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| 2. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 3. |
- Almgren Bäck, Gunilla, et al.
(författare)
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Speech-to-text intervention to support text production among students with writing difficulties: a single-case study in nordic countries
- 2024
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Ingår i: Disability and Rehabilitation. - 1748-3107 .- 1748-3115. ; , s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- Studies report that speech-to-text applications (STT) may support students with writing difficulties in text production. However, existing research is sparse, shows mixed results, and lacks information on STT interventions and their applicability in schools. Therefore, this study aimed to investigate whether a systematic and intensive assistive technology intervention focusing on STT can improve text production. A modified multiple-baseline across-subject design was used involving eight middle school students, four Norwegian and four Swedish. Their STT-produced narrative texts were collected during and after the intervention and the productivity, accuracy, and text quality were analysed. Keyboarding was the baseline control condition. The results demonstrated that seven of the eight students increased text productivity and that the proportion of word-level accuracy was maintained or improved. The use of punctuation progressed in participants with poor baseline skills. Most students’ STT-produced texts had at least a similar ratio of meaningfulness and text quality as keyboarding. However, the magnitude of the changes and development patterns varied, with three students showing the most notable impacts. In conclusion, this study’s intervention seemed beneficial in initially instructing STT, and the progress monitoring guided individually adapted future interventions such as balancing productivity and formal language aspects. Removing the spelling barrier with STT provided an opportunity for students to improve their higher-order skills, such as vocabulary diversity and overall text quality. Furthermore, visible progress, such as the ability to produce longer texts, might motivate continued STT usage. However, such development may not always be immediate.
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| 4. |
- Berghauser Pont, Meta, 1972, et al.
(författare)
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Förtätning av stationsnära områden för god tillgänglighet. Utveckling av en analys - och utvärderingsmetod
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Det finns en vilja att förtäta i närheten av stationer för att öka användningen av kollektivtrafik och därmed minska klimatpåverkan kopplad till transpor- ter. Förtätning bidrar bland annat till att skapa levande stationssamhällen, med blandade funktioner, god tillgäng- lighet och miljöer som är trygga och vistelsevänliga där olika grupper och behov möts. Potentialerna är många men så även utmaningarna. Förtätning av stationsnära områden kan också leda till oönskade konsekven- ser för social, ekonomisk och ekologisk hållbarhet. Den här rap- porten kan förhoppningsvis ge ökad förståelse för förtätning i relation till regional tillgänglighet samt för positiva och negativa konsekvenser av förtätning i stationsnära områden. Den kan också skapa insikter om hur olika alternativ för utveckling av stations- nära områden kan värderas utifrån Agenda 2030, särskilt Mål 11: Hållbara städer och samhällen. Rapporten är framtagen inom projektet Urbana stationssamhäll- en – förtätning av stationsnära områden för god tillgänglighet (2020–2022) som finansierats av Trafikverket och bedrivits i sam- verkan mellan Urban Futures vid GMV (projektägare), Arkitektur och samhällsbyggnadsteknik vid Chalmers tekniska högskola, Gö- teborgsregionen (GR), Samhällsplanering vid Högskolan Dalarna och Samhällsplanering och miljö vid KTH.
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| 5. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 6. |
- Bromée, Torun, 1973-
(författare)
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Evolution and Pharmacology of Receptors for Bradykinin and Neuropeptide Y in Vertebrates
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The bradykinin and neuropeptide Y (NPY) receptors belong to the superfamily of G-protein coupled receptors (GPCRs). The GPCRs form the largest class of therapeutic targets and it is therefore of great interest to investigate the pharmacological properties, functions and evolution of these receptors.Bradykinin (BK) is a nonapeptide that contributes to inflammatory responses, mediates pain signals and influences blood pressure. The two bradykinin receptor subtypes B1 and B2 are well characterized in mammals, but have received little attention in non-mammals. This thesis describes the cloning and characterization of the first piscine bradykinin receptor, from the Danio rerio (zebrafish). Ligand-receptor interactions were measured as production of intracellular inositol phosphate. Zebrafish BK activated the receptor with highest potency (pEC50=6.97±0.1) while mammalian BK was almost inactive. A complete alanine and D-amino acid scan of the BK peptide revealed important roles for receptor interaction for residues Gly4, Ser6, Pro7, Leu8 and Arg9. The receptor gene was mapped to chromosome 17 in the zebrafish genome in a region that shows conserved synteny to the human B1-B2 gene region on chromosome 14. The release of the zebrafish and pufferfish genomes enabled us to identify both B1 and B2 genes in Danio rerio and pufferfishes (Takifugu rubripes and Tetraodon nigroviridis) as well as the B1 gene in chicken. All of these species display conserved synteny of the gene region. Interestingly, the evolutionary rate is clearly greater for B1 than for B2. Kininogen, the precursor for bradykinin, is also located in a chromosome region with extensive conserved synteny.Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) comprise a family of related peptides and are involved in a variety of neuronal and endocrine functions. Receptor subtypes Y6 and Y7 were cloned and pharmacologically characterized in chicken. The genes are located one megabase apart on chromosome 13 in a region with conserved synteny to human chromosome 5. Porcine PYY bound to chicken Y6 with a Kd of 0.80±0.36 nM and chicken Y7 with a Kd of 0.14±0.01 nM. The Y6 mRNA is expressed in hypothalamus, gastrointestinal tract and adipose tissue and may be involved in appetite regulation like other NPY receptors. Chicken Y7 mRNA was only detected in adrenal gland. These results may help explain why these receptors have lost function in humans.
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| 7. |
- Callen, Michael, et al.
(författare)
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COVID-19 vaccine acceptance and hesitancy in low- and middle-income countries
- 2021
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Ingår i: Nature Medicine. - : Springer Nature. - 1546-170X .- 1078-8956. ; 27:8, s. 1385-1394
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Tidskriftsartikel (refereegranskat)abstract
- Widespread acceptance of COVID-19 vaccines is crucial for achieving sufficient immunization coverage to end the global pandemic, yet few studies have investigated COVID-19 vaccination attitudes in lower-income countries, where large-scale vaccination is just beginning. We analyze COVID-19 vaccine acceptance across 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa and South America, Russia (an upper-middle-income country) and the United States, including a total of 44,260 individuals. We find considerably higher willingness to take a COVID-19 vaccine in our LMIC samples (mean 80.3%; median 78%; range 30.1 percentage points) compared with the United States (mean 64.6%) and Russia (mean 30.4%). Vaccine acceptance in LMICs is primarily explained by an interest in personal protection against COVID-19, while concern about side effects is the most common reason for hesitancy. Health workers are the most trusted sources of guidance about COVID-19 vaccines. Evidence from this sample of LMICs suggests that prioritizing vaccine distribution to the Global South should yield high returns in advancing global immunization coverage. Vaccination campaigns should focus on translating the high levels of stated acceptance into actual uptake. Messages highlighting vaccine efficacy and safety, delivered by healthcare workers, could be effective for addressing any remaining hesitancy in the analyzed LMICs. © 2021, The Author(s).
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| 8. |
- Carrick, Richard T., et al.
(författare)
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Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe
- 2024
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Ingår i: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645.
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC.Methods This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed.Results One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans.Conclusions North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.
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| 9. |
- de Villiers, Sabina H. L., et al.
(författare)
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Nicotine hapten structure, antibody selectivity and effect relationships : Results from a nicotine vaccine screening procedure
- 2010
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 28:10, s. 2161-2168
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to synthesise and screen a set of novel nicotine hapten immunogens used for the treatment of nicotine dependence. In the screening process we studied the amount of antibodies generated and their selectivity, using ELISA techniques, and their effects on nicotine-induced dopamine release in the NAC(shell) of the rat, assessed by in vivo voltammetry. We conclude that even small changes such as the linker attachment on the nicotine molecule as well as the structure of the linker may greatly influence the selectivity of the antibodies and the central neurobiological effects of nicotine that are considered critical for its dependence producing properties. (C) 2010 Elsevier Ltd. All rights reserved.
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| 10. |
- Edström, Isabelle, et al.
(författare)
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Does production facilitate discrimination? : An infant mismatch negativity study
- 2013
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Ingår i: Proceedings of Fonetik 2013. - Linköping. ; , s. 17-20
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Konferensbidrag (refereegranskat)abstract
- MMN is an ERP component that reflects preattentive discrimination between a recurring standard sound and a deviating sound. MMN is frequently used in infant studies focused on speech development since its elicitation does not require the attention of the child. The general ability of infants to discriminate speech sounds is gradually specialized towards discrimination of phonetic contrasts in their mother tongue. The aim of the present study was to examine if an MMN response is elicited by naturally varying speech stimuli (/ ti/ and / ki/) and if this response is stronger for the speech sound that infants typically produce at this age (/ t/). An EEG experiment with an oddball paradigm was designed. Participants were 19 infants (9-mo). An MMN-like negative response to deviants compared to standards was found, however it was not statistically significant. No significant interaction effect was found for MMN and type of deviant stimulus. Variation in the standard stimuli may have contributed to the lack of effect. It is also possible that the infants already were equally competent in discriminating both speech sounds, which may account for the small difference between the deviant waveforms.
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