Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models.

Accumulation of amyloid β-peptide (Aβ) is a driver of Alzheimer's disease (AD). Amyloid precursor protein (App) knock-in mouse models recapitulate AD-associated Aβ pathology, allowing elucidation of downstream effects of Aβ accumulation and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in AppNL-F and AppNL-G-F knock-in mice by time-course transcriptome analysis of hippocampus, a region severely affected in AD. Strikingly, energy metabolism emerged as one of the most significantly altered pathways already at an early stage of pathology. Functional experiments in isolated mitochondria from hippocampus of both AppNL-F and AppNL-G-F mice confirmed an upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, associated with higher susceptibility to oxidative damage and Ca2+-overload. Upon increasing pathologies, the brain shifts to a state of hypometabolism with reduced abundancy of mitochondria in presynaptic terminals. These late-stage mice also displayed enlarged presynaptic areas associated with abnormal accumulation of synaptic vesicles and autophagosomes, the latter ultimately leading to local autophagy impairment in the synapses. In summary, we report that Aβ-induced pathways in App knock-in mouse models recapitulate key pathologies observed in AD brain, and our data herein adds a comprehensive understanding of the pathologies including dysregulated metabolism and synapses and their timewise appearance to find new therapeutic approaches for AD

Exploring childhood cancer survivors' views about sex and sexual experiences -findings from online focus group discussions

PURPOSE: To explore childhood cancer survivors' views about sex and sexual experiences and, as an additional aim, their possible needs for care and support from health care professionals regarding sexual life. METHODS: Written online focus group discussions were performed with survivors of childhood cancer, identified through the Swedish Childhood Cancer Registry; 133 (36%; aged 16-25) participated. Written text was analysed using qualitative content analysis. RESULTS: The analysis resulted in one main category: Could my cancer experience have an impact on my sexual life? with four generic categories: Sex considered to be good, Feeling insecure and falling behind, Relating sex to a stable relationship and Concerns related to the physical body. In general, participants had not reflected on the possibility that their cancer experience could impact on sexual life. Sex was often considered to be something natural, important and taken for granted. However, thoughts and worries were expressed including being shy, feeling insecure and falling behind peers. Physical concerns included vaginal dryness and difficulties related to erection and reaching orgasm. Many participants stated that sexual issues had not been discussed with health care professionals, however, the need for such support differed. CONCLUSIONS: Many of the childhood cancer survivors' did not relate their sexual experiences to previous cancer treatment. However, problems were expressed, both of emotional and physical nature. Many participants stated that they had not received any information or support regarding sexual issues from health care professionals, why it is recommended to be regularly addressed in follow-up care

Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling

Background: Mitochondrial dysfunction is a common feature of aging, neurodegeneration, and metabolic diseases. Hence, mitotherapeutics may be valuable disease modifiers for a large number of conditions. In this study, we have set up a large-scale screening platform for mitochondrial-based modulators with promising therapeutic potential. Results: Using differentiated human neuroblastoma cells, we screened 1200 FDA-approved compounds and identified 61 molecules that significantly increased cellular ATP without any cytotoxic effect. Following dose response curve-dependent selection, we identified the flavonoid luteolin as a primary hit. Further validation in neuronal models indicated that luteolin increased mitochondrial respiration in primary neurons, despite not affecting mitochondrial mass, structure, or mitochondria-derived reactive oxygen species. However, we found that luteolin increased contacts between mitochondria and endoplasmic reticulum (ER), contributing to increased mitochondrial calcium (Ca2+) and Ca2+-dependent pyruvate dehydrogenase activity. This signaling pathway likely contributed to the observed effect of luteolin on enhanced mitochondrial complexes I and II activities. Importantly, we observed that increased mitochondrial functions were dependent on the activity of ER Ca2+-releasing channels inositol 1,4,5-trisphosphate receptors (IP3Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin treatment improved mitochondrial and locomotory activities in primary neurons and Caenorhabditis elegans expressing an expanded polyglutamine tract of the huntingtin protein. Conclusion: We provide a new screening platform for drug discovery validated in vitro and ex vivo. In addition, we describe a novel mechanism through which luteolin modulates mitochondrial activity in neuronal models with potential therapeutic validity for treatment of a variety of human diseases

Altered plasma protein profiles in genetic FTD – a GENFI study

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Methods: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. Results: We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers. Conclusion: We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.Open access funding provided by Karolinska Institute. C.G. received funding from EU Joint Programme—Neurodegenerative Disease Research -Prefrontals Vetenskapsrådet Dnr 529–2014-7504, Vetenskapsrådet 2015–02926, Vetenskapsrådet 2018–02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation, Dementia Foundation and Region Stockholm ALF-project. PN received funding from KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, the Swedish FTD Inititative-Schörling Foundation and Åhlén foundation. D.G. received support from the EU Joint Programme—Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. E.F. has received funding from a Canadian Institute of Health Research grant #327387. F.M. received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease. J.B.R. has received funding from the Welcome Trust (103838) and is supported by the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (SUAG/051 G101400) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215–20014). J.C.V.S. was supported by the Dioraphte Foundation grant 09–02-03–00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056–13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield Project. J.D.R. is supported by the Bluefield Project and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and a Miriam Marks Brain Research UK Senior Fellowship. M.M. has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. M.O. has received funding from Germany’s Federal Ministry of Education and Research (BMBF). R.S-V. is supported by Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2) and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. This work was also supported by the EU Joint Programme—Neurodegenerative Disease Research GENFI-PROX grant [2019–02248; to J.D.R., M.O., B.B., C.G., J.C.V.S. and M.S.info:eu-repo/semantics/publishedVersio

“I can if I want to”... : A qualitative study of how students understand their learning and how teaching prevention can support students in the learning process.

Studiens syfte är att med utgångspunkt i elevernas förståelse för sitt lärande öka förståelsen för hur lärare i ett förebyggande arbete, utifrån hur undervisningen struktureras och organiseras, kan stödja elevernas lärande. Hur kan eleverna ges stöd men även möjlighet till att kunna vara delaktiga och ta ansvar i sin lärprocess? Kunskap om hur lärandet ser ut från elevperspektivet är viktigt för lärare att veta, så de kan planera en undervisning som möter elevernas behov. Kvalitativ metodansats har använts i observationer och intervjuer. Den proximala utvecklingszonen är den teori som tillsammans med formativ bedömning, entreprenöriellt lärande och metakognition samspelar i en analysmodell (figur 4:5) där elevens inre motivation, delaktighet och ansvar är central.   Det mönster som framträder i resultatet är att de elever som i sina tidigare skolor getts möjlighet att bli medvetna om hur de lär sig också är de elever som beskriver att de når de högre kunskapskraven. Deras utsagor visar på ett samspel mellan förmågan att arbeta självständigt och lära nytt. De har en större tillit till sin egen förmåga att lära. När ett tydligt varför framträder ur elevens livsvärld ökar deras motivation, delaktighet och ansvar

Rituella landskap - finns dom?: Döserygg och dess grannar ur ett landskapsperspektiv

In this essay I discuss the expression ritual landscape regarding the burial and gathering site of Döserygg and its surroundings in south-western Scania, Sweden. Döserygg is dated to the early Neolithic-mid Neolithic period. I have studied literature, searched the Swedish National Heritage Board’s database, and studied maps to answer my questions: What is a ritual landscape? What other Neolithic sites are there in this part of Scania? How do they relate to Döserygg? and Can I see a ritual landscape in the archaeological material? There is not one definition of ritual landscape, but several. They all have in common that monuments are built in the vicinity of each other. By studying the patterns and locations of megalithic tombs (primarily dolmens), settlements and flint axe finds, I have found in my analysis that the term ritual landscape can be used, but that it may be better to use the expression ritual centre. This does not imply that it is not a ritual landscape, but that the link may be something other than monumental

Volitve 2000 in predvolilna kampanja

V članku analiziram predvolilno kampanjo, programe strank in politične konflikte v predvolilnem obdobju. Programe strank osvetlim s trendi ekonomske in politične globalizacijeugotavljam, da programi premalo upoštevajo pasti nove informacijske in komunikacijske tehnologije. Obravnavam ideološko in politično vsebino predvolilne kampanje, primere pristranske in negativne propagande, pa metode predvolilnega marketinga. Volilno izbiranje skušam pojasnjevati z opredelitvami volilcev, neopredeljnih volilcev in nevolilcev ter rezultati javnomnenjskih raziskav. Analiziram pozitivne in negativne primere televizijskih soočanj in informativnih oddaj. Odpiram dilemo, ali so mediji \u27objektivno\u27 spremljali predvolilna dogajanja, ali so ohranjali status neodvisnih javnih institucij ali pa je prevladovala levosredinska \u27oligarhija medijev\u27.The article analyzes pre-electoral campaigns, parties\u27 programs and political conflicts in the pre-electoral period. Party programs are elucidated by trendsof economic and political globalisation. The author finds that these programs take too little into consideration the snares of new information and communication technologies. Issues that are dealt with are: the ideological and political contents of the pre-electoral campaign, examples of prejudiced and negative propaganda, methods of pre-electoral marketing. Electoral choice is being explained through voters\u27 declarations, undeclared voters, non-votersand public opinion poll researches. Positive and negative examples of television confrontations and informative broadcasts are analyzed. The dilemma is put forward whether the media "objectively" followed pre-electoral activities, did they retain the status of independent public institutions, or was there a predominance of the left-middle "media oligarhy"

Digitalisering i förskolan : En kvalitativ studie om hur digitalisering framställs i pedagogiska medier

I denna kvalitativa studie undersöks hur begreppet digitalisering framställs i pedagogiska medier. Studien utsätter dominerande språkliga konstruktioner för kritisk analys, detta för att bidra till förändring vad gäller inlåsta föreställningar om verkligheten och maktstrukturer. Syftet i studien är att granska och analysera begreppet digitalisering i förhållande till förskolans utbildning. Frågeställningarna är: Hur framställs digitalisering i pedagogiska medier? Vilken betydelse får framställningen av digitalisering i pedagogiska medier för förskolans utbildning? Studien genomsyras av socialkonstruktionistisk utgångspunkt där kunskap om verkligheten förstås genom sociala, kulturella och historiska förhållanden. Den metodologiska ansatsen är kritisk diskursanalys där språkliga konstruktioner i olika texter i pedagogiska medier (pedagogiskamagasinet.se och förskolan.se) har utsatts för kritisk analys. Resultatet för studien presenteras i tre tematiseringar: Pedagogers kompetens, Högra krav på pedagoger och Digitalisering som samhällsnytta. Resultatet visar att digitalisering å ena sidan framställs som en samhällsnytta där digitala verktyg ger möjlighet att minska ojämlikheter med hjälp av pedagogers kompetens att använda dessa å andra sidan ifrågasätts nyttan av digitaliseringen då pedagogers kompetens ses som bristande. Detta ställer höga krav på förskollärare som antingen måste höja sin kompetens eller försvara den. Studiens slutsats är att framställningen av digitalisering i pedagogiska medier visar en polariserad debatt där digitalisering i förskolan ifrågasätts som användbar eller inte vilket försvårar pedagogers arbete