| 1. |
- Koziolek, M., et al.
(author)
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Challenges in Permeability Assessment for Oral Drug Product Development
- 2023
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In: Pharmaceutics. - : MDPI. - 1999-4923. ; 15:10
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Journal article (peer-reviewed)abstract
- Drug permeation across the intestinal epithelium is a prerequisite for successful oral drug delivery. The increased interest in oral administration of peptides, as well as poorly soluble and poorly permeable compounds such as drugs for targeted protein degradation, have made permeability a key parameter in oral drug product development. This review describes the various in vitro, in silico and in vivo methodologies that are applied to determine drug permeability in the human gastrointestinal tract and identifies how they are applied in the different stages of drug development. The various methods used to predict, estimate or measure permeability values, ranging from in silico and in vitro methods all the way to studies in animals and humans, are discussed with regard to their advantages, limitations and applications. A special focus is put on novel techniques such as computational approaches, gut-on-chip models and human tissue-based models, where significant progress has been made in the last few years. In addition, the impact of permeability estimations on PK predictions in PBPK modeling, the degree to which excipients can affect drug permeability in clinical studies and the requirements for colonic drug absorption are addressed.
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| 2. |
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| 3. |
- Chu, X., et al.
(author)
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Intracellular Drug Concentrations and Transporters : Measurement, Modeling, and Implications for the Liver
- 2013
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In: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 94:1, s. 126-141
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Research review (peer-reviewed)abstract
- Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism.This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed.
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| 4. |
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| 5. |
- Galetin, Aleksandra, et al.
(author)
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Membrane transporters in drug development and as determinants of precision medicine
- 2024
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In: NATURE REVIEWS DRUG DISCOVERY. - 1474-1776 .- 1474-1784.
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Research review (peer-reviewed)abstract
- The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions. Significant progress has been made in understanding the influence of membrane transporters in drug disposition and response. Here, the International Transporter Consortium provides an update on the current status of membrane transporters in drug development and regulatory requirements, discusses recent scientific advances in the field and highlights future directions and unanswered questions.
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| 6. |
- Hesselson, Stephanie E, et al.
(author)
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Genetic variation in the proximal promoter of ABC and SLC superfamilies : liver and kidney specific expression and promoter activity predict variation
- 2009
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:9, s. e6942-
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Journal article (peer-reviewed)abstract
- Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (-250 to +50 bp) and flanking 5' sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (pi) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.
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| 7. |
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| 8. |
- Mateus, André, 1986-, et al.
(author)
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Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery
- 2017
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In: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:30, s. E6231-E6239
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Journal article (peer-reviewed)abstract
- Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F-ic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F-ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F-ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.
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| 9. |
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| 10. |
- Dahlqvist, J, et al.
(author)
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Multiple epiphyseal dysplasia
- 2009
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In: Acta orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 80:6, s. 711-715
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Journal article (peer-reviewed)
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| 11. |
- Einarsdottir, Elisabet, et al.
(author)
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Identification of NCAN as a candidate gene for developmental dyslexia.
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Journal article (peer-reviewed)abstract
- A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G > A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This variant prompted us to consider this gene as a putative candidate for DD. The RNA expression pattern of the NCAN gene in human tissues was highly correlated (R > 0.8) with that of the previously suggested DD susceptibility genes KIAA0319, CTNND2, CNTNAP2 and GRIN2B. We investigated the association of common variation in NCAN to brain structures in two data sets: young adults (Brainchild study, Sweden) and infants (FinnBrain study, Finland). In young adults, we found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. In infants, this same variant was found to be associated with cingulate and prefrontal grey matter volumes. Our results suggest NCAN as a new candidate gene for DD and indicate that NCAN variants affect brain structure.
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| 12. |
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| 13. |
- Flygare, Johan, et al.
(author)
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Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia
- 2005
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 105:12, s. 4627-4634
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Journal article (peer-reviewed)abstract
- Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 (RPS19) gene. To study effects of RPS19 deficiency in hematopoiesis we transduced CD34+ umbilical cord blood (CB) and bone marrow (BM) cells with 3 lentiviral vectors expressing small interfering RNA (siRNA) against RPS19 and 1 scrambled control vector. All vectors also express green fluorescent protein (GFP). Transduction with the siRNA vectors reduced RPS19 mRNA levels to various degrees, which resulted in erythroid defects, correlating to the degree of RPS19 down-regulation, and was rescued by expression of an siRNA-resistant RPS19 transcript. Erythroid colony formation capacity conjointly decreased with RPS19 levels in CD34+ CB and BM cells. In liquid culture supporting erythroid differentiation, RPS19-silenced as well as DBA patient CD34+ cells exhibited reduced proliferative capacity and impaired erythroid differentiation resulting in fewer erythroid colony-forming units (CFU-Es). When assaying myeloid development, a less pronounced influence on proliferation was seen. This study shows for the first time that RPS19 silencing decreases the proliferative capacity of hematopoietic progenitors and leads to a defect in erythroid development.
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| 14. |
- Guo, Yingying, et al.
(author)
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Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches
- 2018
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In: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 104:5, s. 865-889
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Research review (peer-reviewed)abstract
- This white paper examines recent progress, applications, and challenges in predicting unbound and total tissue and intra/subcellular drug concentrations using in vitro and preclinical models, imaging techniques, and physiologically based pharmacokinetic (PBPK) modeling. Published examples, regulatory submissions, and case studies illustrate the application of different types of data in drug development to support modeling and decision making for compounds with transporter-mediated disposition, and likely disconnects between tissue and systemic drug exposure. The goals of this article are to illustrate current best practices and outline practical strategies for selecting appropriate in vitro and in vivo experimental methods to estimate or predict tissue and plasma concentrations, and to use these data in the application of PBPK modeling for human pharmacokinetic (PK), efficacy, and safety assessment in drug development.
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| 15. |
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| 16. |
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| 17. |
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| 18. |
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| 19. |
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| 20. |
- Lindh, Magnus, 1960, et al.
(author)
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Clinical Effectiveness of Liraglutide vs Sitagliptin on Glycemic Control and Body Weight in Patients with Type 2 Diabetes: A Retrospective Assessment in Sweden
- 2016
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In: Diabetes Therapy. - : Springer Science and Business Media LLC. - 1869-6953 .- 1869-6961. ; 7:2, s. 321-333
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Journal article (peer-reviewed)abstract
- Introduction: The aim of the present study was to use real-world data from Swedish primary-care and national registries to understand clinical outcomes in patients with Type 2 diabetes (T2D) treated with liraglutide in clinical practice, and to compare with data from those treated with sitagliptin. Methods: This was a non-interventional, retrospective study conducted between February 2014 and September 2014 using T2D patient data from Swedish primary-care centers and national healthcare registries. The primary objective was to assess the effectiveness of liraglutide in control of glycemia and body weight in clinical practice (stage 1). The secondary objective was to compare the clinical effectiveness of liraglutide with sitagliptin on glycemic control and body weight in clinical practice in a propensity-score-matched population (stage 2). Results: In stage 1 (n = 402), 39.4% of patients treated with liraglutide achieved >= 1.0% (10.9 mmol/mol) reduction in glycated hemoglobin (HbA1c) after 180 days of treatment and 54.9% achieved the target HbA1c of <7.0% (53.0 mmol/mol). Moreover, compared with baseline, 22.5% of patients treated with liraglutide achieved both >= 1.0% reduction in HbA1c and >= 3.0% reduction in body weight. In stage 2, a significantly greater proportion of patients receiving liraglutide (n = 180) than sitagliptin (n = 208) achieved >= 1.0% reduction in HbA1c [52.9% vs 33.5%, respectively (P = 0.0002)]. Mean body-weight loss was also significantly greater in patients receiving liraglutide vs sitagliptin [-3.5 vs -1.3 kg, respectively (P < 0.0001)]. Conclusion: This study provides real-world evidence from Sweden corroborating previous clinical trials that demonstrate greater efficacy of liraglutide over sitagliptin on glycemic control and body-weight reduction in patients with T2D.
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| 21. |
- Lodén, M., et al.
(author)
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Sunscreen use : controversies, challenges and regulatory aspects
- 2011
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In: British Journal of Dermatology. - : Wiley-Blackwell Publishing Inc.. - 0007-0963 .- 1365-2133. ; 165:2, s. 255-262
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Journal article (peer-reviewed)abstract
- Mismatches between skin pigmentation and modern lifestyle continue to challenge our naked skin. One of our responses to these challenges is the development and use of sunscreens. The management of sunscreens has to balance their protective effect against erythema, photocarcinogenesis and photoageing owing to the potential toxicity of the ultraviolet (UV) filters for humans and the environment. The protection against UV radiation offered by sunscreens was recently standardized in the European Union (EU) based on international harmonization of measurement techniques. Four different categories of sun protection have been implemented along with recommendations on how to use sunscreen products in order to obtain the labelled protection. The UV filters in sunscreens have long been authorized for use by the EU authority on the basis of data from studies on acute toxicity, subchronic and chronic toxicity, reproductive toxicity, genotoxicity, photogenotoxicity, carcinogenicity, irritation, sensitization, phototoxicity and photosensitization as well as on environmental aspects. New challenges with respect to the safety of UV filters have arisen from the banning of animal experiments for the development of cosmetics. Future debates on sunscreens are likely to focus on nanoparticles and environmental issues, along with motivation campaigns to persuade consumers to protect their skin. However, more efficient sunscreen use will also continue to raise questions on the benefit in preventing vitamin D synthesis in the skin induced by sunlight.
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| 22. |
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| 23. |
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| 24. |
- Matsson, Anton, 1994, et al.
(author)
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Patterns in the Sequential Treatment of Patients With Rheumatoid Arthritis Starting a Biologic or Targeted Synthetic Disease-Modifying Antirheumatic Drug: 10-Year Experience From a US-Based Registry
- 2024
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In: ACR Open Rheumatology. - 2578-5745. ; 6:1, s. 5-13
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Journal article (peer-reviewed)abstract
- Objective: Developing and evaluating new treatment guidelines for rheumatoid arthritis (RA) based on observational data requires a quantitative understanding of patterns in current treatment practice with biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Methods: We used data from the CorEvitas RA registry to study patients starting their first b/tsDMARD therapy, defined as the first line of therapy, between 2012 and the end of 2021. We identified treatment patterns as unique sequences of therapy changes following and including the first-line therapy. Therapy cycling was defined as switching back to a treatment from a previously used therapeutic class. Results: A total of 6015 b/tsDMARD-naïve patients (77% female) were included in the analysis. Their median age was 58 years, and their median disease duration was 3 years. In 2012–2014, 80% of the patients started a tumor necrosis factor inhibitor (TNFi) as their first b/tsDMARD. However, the use of TNFi decreased in favor of Janus kinase inhibitors since 2015. Although the number of treatment patterns was large, therapy cycling was relatively common. For example, 601 patterns were observed among 1133 patients who changed therapy at least four times, of whom 85.3% experienced therapy cycling. Furthermore, the duration of each of the first three lines of therapy decreased over the past decade. For example, the median duration of the first-line therapy was 153 days in 2018–2021 compared to 208 days in 2015–2017 (P < 0.001). Conclusion: First-line therapy was almost always TNFi, but diversity in treatment choice was high after that. This practice variation allows for proposing and evaluating new guidelines for sequential treatment of RA. It also presents statistical challenges to compare patients with different treatment sequences.
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| 25. |
- Matsson, Hans, et al.
(author)
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Alpha-cardiac actin mutations produce atrial septal defects.
- 2008
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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 17:2, s. 256-65
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Journal article (peer-reviewed)abstract
- Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHDs) with a variable phenotypic effect depending on the size of the septal shunt. We identified two pedigrees comprising 20 members segregating isolated autosomal dominant secundum ASD. By genetic mapping, we identified the gene-encoding alpha-cardiac actin (ACTC1), which is essential for cardiac contraction, as the likely candidate. A mutation screen of the coding regions of ACTC1 revealed a founder mutation predicting an M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with an M123V substitution shows a reduced affinity for myosin, but with retained actomyosin motor properties. We also screened 408 sporadic patients with CHDs and identified a case with ASD and a 17-bp deletion in ACTC1 predicting a non-functional protein. Morpholino (MO) knockdown of ACTC1 in chick embryos produces delayed looping and reduced atrial septa, supporting a developmental role for this protein. The combined results indicate, for the first time, that ACTC1 mutations or reduced ACTC1 levels may lead to ASD without signs of cardiomyopathy.
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| 26. |
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| 27. |
- Matsson, Hans, et al.
(author)
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Targeted disruption of the ribosomal protein S19 gene is lethal prior to implantation.
- 2004
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In: Mol Cell Biol. - 0270-7306. ; 24:9, s. 4032-4037
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Journal article (peer-reviewed)abstract
- The ribosomal protein S19 (RPS19) is located in the small (40S) subunit and is one of 79 ribosomal proteins. The gene encoding RPS19 is mutated in approximately 25% of patients with Diamond-Blackfan anemia, which is a rare congenital erythroblastopenia. Affected individuals present with decreased numbers or the absence of erythroid precursors in the bone marrow, and associated malformations of various organs are common. We produced C57BL/6J mice with a targeted disruption of murine Rps19 to study its role in erythropoiesis and development. Mice homozygous for the disrupted Rps19 were not identified as early as the blastocyst stage, indicating a lethal effect. In contrast, mice heterozygous for the disrupted Rps19 allele have normal growth and organ development, including that of the hematopoietic system. Our findings indicate that zygotes which are Rps19(-/-) do not form blastocysts, whereas one normal Rps19 allele in C57BL/6J mice is sufficient to maintain normal ribosomal and possibly extraribosomal functions.
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| 28. |
- Matsson, H., et al.
(author)
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Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease
- 2016
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In: Bmc Pulmonary Medicine. - : Springer Science and Business Media LLC. - 1471-2466. ; 16
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Journal article (peer-reviewed)abstract
- Background: Reduced lung function in patients with chronic obstructive pulmonary disease (COPD) is likely due to both environmental and genetic factors. We report here a targeted high-throughput DNA sequencing approach to identify new and previously known genetic variants in a set of candidate genes for COPD. Methods: Exons in 22 genes implicated in lung development as well as 61 genes and 10 genomic regions previously associated with COPD were sequenced using individual DNA samples from 68 cases with moderate or severe COPD and 66 controls matched for age, gender and smoking. Cases and controls were selected from the Obstructive Lung Disease in Northern Sweden (OLIN) studies. Results: In total, 37 genetic variants showed association with COPD (p < 0.05, uncorrected). Several variants previously discovered to be associated with COPD from genetic genome-wide analysis studies were replicated using our sample. Two high-risk variants were followed-up for functional characterization in a large eQTL mapping study of 1,111 human lung specimens. The C allele of a synonymous variant, rs8040868, predicting a p.(S45=) in the gene for cholinergic receptor nicotinic alpha 3 (CHRNA3) was associated with COPD (p = 8.8 x 10(-3)). This association remained (p = 0.003 and OR = 1.4, 95 % CI 1.1-1.7) when analysing all available cases and controls in OLIN (n = 1,534). The rs8040868 variant is in linkage disequilibrium with rs16969968 previously associated with COPD and altered expression of the CHRNA5 gene. A follow-up analysis for detection of expression quantitative trait loci revealed that rs8040868-C was found to be significantly associated with a decreased expression of the nearby gene cholinergic receptor, nicotinic, alpha 5 (CHRNA5) in lung tissue. Conclusion: Our data replicate previous result suggesting CHRNA5 as a candidate gene for COPD and rs8040868 as a risk variant for the development of COPD in the Swedish population.
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| 29. |
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| 30. |
- Matsson, Pär, et al.
(author)
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Discovery of regulatory elements in human ATP-binding cassette transporters through expression quantitative trait mapping
- 2012
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In: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 12, s. 214-226
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Journal article (peer-reviewed)abstract
- ATP-binding cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic basis and functional outcome of ABC transporter expression level variation. We used genotype and mRNA transcript level data from human lymphoblastoid cell lines to assess population and gender differences in ABC transporter expression, and to guide the discovery of genomic regions involved in transcriptional regulation. Nineteen of 49 ABC genes were differentially expressed between individuals of African, Asian and European descent, suggesting an important influence of race on expression level of ABC transporters. Twenty-four significant associations were found between transporter transcript levels and proximally located genetic variants. Several of the associations were experimentally validated in reporter assays. Through influencing ABC expression levels, these single-nucleotide polymorphisms may affect disease susceptibility and response to drugs.
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| 31. |
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| 32. |
- Over, Bjorn, et al.
(author)
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Structural and conformational determinants of macrocycle cell permeability
- 2016
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In: Nature Chemical Biology. - New York : Nature Publishing Group. - 1552-4450 .- 1552-4469. ; 12:12, s. 1065-1074
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Journal article (peer-reviewed)abstract
- Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 nonpeptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.
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| 33. |
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| 34. |
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Sawadjoon, Supaporn, et al.
(author)
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Mechanistic Insights into the Pd-Catalyzed Direct Amination of Allyl Alcohols : Evidence for an Outer-sphere Mechanism Involving a Palladium Hydride Intermediate
- 2014
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In: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 20:6, s. 1520-1524
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Journal article (peer-reviewed)abstract
- The mechanism of direct amination of allyl alcohol by a palladium triphenylphosphite complex has been explored. Labelling studies show that the reaction proceeds through a π-allylpalladium intermediate. A second-order dependence of reaction rate on allyl alcohol concentration was observed. Kinetic isotope effect studies and ESI-MS studies are in agreement with a reaction proceeding through a palladium hydride intermediate in which both O-H bond and C-O bond cleavages are involved in rate-determining steps. A stereochemical study supports an outer-sphere nucleophilic attack of the π-allylpalladium intermediate giving complete chiral transfer from starting material to product.
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| 39. |
- Scerri, Thomas S, et al.
(author)
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The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure.
- 2012
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11
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Journal article (peer-reviewed)abstract
- Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.
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| 40. |
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| 41. |
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| 42. |
- Weihed, Pär, 1959-, et al.
(author)
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Post-deformation, sulphide-quartz vein hosted gold ore in the footwall alteration zone of the Palaeoproterozoic Långdal VHMS deposit, Skellefte District, northern Sweden
- 2002
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In: GFF. - : Informa UK Limited. - 1103-5897 .- 2000-0863. ; 124:4, s. 201-210
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Journal article (peer-reviewed)abstract
- The Palaeoproterozoic, c. 1.88 Ga old Långdal VHMS deposit is situated in the eastern part of the Skellefte District, northern Sweden. In the stratigraphic footwall to the VHMS ore a sulphidequartz vein system with high gold grades was mined in the second half of the 1990’s. The Långdal VHMS ore is hosted by the uppermost part of the Skellefte Group volcanic rocks, close to the contact with an overlying fine-grained sedimentary unit. Regional structural studies indicate that bedding surfaces in volcanic rocks are parallel to the contact between the volcanic and the sedimentary rocks. Based on the differences in structural style on each side, the contact is interpreted as a major structural break. The Långdal ore is situated close to this break that may have focussed fluid flow during metamorphism and deformation. The orientation of the contact indicates that it either is a D2 structure or that it was at least active during D2. The structural development in the altered footwall rocks to the Långdal VHMS ore indicates that gold-bearing sulphide and sulphide-quartz veins both pre- and post-date the first deformation. Gold associated with the vein system can thus not only be attributed to syngenetic exhalative or replacement processes. The close spatial relationship with the massive sulphide deposits suggests, however, that the gold was remobilized from these syngenetic systems. It is concluded that sulphides were introduced at several stages during the geological evolution of the area as: a) syngenetic disseminations of sulphide and folded, pre-S1 stringer sulphide±quartz veins in the footwall related to the syngenetic VHMS deposit, b) syn-S1 sulphide veins in the footwall gold ore, c) main, post-S1, sulphide-quartz veins associated with the gold ore in the footwall rocks to the Långdal VHMS deposit, and d) post-S1 to pre-S2 galena and sphalerite rich veins post-dating the main, post-S1, sulphide-quartz vein system in the footwall to the Långdal ore. From these relationships it is suggested that gold was re-mobilized from the sulphide rich parts of the VHMS system into post-D1 structures during or slightly after the peak metamorphism. The timing of this event is poorly constrained to post-date the syngenetic ore emplacement by 20–80 m.y.
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| 43. |
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| 44. |
- Ziermans, T, et al.
(author)
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Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development.
- 2012
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 2
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Journal article (peer-reviewed)abstract
- A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene-brain-behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ~6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.
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