293 research outputs found
Identification of Muscle Activation at Rest
No full textOffset muscle activation is the constant neural firing to muscles, even at rest, defining the minimum muscle contraction. Until now, the offset muscle activation has been neglected in the analysis of the dynamical behavior of joints. There is a clinical need for an assessment method to estimate the contribution of the offset muscle activation to the total joint torque in stroke patients, in order to choose the optimum treatment method. The goal of this study was to develop a method that estimates the offset muscle activation of the wrist joint muscles in vivo, in addition to other contributions from tissue viscoelasticity and stretch reflexes. For this purpose, an existing one-sided neuromuscular model of the ankle was extended to a two-sided wrist model for full biomechanical characterization over the whole range of flexion-extension movement. The model parameters (including offset activation, amongst others) were estimated from measured wrist torque, angle and EMG as recorded during imposed ramp-and-hold flexion and extension rotation. It was found that offset muscle activation was present at rest, in both stroke patients and healthy controls. Both offset activity of the extensor carpi radialis (ECR) and reflex activity of the flexor carpi radialis (FCR) were increased in stroke patients compared to controls. The viscoelastic behavior of the FCR was changed in patients compared to controls. From the results of this study it was concluded that following stroke a constant muscle force can be applied by the ECR, which may act as a counterbalance to the altered tissue viscoelasticity and possible shortening of the FCR muscle (or vice versa). Apparently, a new antagonistic force balance had developed around the wrist joint in the stroke patients, having a structural origin on one side and an active (neural) origin on the opposite side. The results may be of importance for targeted treatment of the movement disorder, when choosing for casting, drug therapy or surgical intervention.BMEBioMechanical EngineeringMechanical, Maritime and Materials Engineerin
Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
No full textGenetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10<sup>−11</sup>; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28–1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes
Somatic mutagenesis in satellite cells associates with human skeletal muscle aging
No full textHuman aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.Funding Agencies|Swedish Research Council; Center for Innovative Medicine; Hagelen Foundation; Osterman Foundation; Svenska Lakaresallskapet; Stohnes Foundation; INFERNET [734439]; Swedish Medical Research Council [2013-09305]; Marcus and Marianne Wallenberg foundation; Wallenberg Foundation; Science for Life Laboratory; Knut and Alice Wallenberg Foundation; National Genomics Infrastructure - the Swedish Research Council; Mutation Analysis Core Facility (MAF) at the Karolinska University Hospital</p
Social sustainability of tourism in Iceland: A qualitative inquiry
No full textSustainability research in tourism increasingly focuses on social issues such as the relationship between resident quality of life and community resilience through adaptive capacity. This study of resident and tourism relations in Iceland contributes to this growing body of literature. The research was supported by the Icelandic Tourist Board to meet the need to monitor the social sustainability of tourism in Iceland. Observation in public spaces showed disruption in daily routines for residents as physical infrastructure filled with tourists and the activities of tourism enterprises. In-depth interviews revealed residents’ awareness of potential benefits and problems with tourism, but a positive experience of and attitude toward tourists. A concern for the well-being of tourists was a theme in the interviews. However, residents were critical of the tourism industry and tourism management in both the private and public sector and questioned the sustainability of tourism growth. This leads us to consider the concepts of quality of life and resilience and responsible tourism as aspects of how communities experience and cope with tourism. We conclude that social sustainability, understood as both procedural and substantive, is a useful concept in addressing issues in tourism development.Full Tex
Somatic mutations in healthy cells and age-associated diseases
No full textAging is a complex process that affects all living organisms. As we age, the biological functions are affected, resulting in a decline of the tissue and possibly age-related diseases. Several environmental and genetic factors have been suggested to contribute to aging. Among these factors, a progressive loss of genome integrity, caused by the occurrence of somatic mutations, is proposed as a cause of deterioration of cellular functions. The aim of this thesis was to analyze the effect of somatic mutations in healthy cells and analyze the contribution of somatic mutations to age-related diseases.In paper I, we showed that satellite cells, stem cells of the skeletal muscle, accumulate 13 somatic mutations per genome per year during adult life. Although genes expressed in the skeletal muscle were protected from mutations by the DNA repair machinery, we observed that this protection was less efficient at increased age, resulting in higher mutation load in the exons of old compared to young satellite cells. A somatic mutation identified in a satellite cell was also detected in a small percentage of the cells of the muscle biopsy, suggesting that somatic mutations propagate from satellite cells to the differentiated muscle during adult age and might contribute to its age-related decline.In paper II, we created a genetic atlas of somatic mutations in healthy cells from different tissues based on newly generated and publicly-available sequencing data. In contrast to the current view of a tissue-specific mutational profile, several cell types showed the same mutational profile despite coming from different tissues. Furthermore, two distinct cell types from the same tissue showed different mutational profiles and rates of mutation accumulation. Thanks to these data, we identified multiple factors influencing mutagen exposure and consequent mutational profiles. These factors include the cell´s localization within the tissue, the degree of differentiation and the presence of a protective stem cell niche. In addition, we identified an epithelial cell of the kidney that shows a unique distribution of mutations, characterized by mutation enrichment in highly transcribed genes. This pattern increases the chances of mutating a cancer-driver gene and is in agreement with an increased predisposition to cancer in this cell type. Finally, our analyses provide evidence of a decline of DNA-repair with aging.In paper III, we identified somatic mutations in the brain of Alzheimer´s disease (AD) patients. Using ultra-deep sequencing and tailored bioinformatics analysis, we could detect low-frequency variants in bulk tissue. In total, 2.86 Mb of candidate genes and AD-linked genomic regions were included in the study, and 11 somatic single nucleotide variants (SNVs) were identified in AD brains, but none in non-AD brains. One variant was validated and predicted to affect transcription factor binding sites upstream of the CD55 gene, possibly contributing to AD through the regulation of the complement system.In paper IV, we showed that patients with end-stage chronic kidney disease (CKD) express progerin within their arterial media, the same mutated form of the protein lamin A found in premature aging patients. Importantly, we could identify the mutation that causes progeria, the LMNA c.1824C>T, in DNA extracted from the arteries. In total, we could identify the progerin protein or the mutation in 34 of the 40 CKD patients. DNA damage and increased proliferation were detected in the CKD patients, indicating extensive vascular regeneration. Our result suggests that progenitor cells carrying LMNA c.1824C>T contribute to the vascular pathology and thereby to the disease progression observed in CKD patients.In conclusion, the work presented in this thesis provides a new understanding of the contribution of mutation accumulation in healthy cells with possible implications for aging and age-associated diseases.List of scientific papersI. Somatic mutagenesis in satellite cells associates with human skeletal muscle aging. Irene Franco, Anna Johansson, Karl Olsson, Peter Vrtačnik, Pär Lundin, Hafdis T. Helgadottir, Malin Larsson, Gwladys Revêchon, Carla Bosia, Andrea Pagnani, Paolo Provero, Thomas Gustafsson, Helen Fischer, Maria Eriksson. Nature Communications. 2018 Feb 23;9(1):800. https://doi.org/10.1038/s41467-018-03244-6 II. Basal and mutagen-driven somatic mutagenesis shapes the genome of healthy human cells. Irene Franco*, Hafdis T. Helgadottir*, Aldo Moggio, Malin Larsson, Peter Vrtačnik, Anna Johansson, Nina Norgren, Pär Lundin, David Mas-Ponte, Johan Nordström, Torbjörn Lundgren, Peter Stenvinkel, Lars Wennberg, Fran Supek, Maria Eriksson. *Equal contribution. [Submitted]III. Somatic mutation that affects transcription factor binding upstream of CD55 in the temporal cortex of a late-onset Alzheimer disease patient. Hafdis T. Helgadottir, Pär Lundin, Emelie Wallén Arzt, Anna-Karin Lindström, Caroline Graff, Maria Eriksson. Human Molecular Genetics. 2019 Aug 15;28(16):2675-2685. https://doi.org/10.1093/hmg/ddz085 IV. The Hutchinson-Gilford progeria syndrome mutation, LMNA c.1824C>T, is a somatic mutation in patients with chronic kidney disease. Hafdis T. Helgadottir*, Nikenza Viceconte*, Anna Witasp, Agustin Sola Carvajal, Gwladys Revêchon, Daniel Whisenant, Ece Somuncular, Anne-Sofie Johansson, Emelie Wallén Arzt, Anders Thorell, Anne Babler, Susanne Ziegler, Dagmara McGuinness, Sidinh Luc, Rafael Kramann, Paul G. Shiels, Annika Wernerson, Peter Stenvinkel, Maria Eriksson. *Equal contribution. [Manuscript]</p
Evaluation of genetic cancer predisposition and potential cancer genes
No full textGermline pathogenic TP53 variants are associated with a broad spectrum of hereditary cancers characterized from Li-Fraumeni syndrome (LFS) to hereditary breast cancer (HBC) outcomes, known as heritable TP53-related cancer (hTP53rc) syndrome. LFS is a rare inherited cancer syndrome characterized by premenopausal breast cancer, soft tissue sarcoma, brain tumor, osteosarcoma, and adrenocortical carcinoma. To identify carriers with high risk of LFS phenotype and explore stratifying clinical management for these carriers, we developed a phenotypic prediction model of LFS in relation to HBC risk based on predicted protein conformation changes for germline TP53 missense variants in the international agency for research on cancer (IARC) TP53 database and published papers in Paper I. This model was validated in our Swedish TP53 cohort with more reliable pedigree and clinical information in Paper II. Our results indicated that this tool could be considered helpful in the genetic counseling of families with hTP53rc, in particular as a psychological relief for families with a predominance of HBC phenotype. Also, we summarized the clinical characterization of all known TP53-carriers in hTP53rc families in Sweden and explored genotype-phenotype correlations. Except for the very high lifetime risk of a broad spectrum of tumor types in LFS families, chemo- and radiotherapy can increase these patients' risk of secondary tumors. Thus, efficient preventive treatment would be important to these tumor-prone carriers. We have seen an indication of delayed tumor onset using the mutant TP53-targeting compound APR-246 in a mouse model of LFS with R172H (amino acid change at residue 172 from arginine to histidine) mutant Trp53, and it had the potential to be used in the clinical study in Paper III.HBC is characterized by early-onset age of breast cancer, bilateral breast cancer, male breast cancer, and it can be accompanied by ovarian cancer or other cancer types. BRCA1 and BRCA2 are the most prevalent genes for HBC, however, most families are not associated with variants in any known breast cancer-related genes. We identified several potential high-risk genes that could contribute to breast cancer in three Swedish HBC families in Paper IV. In summary, this thesis enriches the knowledge of genetic predisposition and prevention of hereditary breast cancer syndromes and potential cancer genes.List of scientific papersI. Association between predicted effects of TP53 missense variants on protein conformation and their phenotypic presentation as Li-Fraumeni syndrome or hereditary breast cancer. Yaxuan Liu, Olga Axell, Tom van Leeuwen, Robert Konrat, Pedram Kharaziha, Catharina Larsson, Anthony P H Wright, Svetlana Bajalica-Lagercrantz. International Journal of Molecular Sciences. 2021 Jun 14; 22 (12), 6345. https://doi.org/10.3390/ijms22126345 II. Characterization of heritable TP53-related cancer syndrome in Sweden – a retrospective nationwide study of genotype-phenotype correlations in 98 families. Yaxuan Liu#, Meis Omran#,*, Alexander Sun Zhang, Marie Stenmark-Askmalm, Anna Rosén, Anna-Lotta Hallbeck, Anna Poluha, Fredrik Persson, Hafdis T. Helgadottir, Emma Tham, Svetlana Bajalica-Lagercrantz. [Manuscript]III. Evaluation of the prophylactic use of APR-246 in a mouse model of the Li-Fraumeni syndrome with R172H mutant Trp53. Yaxuan Liu*, Charlotte Strandgren, Yajie Yang, Alexander Sun Zhang, Felix Haglund de Flon, Lennart Blomquist, Svetlana Bajalica-Lagercrantz, Klas G Wiman. [Manuscript]IV. Whole exome sequencing of germline variants in non-BRCA families with hereditary breast cancer. Yaxuan Liu, Hafdis T. Helgadottir, Pedram Kharaziha, Jungmin Choi, Francesc Lopez-Giraldez, Shrikant M. Mane, Veronica Höiom, Carl Christofer Juhlin, Catharina Larsson, Svetlana Bajalica-Lagercrantz. biomedicines. 2022 April 26; 10 (5), 1004. https://doi.org/10.3390/biomedicines10051004 </p
Identification of known and novel familial cancer genes in Swedish colorectal cancer families
No full textIdentifying new candidate colorectal cancer (CRC) genes and mutations are important for clinical cancer prevention as well as in cancer care. Genetic counseling is already implemented for known high-risk variants; however, the majority of CRC are of unknown causes. In our study, 110 CRC patients in 55 Swedish families with a strong history of CRC but unknown genetic causes were analyzed with the aim of identifying novel candidate CRC predisposing genes. Exome sequencing was used to identify rare and high-impact variants enriched in the families. No clear pathogenic variants were found in known CRC predisposing genes; however, potential pathogenic variants in novel CRC predisposing genes were identified. Over 3000 variants with minor allele frequency (MAF) 20 were seen aggregating in the CRC families. Of those, 27 variants with MAF 25 were considered high-risk mutations. Interestingly, more than half of the high-risk variants were detected in three families, suggesting cumulating contribution of several variants to CRC. In summary, our study shows that despite a strong history of CRC within families, identifying pathogenic variants is challenging. In a small number of families, few rare mutations were shared by affected family members. This could indicate that in the absence of known CRC predisposing genes, a cumulating contribution of mutations leads to CRC observed in these families
Social sustainability of tourism in Iceland: A qualitative inquiry
No full textSustainability research in tourism increasingly focuses on social issues such as the relationship between resident quality of life and community resilience through adaptive capacity. This study of resident and tourism relations in Iceland contributes to this growing body of literature. The research was supported by the Icelandic Tourist Board to meet the need to monitor the social sustainability of tourism in Iceland. Observation in public spaces showed disruption in daily routines for residents as physical infrastructure filled with tourists and the activities of tourism enterprises. In-depth interviews revealed residents’ awareness of potential benefits and problems with tourism, but a positive experience of and attitude toward tourists. A concern for the well-being of tourists was a theme in the interviews. However, residents were critical of the tourism industry and tourism management in both the private and public sector and questioned the sustainability of tourism growth. This leads us to consider the concepts of quality of life and resilience and responsible tourism as aspects of how communities experience and cope with tourism. We conclude that social sustainability, understood as both procedural and substantive, is a useful concept in addressing issues in tourism development
Somatic mutation that affects transcription factor binding upstream of CD55 in the temporal cortex of a late-onset Alzheimer disease patient
No full textAlzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Familial cases suggest genetic components; however, monogenetic causes are few, and the vast majority of incidences have unknown cause. Sequencing efforts have focused on germline mutations, but improved technology has opened up for studies on somatic mutations in affected brain tissue samples. Here we use ultra-deep sequencing on brain and blood from early-onset AD (EOAD) and late-onset AD (LOAD) patients and non-AD individuals (n = 16). In total, 2.86 Mb of genomic regions, previously associated with AD, were targeted included 28 genes and upstream and downstream regulatory regions. Tailored downstream bioinformatics filtering identified 11 somatic single nucleotide variants in the temporal cortex in AD patients and none in the controls. One variant was validated to be present at 0.4% allele frequency in temporal cortex of a LOAD patient. This variant was predicted to affect transcription factor binding sites upstream of the CD55 gene, contributing to AD pathogenesis by affecting the complement system. Our results suggest that future studies targeting larger portions of the genome for somatic mutation analysis are important to obtain an increased understanding for the molecular basis of both EOAD and LOAD.</p
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