| 1. |
- Åkerberg, Helena, et al.
(author)
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Mutagenesis of human neuropeptide Y/peptide YY receptor Y2 reveals additional differences to Y1 in interactions with highly conserved ligand positions
- 2010
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In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 163:1-3, s. 120-129
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Journal article (peer-reviewed)abstract
- Neuropeptide Y (NPY) and peptide YY (PYY) share similar to 70% of their 36 amino acids and bind to the same three human receptor subtypes, Y1, Y2 and Y5, even though these receptors only share similar to 30% sequence identity Based on our previous investigation of human Y1 we describe here a mutagenesis study of three corresponding positions in human Y2, i e Tyr(2 64), Val(6 58) and Tyr(7 31) Pharmacological characterization was performed with the four peptide agonists PYY, NPY, PYY(3-36) and NPY(13-36) as well as the non-peptide antagonist BIIE0246 Results from mutants where Tyr(2 64) has been substituted by Ala suggest that Tyr(2 64) is involved in the interaction with all investigated ligands whereas position Tyr(7 31) seems to be more important for interaction with the truncated peptide PYY(3-36) than with intact NPY Surprisingly, substitution of Tyr(7 31) with His, the corresponding residue in Y1, resulted in total loss of binding of iodinated porcine PYY The third position. Val(6 58), did not influence binding of any of the ligands. These findings differ from those obtained for Y1 where Ala substitution resulted in lost or changed binding for each of the three positions. Although Tyr(2 64) and Tyr(7 31) in Y2 are involved in ligand binding, their interactions with the peptide ligands seem to be different from the corresponding positions in Y1 This suggests that the receptor-ligand interactions have changed during evolution after Y1 and Y2 arose from a common ancestral receptor.
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| 2. |
- Adnan, Ali, et al.
(author)
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Health-related quality of life among tonsillar carcinoma patients in Sweden in relation to treatment and comparison with quality of life among the population
- 2020
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In: Head and Neck-Journal for the Sciences and Specialties of the Head and Neck. - : Wiley. - 1043-3074 .- 1097-0347. ; 42:5, s. 860-872
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Journal article (peer-reviewed)abstract
- Background The health-related quality of life (HRQOL) of tonsillar carcinoma survivors was explored to investigate any HRQOL differences associated with tumor stage and treatment. The survivors' HRQOL was also compared to reference scores from the population. Methods In this exploratory cross-sectional study patients were invited 15 months after their diagnosis and asked to answer two quality of life questionnaires (EORTC QLQ- C30, EORTC QLQ- HN35), 405 participated. Results HRQOL was associated with gender, with males scoring better than females on a few scales. Patients' HRQOL was more associated with treatment than tumor stage. Patients' HRQOL was worse than that in an age- and sex-matched reference group from the normal population, the largest differences were found for problems with dry mouth followed by problems with sticky saliva, senses, swallowing and appetite loss. Conclusions The tonsillar carcinoma patients had a worse HRQOL compared to the general population one year after treatment.
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| 3. |
- Danielsson, Henrik, et al.
(author)
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A Systematic Review of Longitudinal Trajectories of Mental Health Problems in Children with Neurodevelopmental Disabilities
- 2024
-
In: Journal of Developmental and Physical Disabilities. - : Springer. - 1056-263X .- 1573-3580. ; 36, s. 203-242
-
Research review (peer-reviewed)abstract
- To review the longitudinal trajectories - and the factors influencing their development - of mental health problems in children with neurodevelopmental disabilities. Systematic review methods were employed. Searches of six databases used keywords and MeSH terms related to children with neurodevelopmental disabilities, mental health problems, and longitudinal research. After the removal of duplicates, reviewers independently screened records for inclusion, extracted data (outcomes and influencing factors), and evaluated the risk of bias. Findings were tabulated and synthesized using graphs and a narrative. Searches identified 94,662 unique records, from which 49 publications were included. The median publication year was 2015. Children with attention deficit hyperactivity disorder were the most commonly included population in retrieved studies. In almost 50% of studies, trajectories of mental health problems changed by < 10% between the first and last time point. Despite multiple studies reporting longitudinal trajectories of mental health problems, greater conceptual clarity and consideration of the measures included in research is needed, along with the inclusion of a more diverse range of populations of children with neurodevelopmental disabilities.
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| 4. |
- Gebre-Medhin, Maria, et al.
(author)
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ARTSCAN III : A randomized phase III study comparing chemoradiotherapy with cisplatin versus cetuximab in patients with locoregionally advanced head and neck squamous cell cancer
- 2021
-
In: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 39:1, s. 38-47
-
Journal article (peer-reviewed)abstract
- PURPOSE We performed an open-label randomized controlled phase III study comparing treatment outcome and toxicity between radiotherapy (RT) with concomitant cisplatin versus concomitant cetuximab in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC; stage III-IV according to the Union for International Cancer Control TNM classification, 7th edition). MATERIALS AND METHODS Eligible patients were randomly assigned 1:1 to receive either intravenous cetuximab 400 mg/m2 1 week before start of RT followed by 250 mg/m2/wk, or weekly intravenous cisplatin 40 mg/m2, during RT. RT was conventionally fractionated. Patients with T3-T4 tumors underwent a second random assignment 1:1 between standard RT dose 68.0 Gy to the primary tumor or dose escalation to 73.1 Gy. Primary end point was overall survival (OS) evaluated using adjusted Cox regression analysis. Secondary end points were locoregional control, local control with dose-escalated RT, pattern of failure, and adverse effects. RESULTS Study inclusion was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. At 3 years, OS was 88% (95% CI, 83% to 94%) and 78% (95% CI, 71% to 85%) in the cisplatin and cetuximab groups, respectively (adjusted hazard ratio, 1.63; 95% CI, 0.93 to 2.86; P 5 .086). The cumulative incidence of locoregional failures at 3 years was 23% (95% CI, 16% to 31%) compared with 9% (95% CI, 4% to 14%) in the cetuximab versus the cisplatin group (Gray’s test P 5 .0036). The cumulative incidence of distant failures did not differ between the treatment groups. Dose escalation in T3-T4 tumors did not increase local control. CONCLUSION Cetuximab is inferior to cisplatin regarding locoregional control for concomitant treatment with RT in patients with locoregionally advanced HNSCC. Additional studies are needed to identify possible subgroups that still may benefit from concomitant cetuximab treatment.
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| 5. |
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| 6. |
- Högmo, Anders, et al.
(author)
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Base of tongue squamous cell carcinomas, outcome depending on treatment strategy and p16 status. A population-based study from the Swedish Head and Neck Cancer Register
- 2022
-
In: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 61:4, s. 433-440
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Journal article (peer-reviewed)abstract
- Background: The base of tongue squamous cell carcinoma (BOTSCC) is mainly an HPV-related tumor. Radiotherapy (EBRT) ± concomitant chemotherapy (CT) is the backbone of the curatively intended treatment, with brachytherapy (BT) boost as an option. With four different treatment strategies in Sweden, a retrospective study based on the population-based Swedish Head and Neck Cancer Register (SweHNCR) was initiated.Material and methods: Data on tumors, treatment and outcomes in patients with BOTSCC treated between 2008 and 2014 were validated through medical records and updated as needed. Data on p16 status were updated or completed with immunohistochemical analysis of archived tumor material. Tumors were reclassified according to the UICC 8th edition.Results: Treatment was EBRT, EBRT + CT, EBRT + BT or EBRT + CT + BT in 151, 145, 82 and 167 patients respectively (n = 545). A p16 analysis was available in 414 cases; 338 were p16+ and 76 p16−. 5-year overall survival (OS) was 68% (95% CI: 64–72%), with76% and 37% for p16+ patients and p16− patients, respectively. An increase in OS was found with the addition of CT to EBRT for patients with p16+ tumors, stages II–III, but for patients with tumor stage I, p16+ (UICC 8) none of the treatment strategies was superior to EBRT alone.Conclusion: In the present retrospective population-based study of BOTSCC brachytherapy was found to be of no beneficial value in curatively intended treatment. An increase in survival was found for EBRT + CT compared to EBRT alone in patients with advanced cases, stages II and III (UICC 8), but none of the regimes was significantly superior to EBRT as a single treatment modality for stage I (UICC 8), provided there was p16 positivity in the tumor. In the small group of patients with p16− tumors, a poorer prognosis was found, but the small sample size did not allow any comparisons between different treatment strategies.
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| 7. |
- Larena, Maximilian, et al.
(author)
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Multiple migrations to the Philippines during the last 50,000 years
- 2021
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 118:13
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Journal article (peer-reviewed)abstract
- Island Southeast Asia has recently produced several surprises regarding human history, but the region's complex demography remains poorly understood. Here, we report similar to 2.3 million genotypes from 1,028 individuals representing 115 indigenous Philippine populations and genome-sequence data from two similar to 8,000-y-old individuals from Liangdao in the Taiwan Strait. We show that the Philippine islands were populated by at least five waves of human migration: initially by Northern and Southern Negritos (distantly related to Australian and Papuan groups), followed by Manobo, Sama, Papuan, and Cordilleran-related populations. The ancestors of Cordillerans diverged from indigenous peoples of Taiwan at least similar to 8,000 y ago, prior to the arrival of paddy field rice agriculture in the Philippines similar to 2,500 y ago, where some of their descendants remain to be the least admixed East Asian groups carrying an ancestry shared by all Austronesian-speaking populations. These observations contradict an exclusive "out-of-Taiwan" model of farming-language-people dispersal within the last four millennia for the Philippines and Island Southeast Asia. Sama-related ethnic groups of southwestern Philippines additionally experienced some minimal South Asian gene flow starting similar to 1,000 y ago. Lastly, only a few lowlanders, accounting for <1% of all individuals, presented a low level of West Eurasian admixture, indicating a limited genetic legacy of Spanish colonization in the Philippines. Altogether, our findings reveal a multilayered history of the Philippines, which served as a crucial gateway for the movement of people that ultimately changed the genetic landscape of the Asia-Pacific region.
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| 8. |
- Lindholm, Christer, et al.
(author)
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Invasive cutaneous malignant melanoma in Sweden, 1990-1999. A prospective, population-based study of survival and prognostic factors.
- 2004
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In: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 101:9, s. 2067-78
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Journal article (peer-reviewed)abstract
- BACKGROUND: The objective of the current study was to compile prospective, population-based data on cutaneous invasive melanomas in Sweden during the period from 1990 to 1999, to describe and analyze survival data and prognostic factors, and to make comparisons with previously published Swedish and international data. METHODS: Twelve thousand five hundred thirty-three patients, which included 97% of all registered melanomas in Sweden, were included and described. Among these, 9515 patients with clinical Stage I and II melanoma were included in an analysis of survival and in a univariate analysis, and 6191 patients were included in a multivariate analysis of prognostic factors. RESULTS: There was no significant change in melanoma incidence during 1990-1999. Favorable prognostic factors were found, especially in younger and female patients, resulting in a relative 5-year survival rate of 91.5%. In the multivariate analysis, significant factors that had a negative effect on survival were Clark level of invasion, Breslow thickness, ulceration, older patient age, trunk location, greatest tumor dimension, nodular histogenetic type, and male gender. CONCLUSIONS: During the period from 1990 to 1999, the 5-year survival of patients with malignant melanoma in Sweden was better compared with the previously reported rates in published, population-based studies from Sweden, probably as a result of better secondary prevention due to better knowledge and awareness by both patients and the medical profession. The more favorable prognostic factors and the change in melanoma location found in younger patients, compared with earlier reports, may reflect changes in clothing as well as tanning habits; however, a decrease also was found in Clark Level II and thin melanomas for the same patient group. The authors concluded that further improvements can be achieved with better access to health care and with the use of early melanoma detection campaigns.
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| 9. |
- Malmström, Helena Jankovic, et al.
(author)
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Ancient mitochondrial DNA from the northern fringe of the Neolithic farming expansion in Europe sheds light on the dispersion process
- 2015
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In: Philosophical Transactions of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8436 .- 1471-2970. ; 370:1660
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Journal article (peer-reviewed)abstract
- The European Neolithization process started around 12 000 years ago in the Near East. The introduction of agriculture spread north and west throughout Europe and a key question has been if this was brought about by migrating individuals, by an exchange of ideas or a by a mixture of these. The earliest farming evidence in Scandinavia is found within the Funnel Beaker Culture complex (Trichterbecherkultur, TRB) which represents the northernmost extension of Neolithic farmers in Europe. The TRB coexisted for almost a millennium with hunter-gatherers of the Pitted Ware Cultural complex (PWC). If migration was a substantial part of the Neolithization, even the northerly TRB community would display a closer genetic affinity to other farmer populations than to hunter-gatherer populations. We deep-sequenced the mitochondrial hypervariable region 1 from seven farmers (six TRB and one Battle Axe complex, BAC) and 13 hunter-gatherers (PWC) and authenticated the sequences using postmortem DNA damage patterns. A comparison with 124 previously published sequences from prehistoric Europe shows that the TRB individuals share a close affinity to Central European farmer populations, and that they are distinct from hunter-gatherer groups, including the geographically close and partially contemporary PWC that show a close affinity to the European Mesolithic hunter-gatherers.
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| 10. |
- Mannervik, Bengt, et al.
(author)
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Glutathione Transferases as Efficient Ketosteroid Isomerases
- 2021
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In: Frontiers in Molecular Biosciences. - : Frontiers Media SA. - 2296-889X. ; 8
-
Research review (peer-reviewed)abstract
- In addition to their well-established role in detoxication, glutathione transferases (GSTs) have other biological functions. We are focusing on the ketosteroid isomerase activity, which appears to contribute to steroid hormone biosynthesis in mammalian tissues. A highly efficient GST A3-3 is present in some, but not all, mammals. The alpha class enzyme GST A3-3 in humans and the horse shows the highest catalytic efficiency with kcat/Km values of approximately 107 M−1s−1, ranking close to the most active enzymes known. The expression of GST A3-3 in steroidogenic tissues suggests that the enzyme has evolved to support the activity of 3β-hydroxysteroid dehydrogenase, which catalyzes the formation of 5-androsten-3,17-dione and 5-pregnen-3,20-dione that are substrates for the double-bond isomerization catalyzed by GST A3-3. The dehydrogenase also catalyzes the isomerization, but its kcat of approximately 1 s−1 is 200-fold lower than the kcat values of human and equine GST A3-3. Inhibition of GST A3-3 in progesterone-producing human cells suppress the formation of the hormone. Glutathione serves as a coenzyme contributing a thiolate as a base in the isomerase mechanism, which also involves the active-site Tyr9 and Arg15. These conserved residues are necessary but not sufficient for the ketosteroid isomerase activity. A proper assortment of H-site residues is crucial to efficient catalysis by forming the cavity binding the hydrophobic substrate. It remains to elucidate why some mammals, such as rats and mice, lack GSTs with the prominent ketosteroid isomerase activity found in certain other species. Remarkably, the fruit fly Drosophila melanogaster, expresses a GSTE14 with notable steroid isomerase activity, even though Ser14 has evolved as the active-site residue corresponding to Tyr9 in the mammalian alpha class.
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| 11. |
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| 12. |
- Ranlund, Åsa, et al.
(author)
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Metodbeskrivning : 2020 års inventeringar av gräsmarker och lövskogar
- 2021
-
Reports (other academic/artistic)abstract
- En generell stickprovsdesign, inom vilken det går att inventera både vanliga och ovanliga fenomen på såväl nationell som regional nivå, utvecklades under 2019 och 2020. Under 2020 har den nya stickprovsdesignen använts för inventeringar av gräsmarker och lövskogar med syfte att förbättra nationella data på naturtyper med höga naturvärden, dvs. naturtyper som uppfyller kriterierna för EU:s art- och habitatdirektivs annex 1, samtidigt som vanligare naturtyper följdes där behov funnits för att komplettera befintliga data. I den här rapporten redovisar vi metodiken vi utvecklat för flygbilds- och fältinventeringarna samt hur urval av trakter till stickprov och provytor för fältbesök gått till.För gräsmarks- och lövskogsinventeringarna gjordes först ett gemensamt så kallat balanserat urval för att slumpmässigt välja ut trakter ur urvalsramen till stickprov. Sedan klassades alla provytor inom de utvalda trakterna i en flygbildsinventering till både lövskogs- och gräsmarksklasser. Utifrån de flygbildsinventerade klasserna skapades urvalsklasser separat för gräsmarks- respektive lövskogsinventeringen. Urvalsklasserna användes sedan för att välja ut provytor för fältbesök, ett urval som gjordes för gräsmarks- respektive lövskogsinventeringen oberoende av varandra.Metodiken för flygbildsinventering utvecklades för att gräsmarks- och lövskogsinventeringarna skulle kunna använda stora stickprov, i linje med den nya stickprovsdesignen. En viktig princip vid flygbildsinveteringen var överklassning, dvs att provytor inkluderades där klassningen var osäker. Detta för att säkerställa att alla gräsmarker och lövskogar inom inventeringarnas respektive ramverk hade möjlighet att ingå så att det statistiska kravet för stickprovsdesignen var uppfyllda. Provytor som utifrån flygbildsinventeringen helt säkert inte innehöll eftersökta naturtyper behövde inte besökas i fält vilket gjorde att fältbesöken fokuserades till provytor av intresse för gräsmarks- eller lövskogsinventeringarna. Det minskade kostnaden för fältbesök och vi kunde använda större stickprov. Sammantaget flygbildsinventerades över 137 000 provytor fördelat på 701 trakter inför fältinventeringen 2020.För fältinventeringen inom gräsmarks- och lövskogsinventeringarna introducerades flera nyheter jämfört med tidigare inventeringar för att samla in mer data på bl.a. naturtypers kvalitet. Varje delyta klassades t.ex. till en naturtyp oavsett om den uppfyller kravet för att bli klassad som en annex 1-naturtyp. Utöver det registrerades ett antal kvalitetsvariabler som visar vilka kriterier för annex 1 som är uppfyllda eller inte. Det gör att det går att jämföra areal och statusvariabler för en annex 1-naturtyp) med areal och statusvariabler av motsvarande naturtyp med låga naturvärden (dvs. där annex 1-kriterierna inte är uppfyllda). 1763 provytor fördelat på 187 trakter slumpades ut för att inventeras i fält 2020. Av dem inventerades 64 provytor 2021 eftersom de inte hanns med säsongen 2020.Eftersom antalet trakter är den viktigaste faktorn i att bestämma precisionen i skattningarna så vill vi inte minska antalet trakter eftersom det ökar osäkerheten i skattningarna. För att effektivisera inventeringarna arbetar vi därför med två olika angreppssätt för en viss stickprovstäthet. Dels vill vi förbättra möjligheten att korrekt kunna utesluta provytor, och ibland hela trakter, från fältbesök genom att förbättra flygbildsinventeringen. Det kan t.ex. handla om att minska överklassningen, genom att göra kriterierna för klasserna snävare . Under det första inventeringsåret 2020 tog det lite längre tid att inventera en trakt i fält än vad som var önskvärt. För att minska fälttiden kan vi därför behöva minska antalet provytor som vi inventerar per trakt alternativt förenkla fältmetodiken per provyta. Fältinsatsen kan också bli effektivare genom att inventering av smala linjära objekt, som åker- och vägrenar, görs genom en linjekorsningsinventering istället för via gräsmarks- och lövskogsinventeringarnas provytor. För lövskogsinventeringen 2020 var ålderskriteriet >30 år . Ett sätt att fokusera denna inventering mot naturtyper av större intresse är att höja ålderskriteriet så att inventeringen riktas mer mot äldre lövskogar. Utöver färre provytor skulle det antagligen också leda till att vi behöver besöka färre trakter inom lövskogsinventeringen. Nackdelen blir förstås att inventeringen inte inkluderar yngre skogar, så det är ett beslut som bör tas utifrån vilka frågeställningar som ska besvaras och hur prioriteringen ser ut för vilka data som ska samlas in.För att kunna ta tillvara de möjligheter som den nya stickprovsdesignen ger har vi utvecklat ny metodik för flygbildsinventering av stora stickprov inom gräsmarks- och lövskogsinventeringarna. Det förbättrar våra möjligheter att möta kraven på tillfredställande data även för mer ovanliga naturtyper. För att möta de ökade kraven på data till artikel 17-rapporteringen har vi också utvecklat och omprioriterat fältinventeringen. 2020 var det första året för gräsmarks- och lövskogsinventeringarna. Redan då fanns allt på plats men många delar behöver utvecklas vidare för att ytterligare effektivisera dem.
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| 13. |
- Schlebusch, Carina, 1977-, et al.
(author)
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Khoe-San Genomes Reveal Unique Variation and Confirm the Deepest Population Divergence in Homo sapiens
- 2020
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In: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 37:10, s. 2944-2954
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Journal article (peer-reviewed)abstract
- The southern African indigenous Khoe-San populations harbor the most divergent lineages of all living peoples. Exploring their genomes is key to understanding deep human history. We sequenced 25 full genomes from five Khoe-San populations, revealing many novel variants, that 25% of variants are unique to the Khoe-San, and that the Khoe-San group harbors the greatest level of diversity across the globe. In line with previous studies, we found several gene regions with extreme values in genome-wide scans for selection, potentially caused by natural selection in the lineage leading to Homo sapiens and more recent in time. These gene regions included immunity-, sperm-, brain-, diet-, and muscle-related genes. When accounting for recent admixture, all Khoe-San groups display genetic diversity approaching the levels in other African groups and a reduction in effective population size starting around 100,000 years ago. Hence, all human groups show a reduction in effective population size commencing around the time of the Out-of-Africa migrations, which coincides with changes in the paleoclimate records, changes that potentially impacted all humans at the time.
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| 14. |
- Schlebusch, Carina, 1977-, et al.
(author)
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Southern African ancient genomes estimate modern human divergence to 350,000 to 260,000 years ago
- 2017
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 358:6363, s. 652-655
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Journal article (peer-reviewed)abstract
- Southern Africa is consistently placed as a potential region for the evolution of Homo sapiens We present genome sequences, up to 13x coverage, from seven ancient individuals from KwaZulu-Natal, South Africa. The remains of three Stone Age hunter-gatherers (about 2000 years old) were genetically similar to current-day southern San groups, and those of four Iron Age farmers (300 to 500 years old) were genetically similar to present-day Bantu-language speakers. We estimate that all modern-day Khoe-San groups have been influenced by 9 to 30% genetic admixture from East Africans/Eurasians. Using traditional and new approaches, we estimate the first modern human population divergence time to between 350,000 and 260,000 years ago. This estimate increases the deepest divergence among modern humans, coinciding with anatomical developments of archaic humans into modern humans, as represented in the local fossil record.
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| 15. |
- Seipel, Peter, et al.
(author)
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Spionchips kontrollerar dig
- 2004. - 7
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Other publication (pop. science, debate, etc.)abstract
- Peter Seipel, Kia Höök, Gunnar Sjödin, Markus Bylund, Olle Olsson, Helena Andersson, Anders R Olsson
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| 16. |
- Sjödin, Paula, et al.
(author)
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Re-evaluation of receptor–ligand interactions of the human neuropeptide Y receptor Y1 : a site-directed mutagenesis study
- 2006
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In: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 1:393, s. 161-169
-
Journal article (peer-reviewed)abstract
- Interactions of the human NPY (neuropeptide Y) receptor Y1 with the two endogenous agonists NPY and peptide YY and two non-peptide antagonists were investigated using site-directed mutagenesis at 17 positions. The present study was triggered by contradictions among previously published reports and conclusions that seemed inconsistent with sequence comparisons across species and receptor subtypes. Our results show that Asp287, at the border between TM (transmembrane) region 6 and EL3 (extracellular loop 3) influences peptide binding, while two aspartic residues in EL2 do not, in agreement with some previous studies but in disagreement with others. A hydrophobic pocket of the Y1 receptor consisting of Tyr100 (TM2), Phe286 (TM6) and His298 (EL3) has been proposed to interact with the amidated C-terminus of NPY, a theory that is unsupported by sequence comparisons between Y1, Y2 and Y5. Nevertheless, our results confirm that these amino acid residues are critical for peptide binding, but probably interact with NPY differently than proposed previously. Studies with the Y1-selective antagonist SR120819A identified a new site of interaction at Asn116 in TM3. Position Phe173 in TM4 is also important for binding of this antagonist. In contrast with previous reports, we found that Phe173 is not crucial for the binding of BIBP3226, another selective Y1 receptor antagonist. Also, we found that position Thr212 (TM5) is important for binding of both antagonists. Our mutagenesis results and our three-dimensional model of the receptor based on the high-resolution structure of bovine rhodopsin suggest new interactions for agonist as well as antagonist binding to the Y1 receptor.
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| 17. |
- Škerlová, Jana, et al.
(author)
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Structural and functional analysis of the inhibition of equine glutathione transferase A3-3 by organotin endocrine disrupting pollutants
- 2021
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In: Environmental Pollution. - : Elsevier BV. - 0269-7491 .- 1873-6424. ; 268
-
Journal article (peer-reviewed)abstract
- Organotin compounds are highly toxic environmental pollutants with neurotoxic and endocrinedisrupting effects. They are potent inhibitors of glutathione transferases (GSTs), thus impeding their detoxication and antioxidant functions. Several GSTs, including equine GST A3-3 (EcaGST A3-3), exhibit steroid double-bond isomerase activity and are involved in the biosynthesis of testosterone and progesterone. We have performed enzyme kinetics analyses of the inhibition of EcaGST A3-3 by organotin compounds. We have also solved crystal structures of EcaGST A3-3 in complexes with glutathione, and with glutathione together with covalently bound triethyltin. Our structural data indicate that the tin atom forms strong bonds with a covalent character not only with the glutathione, but also with a tyrosyl residue of the enzyme itself, thereby preventing the release of the glutathione-organotin adduct and completely blocking the enzyme function. This work presents a structural basis for the general mechanism of GST inhibition by organotin compounds and contributes to the understanding of their neurotoxic and endocrine disrupting effects.
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| 18. |
- Škerlová, Jana, et al.
(author)
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Structure and steroid isomerase activity of Drosophila glutathione transferase E14 essential for ecdysteroid biosynthesis
- 2020
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In: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 594:7, s. 1187-1195
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Journal article (peer-reviewed)abstract
- Ecdysteroids are critically important for the formation of the insect exoskeleton. Cholesterol is a precursor of ecdysone and its active form 20-hydroxyecdysone, but some steps in the ecdysteroid biosynthesis pathway remain unknown. An essential requirement of glutathione (GSH) transferase GSTE14 in ecdysteroid biosynthesis has been established in Drosophila melanogaster, but its function is entirely unknown. Here, we have determined the crystal structure of GSTE14 in complex with GSH and investigated the kinetic properties of GSTE14 with alternative substrates. GSTE14 has high-ranking steroid double-bond isomerase activity, albeit 50-fold lower than the most efficient mammalian GSTs. Corresponding steroid isomerizations are unknown in insects, and their exact physiological role remains to be shown. Nonetheless, the essential enzyme GSTE14 is here demonstrated to be catalytically competent and have a steroid-binding site.
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| 19. |
- Staron, Miroslaw, 1977, et al.
(author)
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Comparing Anomaly Detection and Classification Algorithms: A Case Study in Two Domains
- 2023
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In: Lecture Notes in Business Information Processing. - 1865-1356 .- 1865-1348. ; 472 LNBIP, s. 121-136
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Conference paper (peer-reviewed)abstract
- Utilizing large data sets in practical scenarios usually requires identifying, annotating and classifying rare events or anomalies. Although several methods exists, there are two classes of algorithms: anomaly detection algorithms and classification algorithms. Both types of algorithms have different characteristics and in this paper, we set out to compare them on two cases. We use data from a neurointensive care unit and from microwave radio transmissions. We apply Isolation Forest and Random Forest algorithms to find events in the data that occur with a frequency of ca. 1%. The results show that classification algorithms (Random Forest) perform better and can achieve up to 100% accuracy, while the anomaly detection algorithms (Isolation Forest) can achieve only 73% at best. Based on the results, we conclude that it is better to invest in annotating data á priori and use classification algorithms, despite the lower costs of using the anomaly detection algorithms.
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| 20. |
- Wennerberg, Johan, et al.
(author)
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Results from a prospective, randomised study on (accelerated) preoperative versus (conventional) postoperative radiotherapy in treatment of patients with resectable squamous cell carcinoma of the oral cavity : The ARTSCAN 2 study
- 2022
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In: Radiotherapy and Oncology. - : Elsevier. - 0167-8140 .- 1879-0887. ; 166, s. 26-32
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Journal article (peer-reviewed)abstract
- Background and purposeAn earlier prospective randomised multicentre study (ARTSCAN) in head and neck cancer patients that compared conventionally fractionated radiotherapy (CF) with accelerated radiotherapy (AF) was inconclusive. In the subgroup of oral cavity squamous cell cancer (OCSCC) a large absolute, but not statistically significant, difference in local control was seen in favour of AF. This difference was more pronounced in resectable tumours. The finding raised the hypothesis that AF could be beneficial for OCSCC patients. In addition, the longstanding controversy on pre- or postoperative radiotherapy was addressed.Materials and methodsPatients with OCSCC, judged to withstand and likely benefit from combined therapy, were recruited. Subjects were randomised to either preoperative AF with 43 fractions given as a concomitant boost with two fractions/day to the tumour bearing volume to a total dose of 68 Gy in 4.5 weeks followed by surgery, or primary surgery with postoperative CF, total dose 60 or 66 Gy in 6–7 weeks. For patients whose tumours had high-risk features, 66 Gy and concomitant cisplatin was prescribed.Results250 patients were randomised. Median follow-up was 5 years for locoregional control (LRC) and 9 years for overall survival (OS). There were no statistically significant differences between the two treatment arms regarding LRC and OS. LRC at five years was 73% (95% CI, 65–82) in preoperative AF and 78% (95% CI, 70–85) in postoperative CF.Toxicity was more pronounced in preoperative AF.ConclusionThis study does not support that AF prior to surgery improves outcome in oral cavity cancer compared with postoperative CF.
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| 21. |
- Xu, Xingxing, et al.
(author)
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Structural Changes of Mercaptohexanol Self-assembled Monolayers on Gold and their Influence on Impedimetric Aptamer Sensors
- 2019
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In: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 91:22, s. 14697-14704
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Journal article (peer-reviewed)abstract
- Despite a large number of publications describing biosensors based on electrochemical impedance spectroscopy (EIS), little attention has been paid to the stability and reproducibility issues of the sensor interfaces. In this work, the stability and reproducibility of faradaic EIS analyses on the aptamer/mercaptohexanol (MCH) self-assembled monolayer (SAM) functionalized gold surfaces in ferri- and ferrocyanide solution were systematically evaluated prior to and after the aptamer-probe DNA hybridization. It is shown that the EIS data exhibited significant drift, and this significantly affected the reproducibility of the EIS signal of the hybridization. As a result, no significant difference between the charge transfer resistance (RCT) changes induced by the aptamer-target DNA hybridization and that caused by the drift could be identified. A conditioning of the electrode in the measurement solution for more than 12 hours was required to reach a stable RCT baseline prior to the aptamer-probe DNA hybridization. The monitored drift in RCT and CDL during the conditioning suggests that the MCH SAM on the gold surface reorganized to a thinner but more closely packed layer. We also observed that the hot binding buffer used in the following aptamer-probe DNA hybridization process could induce additional MCH and aptamer reorganization thus further drift in RCT. As a result, the RCT change caused by the aptamer-probe DNA hybridization was less than that caused by the hot binding buffer (blank control experiment). Therefore, it is suggested that the use of high temperature in the EIS measurement should be carefully evaluated or avoided. This work provides practical guidelines for the EIS measurements. Moreover, since SAM functionalized gold electrodes are widely used in biosensors, e.g., DNA sensors, an improved understanding of the origin of the observed drift is very important for the development of well-functioning and reproducible biosensors.
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| 22. |
- Zackrisson, Björn, et al.
(author)
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Two-year results from a Swedish study on conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma - The ARTSCAN study
- 2011
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In: Radiotherapy and Oncology. - : Elsevier. - 0167-8140 .- 1879-0887. ; 100:1, s. 41-48
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Journal article (peer-reviewed)abstract
- Background and purpose: Studies on accelerated fractionation (AF) in head and neck cancer have shown increased local control and survival compared with conventional fractionation (CF), while others have been non-conclusive. In 1998 a national Swedish group decided to perform a randomised controlled clinical study of AF. Materials and methods: Patients with verified squamous cell carcinoma of the oral cavity, oropharynx, larynx (except glottic T1-T2, N0) and hypopharynx were included. Patients with prior chemotherapy or surgery were excluded. Patients were randomised to either CF (2Gy/day, 5days/week for 7 weeks, total dose 68Gy) or to AF (1.1Gy+2.0Gy/day, 5days/week for 4.5weeks, total dose 68Gy). An extensive quality assurance protocol was followed throughout the study. The primary end point was loco-regional tumour control (LRC) at two years after treatment. RESULTS: The study was closed in 2006 when 750 patients had been randomised. Eighty-three percent of the patients had stages III-IV disease. Forty eight percent had oropharyngeal, 21% laryngeal, 17% hypopharyngeal and 14% oral cancers. There were no significant differences regarding overall survival (OS) or LRC between the two regimens. The OS at two years was 68% for AF and 67% for CF. The corresponding figures for LRC were 71% and 67%, respectively. There was a trend towards improved LRC for oral cancers treated (p=0.07) and for large tumours (T3-T4) (p=0.07) treated with AF. The AF group had significantly worse acute reactions, while there was no significant increase in late effects. Conclusion: Overall the AF regimen did not prove to be more efficacious than CF. However, the trend towards improved results in AF for oral cancers needs to be further investigated.
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