Aβ interaction can be enhanced by a series of small molecules that stabilize its tetrameric form. Hence, TTR stabilizers might act as disease-modifying drugs in Alzheimer's disease. Objective: We monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF), which acts as small-molecule chaperone of the TTR/Aβ interaction, and tolcapone, which does not behave as a small-molecule chaperone, in an animal model of Alzheimer's disease using positron emission tomography (PET). Methods: Female mice (AβPPswe/PS1A246E/TTR+/-) were divided into 3 groups (n=7 per group): IDIF-treated, tolcapone-treated, and non-treated. The oral treatment (100mg/Kg/day) was started at 5 months of age. Treatment efficacy assessment was based on changes in longitudinal deposition of Aβ in the hippocampus (HIP) and the cortex (CTX) and determined using PET-[18F]florbetaben. Immunohistochemical analysis was performed at age=14 months. Results: Standard uptake values relative to the cerebellum (SUVr) of [18F]florbetaben in CTX and HIP of non-treated animals progressively increased from age=5 to 11 months and stabilized afterwards. In contrast, [18F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages=5 and 11 months and significantly increased at 14 months. In the tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in the non-treated group. No significant treatment effect was observed in CTX. Results from immunohistochemistry matched the in vivo data at age=14 months. Conclusion: Our work provides encouraging preliminary results on the ability of small-molecule chaperones to ameliorate Aβ deposition in certain brain regions

Unifying femtosecond and picosecond single-pulse magnetic switching in GdFeCo

Many questions are still open regarding the physical mechanisms behind the magnetic switching in GdFeCo alloys by single optical pulses. Phenomenological models suggest a femtosecond scale exchange relaxation between sublattice magnetization as the driving mechanism for switching. The recent observation of thermally induced switching in GdFeCo by using both several picosecond optical laser pulse as well as electric current pulses has questioned this previous understanding. This has raised the question of whether or not the same switching mechanics are acting at the femo- and picosecond scales. In this work, we aim at filling this gap in the understanding of the switching mechanisms behind thermal single-pulse switching. To that end, we have studied experimentally thermal single-pulse switching in GdFeCo alloys, for a wide range of system parameters, such as composition, laser power and pulse duration. We provide a quantitative description of the switching dynamics using atomistic spin dynamics methods with excellent agreement between the model and our experiments across a wide range of parameters and timescales, ranging from femtoseconds to picoseconds. Furthermore, we find distinct element-specific damping parameters as a key ingredient for switching with long picosecond pulses and argue, that switching with pulse durations as long as 15 picoseconds is possible due to a low damping constant of Gd. Our findings can be easily extended to speed up dynamics in other contexts where ferrimagnetic GdFeCo alloys have been already demonstrated to show fast and energy-efficient processes, e.g. domain-wall motion in a track and spin-orbit torque switching in spintronics devices

Machine Learning Techniques for the Detection of Shockable Rhythms in Automated External Defibrillators

Early recognition of ventricular fibrillation (VF) and electrical therapy are key for the survivalof out-of-hospital cardiac arrest (OHCA) patients treated with automated external defibrilla-tors (AED). AED algorithms for VF-detection are customarily assessed using Holter record-ings from public electrocardiogram (ECG) databases, which may be different from the ECGseen during OHCA events. This study evaluates VF-detection using data from both OHCApatients and public Holter recordings. ECG-segments of 4-s and 8-s duration were ana-lyzed. For each segment 30 features were computed and fed to state of the art machinelearning (ML) algorithms. ML-algorithms with built-in feature selection capabilities wereused to determine the optimal feature subsets for both databases. Patient-wise bootstraptechniques were used to evaluate algorithm performance in terms of sensitivity (Se), speci-ficity (Sp) and balanced error rate (BER). Performance was significantly better for publicdata with a mean Se of 96.6%, Sp of 98.8% and BER 2.2% compared to a mean Se of94.7%, Sp of 96.5% and BER 4.4% for OHCA data. OHCA data required two times morefeatures than the data from public databases for an accurate detection (6 vs 3). No signifi-cant differences in performance were found for different segment lengths, the BER differ-ences were below 0.5-points in all cases. Our results show that VF-detection is morechallenging for OHCA data than for data from public databases, and that accurate VF-detection is possible with segments as short as 4-s

Chapter 1: Assessing a planet in transformation: Rationale and approach of the IPBES Global Assessment on Biodiversity and Ecosystem Services

The challenges of mitigating and adapting to climate change, achieving inclusive food, water, energy and health security, addressing urban vulnerabilities, and the unequal burdens of nature deterioration, are not only predicaments on their own right. Because they interact, often exacerbating each other, they create new risks and uncertainties for people and nature. It is now evident that the rapid deterioration of nature, including that of the global environmental commons on land, ocean, atmosphere and biosphere, upon which humanity as a whole depends, are interconnected and their cascading effects compromise societal goals and aspirations from local to global levels. Growing efforts to respond to these challenges and awareness of our dependence on nature have opened new opportunities for action and collaboration towards fairer and more sustainable futures.The global assessment on biodiversity and ecosystem services (GA) has been designed to be a comprehensive and ambitious intergovernmental integrated assessment of recent anthropogenic transformations of Earth?s living systems, the roots of such transformations, and their implications to society. In the chapters that follow, our mandate is to critically assess the state of knowledge on recent past (from the 1970s), present and possible future trends in multi-scale interactions between people and nature, taking into consideration different worldviews and knowledge systems, including those representing mainstream natural and social sciences and the humanities, and indigenous and local knowledge systems. In doing so, the GA also assesses where the world stands in relation to several international agreements related to biodiversity and sustainable development.Fil: Brondizio, Eduardo. No especifíca;Fil: Díaz, Sandra Myrna. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Settele, Josef. No especifíca;Fil: Ngo, Hien. No especifíca;Fil: Guèze, Maximilien. No especifíca;Fil: Aumeeruddy-Thomas, Y. No especifíca;Fil: Bai, Xuemei. No especifíca;Fil: Geschke, Arne. No especifíca;Fil: Molnár, Zsolt. No especifíca;Fil: Niamir, Aidin. No especifíca;Fil: Pascual, Unai. No especifíca;Fil: Simcock, Alan. No especifíca;Fil: Jaureguiberry, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Hien, Ngo,. No especifíca;Fil: Brancalion, Pedro. No especifíca;Fil: Chan, Kai M. A.. No especifíca;Fil: Dubertret, Fabrice. No especifíca;Fil: Hendry, Andrew. No especifíca;Fil: Liu, Jianguo. No especifíca;Fil: Martin, Adrian. No especifíca;Fil: Martín López, Berta. No especifíca;Fil: Midgley, Guy F.. No especifíca;Fil: Obura, David. No especifíca;Fil: Oliver, Tom. No especifíca;Fil: Scheffran, Jürgen. No especifíca;Fil: Seppelt, Ralf. No especifíca;Fil: Strassburg, Bernardo. No especifíca;Fil: Spangenberg, Joachim H.. No especifíca;Fil: Stenseke, Marie. No especifíca;Fil: Turnhout, Esther. No especifíca;Fil: Williams, Meryl J.. No especifíca;Fil: Zayas, Cynthia. No especifíca

Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD

It is well settled that the amyloidogenic properties of the plasma protein transporter transthyretin (TTR) can be modulated by compounds that stabilize its native tetrameric conformation. TTR is also present in cerebrospinal fluid where it can bind to Aβ-peptides and prevent Aβ aggregation. We have previously shown that treatment of Alzheimer’s Disease (AD) model mice with iododiflunisal (IDIF), a TTR tetramer stabilizing compound, prevents AD pathologies. This evidence positioned IDIF as a new lead drug for AD. In dissecting the mechanism of action of IDIF, we disclose here different labeling strategies for the preparation of 131I-labeled IDIF and 131I- and 124I-labeled TTR, which have been further used for the preparation of IDIF-TTR complexes labeled either on the compound or the protein. The biodistribution of all labeled species after intravenous administration has been investigated in mice using ex vivo and in vivo techniques. Our results confirm the capacity of TTR to cross the blood brain barrier (BBB) and suggest that the formation of TTR-IDIF complexes enhances BBB permeability of both IDIF and TTR. The increased TTR and IDIF brain concentrations may result in higher Aβ-peptide sequestration capacity with the subsequent inhibition of AD symptoms as we have previously observed in mice. © 2019, The Author(s).The work was supported by a grant from the Fundació Marató de TV3 (Neurodegenerative Diseases Call, Project Reference 20140330-31-32-33-34, http://www.ccma.cat/tv3/marato/en/ projectes-financats/2013/212/). The group at CIC biomaGUNE also acknowledges MINECO (Spain) for funding through Grant CTQ2017-87637-R. I. Cardoso worked under the Investigator FCT Program which is financed by national funds through the Foundation for Science and Technology (FCT, Portugal) and co-financed by the European Social Fund (ESF) through the Human Potential Operational Programme (HPOP), type 4.2 - Promotion of Scientific Employment.Peer reviewe

Treatments for people who use anabolic androgenic steroids: a scoping review.

BACKGROUND: A growing body of evidence suggests that anabolic androgenic steroids (AAS) are used globally by a diverse population with varying motivations. Evidence has increased greatly in recent years to support understanding of this form of substance use and the associated health harms, but there remains little evidence regarding interventions to support cessation and treat the consequences of use. In this scoping review, we identify and describe what is known about interventions that aim to support and achieve cessation of AAS, and treat and prevent associated health problems. METHODS: A comprehensive search strategy was developed in four bibliographic databases, supported by an iterative citation searching process to identify eligible studies. Studies of any psychological or medical treatment interventions delivered in response to non-prescribed use of AAS or an associated harm in any setting were eligible. RESULTS: In total, 109 eligible studies were identified, which included case reports representing a diverse range of disciplines and sources. Studies predominantly focussed on treatments for harms associated with AAS use, with scant evidence on interventions to support cessation of AAS use or responding to dependence. The types of conditions requiring treatment included psychiatric, neuroendocrine, hepatic, kidney, cardiovascular, musculoskeletal and infectious. There was limited evidence of engagement with users or delivery of psychosocial interventions as part of treatment for any condition, and of harm reduction interventions initiated alongside, or following, treatment. Findings were limited throughout by the case report study designs and limited information was provided. CONCLUSION: This scoping review indicates that while a range of case reports describe treatments provided to AAS users, there is scarce evidence on treating dependence, managing withdrawal, or initiating behaviour change in users in any settings. Evidence is urgently required to support the development of effective services for users and of evidence-based guidance and interventions to respond to users in a range of healthcare settings. More consistent reporting in articles of whether engagement or assessment relating to AAS was initiated, and publication within broader health- or drug-related journals, will support development of the evidence base

How can community health programmes build enabling environments for transformative communication?: Experiences from India and South Africa

Whilst much research has examined how to empower poor community members to identify the social roots of health problems and articulate demands for health-enabling living conditions, less is known about how to create receptive social environments where the powerful are likely to heed the voices of the poor. This paper seeks to characterise the social environments in which community-led health programmes are most likely to facilitate effective and sustainable health improvements, using three dimensions to characterise social contexts: material, symbolic and relational . We distinguish between technical communication (the transfer of health-related knowledge and skills from experts to communities) and transformative communication (a more politicised process, where marginalised groups develop critical understandings of the social roots of their ill-health, and the confidence and capacity to tackle these). Drawing on secondary sources, we compare two well-documented case studies of HIV/AIDS management projects. Both sought to use technical communication about HIV/AIDS as a springboard for developing transformative communication skills amongst marginalised women. The Entabeni Project in South Africa sought to empower impoverished women to deliver home-based nursing to people with AIDS. Whilst it performed a vital short-term welfare function, it did not achieve its goals of leadership by local participants and long-term sustainability. By contrast, the Sonagachi Project in India, which started as an HIV-prevention programme targeting female sex workers, has achieved both these outcomes. We examine the way in which pre-existing social contexts in West Bengal and rural KwaZulu-Natal impacted on the possibility of effective mobilisation of excluded women in each case. We also highlight the strategies through which Sonagachi, but not Entabeni, was able to alter aspects of the material, symbolic and relational contexts of participants’ communities in ways that opened up significant opportunities for project participants to articulate and assert their needs, and motivated powerful actors and groups to heed these demands