| 1. |
- Bergstrand, Jan, et al.
(författare)
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Scanning inverse fluorescence correlation spectroscopy
- 2014
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Ingår i: Optics Express. - : Optical Society of America. - 1094-4087. ; 22:11, s. 13073-13090
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Tidskriftsartikel (refereegranskat)abstract
- Scanning Inverse Fluorescence Correlation Spectroscopy (siFCS) is introduced to determine the absolute size of nanodomains on surfaces. We describe here equations for obtaining the domain size from cross-and auto-correlation functions, measurement simulations which enabled testing of these equations, and measurements on model surfaces mimicking membranes containing nanodomains. Using a confocal microscope of 270 nm resolution the size of 250 nm domains were estimated by siFCS to 257 +/- 12 nm diameter, and 40 nm domains were estimated to 65 +/- 26 nm diameter. Applications of siFCS for sizing of nanodomains and protein clusters in cell membranes are discussed.
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| 2. |
- Blom, Hans, et al.
(författare)
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Nearest neighbor analysis of dopamine D1 receptors and Na plus -K plus -ATPases in dendritic spines dissected by STED microscopy
- 2012
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Ingår i: Microscopy research and technique (Print). - : Wiley. - 1059-910X .- 1097-0029. ; 75:2, s. 220-228
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Tidskriftsartikel (refereegranskat)abstract
- Protein localization in dendritic spines is the focus of intense investigations within neuroscience. Applications of super-resolution microscopy to dissect nanoscale protein distributions, as shown in this work with dual-color STED, generate spatial correlation coefficients having quite small values. This means that colocalization analysis to some extent looses part of its correlative impact. In this study we thus introduced nearest neighbor analysis to quantify the spatial relations between two important proteins in neurons, the dopamine D1 receptor and Na+,K+-ATPase. The analysis gave new information on how dense the D1 receptor and Na+,K+-ATPase constituting nanoclusters are located both with respect to the homogenous (self to same) and the heterogeneous (same to other) topology. The STED dissected nanoscale topologies provide evidence for both a joint as well as a separated confinement of the D1 receptor and the Na+,K+-ATPase in the postsynaptic areas of dendritic spines. This confined topology may have implications for generation of local sodium gradients and for structural and functional interactions modulating slow synaptic transmission processes. Microsc. Res. Tech., 2011.
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| 3. |
- Blom, Hans, et al.
(författare)
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Spatial Distribution of DARPP-32 in Dendritic Spines
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9, s. e75155-
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Tidskriftsartikel (refereegranskat)abstract
- The phosphoprotein DARPP-32 (dopamine and cyclic adenosine 3́, 5́-monophosphate-regulated phosphoprotein, 32 kDa) is an important component in the molecular regulation of postsynaptic signaling in neostriatum. Despite the importance of this phosphoprotein, there is as yet little known about the nanoscale distribution of DARPP-32. In this study we applied superresolution stimulated emission depletion microscopy (STED) to assess the expression and distribution of DARPP-32 in striatal neurons. Primary culture of striatal neurons were immunofluorescently labeled for DARPP-32 with Alexa-594 and for the dopamine D1 receptor (D1R) with atto-647N. Dual-color STED microscopy revealed discrete localizations of DARPP-32 and D1R in the spine structure, with clustered distributions in both head and neck. Dissected spine structures reveal that the DARPP-32 signal rarely overlapped with the D1R signal. The D1R receptor is positioned in an "aggregated" manner primarily in the spine head and to some extent in the neck, while DARPP-32 forms several neighboring small nanoclusters spanning the whole spine structure. The DARPP-32 clusters have a mean size of 52 +/- 6 nm, which is close to the resolution limit of the microscope and corresponds to the physical size of a few individual phosphoprotein immunocomplexes. Dissection of synaptic proteins using superresolution microscopy gives possibilities to reveal in better detail biologically relevant information, as compared to diffraction-limited microscopy. In this work, the dissected postsynaptic topology of the DARPP-32 phosphoprotein provides strong evidence for a compartmentalized and confined distribution in dendritic spines. The protein topology and the relatively low copy number of phosphoprotein provides a conception of DARPP-32's possibilities to fine-tune the regulation of synaptic signaling, which should have an impact on the performance of the neuronal circuits in which it is expressed.
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| 4. |
- Chen, Xingqi, et al.
(författare)
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Chromatin in situ proximity (ChrISP) : Single-cell analysis of chromatin proximities at a high resolution
- 2014
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Ingår i: BioTechniques. - : Future Science Ltd. - 0736-6205 .- 1940-9818. ; 56:3, s. 117-124
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Tidskriftsartikel (refereegranskat)abstract
- Current techniques for analyzing chromatin structures are hampered by either poor resolution at the individual cell level or the need for a large number of cells to obtain higher resolution. This is a major problem as it hampers our understanding of chromatin conformation in single cells and how these respond to environmental cues. Here we describe a new method, chromatin in situ proximity (ChrISP), which reproducibly scores for proximities between two different chromatin fibers in 3-D with a resolution of similar to 170 angstrom in single cells. The technique is based on the in situ proximity ligation assay (ISPLA), but ChrISP omits the rolling circle amplification step (RCA). Instead, the proximities between chromatin fibers are visualized by a fluorescent connector oligonucleotide DNA, here termed splinter, forming a circular DNA.with another circle-forming oligonucleotide, here termed backbone, upon ligation. In contrast to the regular ISPLA technique, our modification enables detection of chromatin fiber proximities independent of steric hindrances from nuclear structures. We use this method to identify higher order structures of individual chromosomes in relation to structural hallmarks of interphase nuclei and beyond the resolution of the light microscope.
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| 5. |
- Eriksson, Daniel, et al.
(författare)
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Effects of perceived long-term stress on health and memory functioning
- 2010
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Ingår i: Abstracts of the Psychonomic Society. ; , s. 78-78
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Konferensbidrag (refereegranskat)abstract
- The study examined effects of perceived long-term stress on health and memory functioning in middle-aged individuals (40–60 years). Participants in the Betula study (Nilsson et al., 1997) describing themselves as being stressed in general over three measurement occasions (10 years in total) were compared with a matched (sex and education) group (n = 98) reporting no stress. The results revealed a higher incidence of depressive symptoms, flus, and not-healthy-ratings over time for the stress group. In addition, the stress group provided more negative subjective memory ratings, whereas time-related change in memory performance, indicative of a high degree of cognitive stability, did not differ from that of controls. Degree of perceived stress is discussed as a factor underlying variations in regard to the outcome of studies of perceived stress.
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| 6. |
- Eriksson Sörman, Daniel, et al.
(författare)
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Blood Pressure Levels and Longitudinal Changes in Relation to Social Network Factors
- 2016
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Ingår i: Psychological Topics. - 1332-0742. ; 25:1, s. 59-73
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine the relationship between social network variables and levels of and longitudinal changes in blood pressure in a middle-aged/older sample. The participants (50-75 years at baseline; n=1097) responded to questions concerning social relationships at baseline and their blood pressure (diastolic, systolic) was measured. Blood pressure levels were reassessed 5, 10, and 15 years later. Latent growth models with responses to questions concerning social relationships as predictors and basic demographic factors (age, sex) as covariates, unexpectedly indicated that a more limited social network (no close friend, few visits, little contact with friends in other ways, not living with someone, and a composite index based on all questions) was associated with significantly lower diastolic blood pressure levels. For systolic blood pressure a similar result was observed for one of the variables (lack of a close friend). In general, these effects diminished over time, as indexed by the positive relationship between several of the social variables and slope. The results were little affected by inclusion of additional covariates (e.g. measures of psychological distress, smoking/alcohol habits, and BMI) suggesting that the origins of this unexpected pattern of findings must probably be sought for in other subjectrelated factors, such as, for example, increased help seeking. Future studies should consider qualitative aspects (e.g. feelings of loneliness, quality of social relationships) in addition to structural aspects to provide a better understanding of these associations.
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| 7. |
- Eriksson Sörman, Daniel, et al.
(författare)
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Ger en aktiv livsstil bättre minne?
- 2011
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Ingår i: Svensk Idrottsforskning. - Stockholm : Centrum för idrottsforskning. - 1103-4629. ; 20:1, s. 43-45
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Det sägs ibland att aktivteter som stimulerar hjärnan förbättrar minnet. En rad studier indikerar också att olika typer av livsstilsfaktorer hänger samman med prestation i kognitiva test. De visar att dålig minnesförmåga är överrepresenterad hos dem som inte ägnar sig åt fritidsaktiviteter såsom att läsa, idrotta och lägga pussel.
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| 8. |
- Eriksson Sörman, Daniel, et al.
(författare)
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Leisure Activity in Old Age and Risk of Dementia : a 15-Year Prospective Study
- 2014
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Ingår i: The journals of gerontology. Series B, Psychological sciences and social sciences. - : Oxford University Press. - 1079-5014 .- 1758-5368. ; 69:4, s. 493-501
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. The aim of this study was to investigate whether leisure activity is associated with incident dementia in an older sample.Method. We examined a sample of 1,475 elderly (>= 65 years) who were dementia free at baseline over a follow-up period of up to 15 years. In addition to analyses involving the total time period, separate analyses of three time periods were performed, 1-5, 6-10, and 11-15 years, following baseline measurement of leisure activity.Results. After controlling for a variety of potential confounders, analyses of data for the total time period revealed that higher levels of "Total activity" and "Social activity," but not "Mental activity," were associated with decreased risk of dementia. However, analyses of the separate time periods showed that this association was only significant in the first time period, 1-5 years after baseline.Discussion. The results from this study provide little support for the hypothesis that frequent engagement in leisure activities among elderly serve to protect against dementia diseases across a longer time frame. The finding of a relationship for the first time period, 1-5 years after baseline, could indicate short-term protective effects but could also reflect reverse causality.
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| 9. |
- Eriksson Sörman, Daniel, et al.
(författare)
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Leisure-time activity in old age as predictors of impending dementia: A 15-year prospective study
- 2012
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Konferensbidrag (refereegranskat)abstract
- This study examined the relationship between leisure activities and risk of dementia in a sample of healthy older individuals, dementia free at the beginning of the project. Data were drawn from a population-based longitudinal study (the Betula project) and the participants were followed up for 15 years. At baseline, participants were asked about their frequency of participation in 15 selected leisure activities. When age, gender, education, APOE and other potential confounders were controlled for, results revealed quite moderate effects on dementia after analysis of the activities separately. However, by weighting each activity into a mental, social and physical dimension (based on valuation by the participants), and then summarizing into a score for each dimension, we further investigated if level of engagement could predict impending dementia. Preliminary results indicate that the dimensions may have influence on the risk of dementia for certain age groups. The study also showed that the strongest predictor of dementia is being a carrier of the APOE ɛ4 allele. The outcomes are discussed in terms of important methodological difference between studies concerning the effects of leisure activities in preventing dementia diseases.
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| 10. |
- Eriksson Sörman, Daniel, 1974-, et al.
(författare)
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Occupational cognitive complexity and episodic memory in old age
- 2021
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Ingår i: Intelligence. - : Elsevier. - 0160-2896 .- 1873-7935. ; 89
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate occupational cognitive complexity of main lifetime occupation in relation to level and 15-year change in episodic memory recall in a sample of older adults (≥ 65 years, n = 780). We used latent growth curve modelling with occupational cognitive complexity (O*NET indicators) as independent variable. Subgroup analyses in a sample of middle-aged (mean: 49.9 years) men (n = 260) were additionally performed to investigate if a general cognitive ability (g) factor at age 18 was predictive of future occupational cognitive complexity and cognitive performance in midlife. For the older sample, a higher level of occupational cognitive complexity was related to a higher level of episodic recall (β = 0.15, p < .001), but the association with rate of change (β = 0.03, p = .64) was not statistically significant. In the middle-aged sample, g at age 18 was both directly (β = 0.19, p = .01) and indirectly (via years of education after age 18, ab = 0.19) predictive of midlife levels of occupational cognitive complexity. Cognitive ability at age 18 was also a direct predictor of midlife episodic recall (β = 0.60, p ≤ 0.001). Critically, entry of the early adult g factor attenuated the association between occupational complexity and cognitive level (from β = 0.21, p = .01 to β = 0.12, p = .14). Overall, our results support a pattern of preserved differentiation from early to late adulthood for individuals with different histories of occupational complexity.
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| 11. |
- Eriksson Sörman, Daniel, et al.
(författare)
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Reading Habits Among Older Adults in Relation to Level and 15-Year Changes in Verbal Fluency and Episodic Recall
- 2018
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Ingår i: Frontiers in Psychology. - : Frontiers Media S.A.. - 1664-1078. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The main objective of this study was to investigate reading habits in older adults in relation to level and 15-year changes in verbal fluency and episodic recall. We examined a sample of 1157 participants (55 years at baseline) up to 15 years after the baseline assessment using latent growth curve modeling of cognitive measures with baseline reading frequency (books, weekly magazines) as a predictor of cognitive level (intercept) and rate of change (slope). Subgroup analyses were performed to investigate the role of an early adult g factor in the association between reading habits and cognitive ability in midlife. Frequent reading of books, but not of magazines, was associated with higher levels of verbal fluency and recall but unrelated to rate of longitudinal decline. Subgroup analyses indicated that the g factor in early adulthood predicted reading and cognitive level in midlife and this factor removed the current association between reading habits and level of cognitive ability (both cognitive factors). The results indicate an enduring relationship between book reading and level of cognitive ability across the adult life span and provide little support of the hypothesis that frequent reading protects against latelife cognitive decline. The extent to which book reading promotes cognitive functioning in childhood/youth remains to be demonstrated. Intervention studies may be useful in this regard.
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| 12. |
- Eriksson Sörman, Daniel, et al.
(författare)
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Social relationships and risk of dementia : a population-based study
- 2015
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Ingår i: International psychogeriatrics. - : Cambridge University Press. - 1041-6102 .- 1741-203X. ; 27:8, s. 1391-1399
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Tidskriftsartikel (refereegranskat)abstract
- Background: The objective was to examine whether aspects of social relationships in old age are associated with all-cause dementia and Alzheimer's disease (AD).Methods: We studied 1,715 older adults (>= 65 years) who were dementia-free at baseline over a period of up to 16 years. Data on living status, contact/visit frequency, satisfaction with contact frequency, and having/not having a close friend were analyzed using Cox proportional hazards regressions with all-cause dementia or AD as the dependent variable. To control for reverse causality and to identify potential long-term effects, we additionally performed analyses with delayed entry.Results: We identified 373 incident cases of dementia (207 with AD) during follow-up. The variable visiting/visits from friends was associated with reduced risk of all-cause dementia. Further, a higher value on the relationships index (sum of all variables) was associated with reduced risk of all-cause dementia and AD. However, in analyses with delayed entry, restricted to participants with a survival time of three years or more, none of the social relationship variables was associated with all-cause dementia or AD.Conclusions: The results indicate that certain aspects of social relationships are associated with incident dementia or AD, but also that these associations may reflect reverse causality. Future studies aimed at identifying other factors of a person's social life that may have the potential to postpone dementia should consider the effects of reverse causality.
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| 13. |
- Eriksson Sörman, Daniel, 1974-
(författare)
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The influence of social relationships and leisure activity on adult cognitive functioning and risk of dementia : Longitudinal population-based studies
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Today, as we live longer, dementia diseases are becoming more prevalent around the world. Thus, further knowledge of how to maintain levels of cognitive functioning in old age and how to identify factors that postpone the onset of dementia are of acute interest. Lifestyle patterns and social life are important aspects to consider in this regard.This thesis includes three studies. Study I investigated the association between participation in various leisure activities in old age (≥65 years) and risk of incident all-cause dementia. Analyses of the total follow-up time period (15 years) showed that higher levels of “Social” and “Total” leisure activity were associated with decreased risk of dementia. In Study II, the aim was to investigate the association between various aspects of social relationships in old age (≥65 years) and risk of incidents of all-cause dementia and Alzheimer's disease. Results showed that over the total follow-up period (16 years) higher values on the relationship index were associated with reduced risk of both dementia and Alzheimer's disease. Visiting/visits of friends and acquaintances more than once a week was related to decreased risk for all-cause dementia, but not for Alzheimer's disease. However, in neither Study I nor II did any of these factors alter the risk of all-cause dementia or Alzheimer's disease when near-onset dementias were removed from the analyses (Study I, up to five years; Study II, up to three years).In Study III the aim was to investigate the association between social network size and cognitive ability in a middle-aged (40–60 years) sample. The idea was that if social network size can moderate negative age-related influence on memory functions, it might also put an individual on a cognitive trajectory that is beneficial in old age. Results from longitudinal analyses showed that baseline network size was positively related to five-year changes in semantic memory and with changes in both semantic and episodic memory at the ten-year follow-up. Social network size was unrelated to changes in visuospatial performance.Taken together, enrichment factors measured in old age (≥ 65 years) did not alter the risk of all-cause dementia or Alzheimer's disease when near-onset dementias were removed from the analyses. These results might reflect protective short-term effects or reverse causality, meaning that in the prodromal phase of dementia individuals tend to withdraw from activity. Social network size in middle age (40-60 years), however, appears to have beneficial long-term effects on cognitive functioning. The results highlight the importance of long follow-up periods and the need to adjust for the influences of reverse causality when investigating the impact of a socially and mentally active life on cognitive functioning.
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| 14. |
- Gad, Annica K. B., et al.
(författare)
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Rho GTPases link cellular contractile force to the density and distribution of nanoscale adhesions
- 2012
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 26:6, s. 2374-2382
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Tidskriftsartikel (refereegranskat)abstract
- The ability of cells to adhere and to exert contractile forces governs their capacity to move within an organism. The cytoskeletal regulators of the Rho GTPase proteins are involved in control of the contractile forces of cells. To elucidate the basis of cell migration, we analyzed contractile forces and nanoscale adhesion-related particles in single cells expressing constitutively active variants of Rho GTPases by using traction-force microscopy and ultra-high-resolution stimulated emission depletion microscopy, respectively. RhoAV14 induced large increases in the contractile forces of single cells, with Rac1L61 and RhoDV26 having more moderate effects. The RhoAV14- and RhoDV26-induced forces showed similar spatial distributions and were accompanied by reduced or unaltered cell spreading. In contrast, the Rac1L61-induced force had different, scattered, force distributions that were linked to increased cell spreading. All three of these Rho GTPase activities caused a loss of thick stress fibers and focal adhesions and a more homogenous distribution of nanoscale adhesion-related particles over the ventral surface of the cells. Interestingly, only RhoAV14 increased the density of these particles. Our data suggest a Rac1-specific mode for cells to generate contractile forces. Importantly, increased density and a more homogenous distribution of these small adhesion-related particles promote cellular contractile forces.-Gad, A. K. B., Ronnlund, D., Spaar, A., Savchenko, A. A., Petranyi, G., Blom, H., Szekely, L., Widengren, J., Aspenstrom, P. Rho GTPases link cellular contractile force to the density and distribution of nanoscale adhesions.
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| 15. |
- Larhammar, Martin, 1985-, et al.
(författare)
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SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis
- 2015
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 77:6, s. 526-536
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe neuromodulatory transmitters, biogenic amines, have profound effects on multiple neurons and are essential for normal behavior and mental health. Here we report that the orphan transporter SLC10A4, which in the brain is exclusively expressed in presynaptic vesicles of monoaminergic and cholinergic neurons, has a regulatory role in dopamine homeostasis.MethodsWe used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine-regulated behaviors.ResultsWe show that SLC10A4 is localized on the same synaptic vesicles as either vesicular acetylcholine transporter or vesicular monoamine transporter 2. We did not find evidence for direct transport of dopamine by SLC10A4; however, synaptic vesicle preparations lacking SLC10A4 showed decreased dopamine vesicular uptake efficiency. Furthermore, we observed an increased acidification in synaptic vesicles isolated from mice overexpressing SLC10A4. Loss of SLC10A4 in mice resulted in reduced striatal serotonin, noradrenaline, and dopamine concentrations and a significantly higher dopamine turnover ratio. Absence of SLC10A4 led to slower dopamine clearance rates in vivo, which resulted in accumulation of extracellular dopamine. Finally, whereas SLC10A4 null mutant mice were slightly hypoactive, they displayed hypersensitivity to administration of amphetamine and tranylcypromine.ConclusionsOur results demonstrate that SLC10A4 is a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo. The discovery of SLC10A4 and its role in dopaminergic signaling reveals a novel mechanism for neuromodulation and represents an unexplored target for the treatment of neurological and mental disorders.
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| 16. |
- Mellroth, Peter, et al.
(författare)
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LytA, Major Autolysin of Streptococcus pneumoniae, Requires Access to Nascent Peptidoglycan
- 2012
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 287:14, s. 11018-11029
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Tidskriftsartikel (refereegranskat)abstract
- Background: The regulation of cell wall hydrolysis by the pneumococcal autolysin LytA is poorly understood. Results: The cell wall is susceptible to extracellular LytA only during the stationary phase or after cell wall synthesis inhibition. Conclusion: LytA is regulated on the substrate level, where peptidoglycan modifications likely prevent LytA hydrolysis. Significance: The control of amidases is essential for bacterial survival, cell-wall synthesis, and division.
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| 17. |
- Mocsar, Gabor, et al.
(författare)
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MHC I Expression Regulates Co-clustering and Mobility of Interleukin-2 and-15 Receptors in T Cells
- 2016
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Ingår i: Biophysical Journal. - : Cell Press. - 0006-3495 .- 1542-0086. ; 111:1, s. 100-112
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Tidskriftsartikel (refereegranskat)abstract
- MHC glycoproteins form supramolecular clusters with interleukin-2 and -15 receptors in lipid rafts of T cells. The role of highly expressed MHC I in maintaining these clusters is unknown. We knocked down MHC I in FT7.10 human T cells, and studied protein clustering at two hierarchic levels: molecular aggregations and mobility by Forster resonance energy transfer and fluorescence correlation spectroscopy; and segregation into larger domains or superclusters by superresolution stimulated emission depletion microscopy. Fluorescence correlation spectroscopy-based molecular brightness analysis revealed that the studied molecules diffused as tight aggregates of several proteins of a kind. Knockdown reduced the number of MHC I containing molecular aggregates and their average MHC I content, and decreased the heteroassociation of MHC I with IL-2R alpha/IL-15R alpha. The mobility of not only MHC I but also that of IL-2R alpha/IL-15R alpha increased, corroborating the general size decrease of tight aggregates. A multifaceted analysis of stimulated emission depletion images revealed that the diameter of MHC I superclusters diminished from 400-600 to 200-300 nm, whereas those of IL-2R alpha/IL-15R alpha hardly changed. MHC I and IL-2R alpha/IL-15R alpha colocalized with GM1 ganglioside-rich lipid rafts, but MHC I clusters retracted to smaller subsets of GM1-and IL-2R alpha/IL-15R alpha-rich areas upon knockdown. Our results prove that changes in expression level may significantly alter the organization and mobility of interacting membrane proteins.
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| 18. |
- Nordgren, Niklas, et al.
(författare)
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Oncogene induced stiffening of living cells
- 2015
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Ingår i: Abstracts of Papers of the American Chemical Society. - : AMER CHEMICAL SOC. - 0065-7727. ; 249
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 19. |
- Nyberg, Lars, 1966-, et al.
(författare)
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Biological and environmental predictors of heterogeneity in neurocognitive ageing : Evidence from Betula and other longitudinal studies
- 2020
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Ingår i: Ageing Research Reviews. - : Elsevier. - 1568-1637 .- 1872-9649. ; 64
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Forskningsöversikt (refereegranskat)abstract
- Individual differences in cognitive performance increase with advancing age, reflecting marked cognitive changes in some individuals along with little or no change in others. Genetic and lifestyle factors are assumed to influence cognitive performance in aging by affecting the magnitude and extent of age-related brain changes (i.e., brain maintenance or atrophy), as well as the ability to recruit compensatory processes. The purpose of this review is to present findings from the Betula study and other longitudinal studies, with a focus on clarifying the role of key biological and environmental factors assumed to underlie individual differences in brain and cognitive aging. We discuss the vital importance of sampling, analytic methods, consideration of non-ignorable dropout, and related issues for valid conclusions on factors that influence healthy neurocognitive aging.
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| 20. |
- Nyström, Markus, 1973-, et al.
(författare)
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To what extent is subjective well-being in late adulthood related to subjective and objective memory functioning? : Five-year cross-lagged panel analyses
- 2019
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Ingår i: Aging & Mental Health. - : Taylor & Francis. - 1360-7863 .- 1364-6915. ; 23:1, s. 92-99
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Tidskriftsartikel (refereegranskat)abstract
- Background: Population aging motivated a focus in contemporary research on factors, e.g. cognitive functioning, that contribute to ‘aging well.’ However, something that has been overlooked is relation between memory functioning, determined by objective tests as well as subjective memory ratings, and subjective well-being (SWB).Objectives: The aim of the present study was to investigate cross-sectional and longitudinal (cross-lagged) relationships between episodic memory (both subjective and objective) and SWB.Method: A total of 586 older individuals (60–90 years) were assessed on multiple measures of the targeted constructs at baseline (Time 1) as part of the Betula cohort study. Five years later (Time 2), 354 of the participants returned for follow-up measurements and were included in cross-lagged panel analyses.Results: As expected, objective memory and subjective memory showed a pattern of cross-sectional age deficits and a mean level longitudinal decline was observed for objective memory. By contrast, SWB showed stable mean levels both across age and time. No cross-sectional or cross-lagged associations were observed between SWB and objective memory, whereas subjective memory and SWB showed a cross-sectional association.Conclusion: The results underscore that successful aging is a multifaceted construct with no or only weak associations between the investigated components. However, SWB and rate of change at the individual level should be considered to define successful aging.
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| 21. |
- Rathje, Li-Sophie Z., et al.
(författare)
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Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:4, s. 1515-1520
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Tidskriftsartikel (refereegranskat)abstract
- Oncogenes deregulate fundamental cellular functions, which can lead to development of tumors, tumor-cell invasion, and metastasis. As the mechanical properties of cells govern cell motility, we hypothesized that oncogenes promote cell invasion by inducing cytoskeletal changes that increase cellular stiffness. We show that the oncogenes simian virus 40 large T antigen, c-Myc, and cyclin E induce spatial reorganization of the vimentin intermediate filament network in cells. At the cellular level, this reorganization manifests as increased width of vimentin fibers and the collapse of the vimentin network. At nanoscale resolution, the organization of vimentin fibers in these oncogene-expressing cells was more entangled, with increased width of the fibers compared with control cells. Expression of these oncogenes also resulted in up-regulation of the tubulin deacetylase histone deacetylase 6 (HDAC6) and altered spatial distribution of acetylated microtubules. This oncogene expression also induced increases in cellular stiffness and promoted the invasive capacity of the cells. Importantly, HDAC6 was required and sufficient for the structural collapse of the vimentin filament network, and was required for increased cellular stiffness of the oncogene-expressing cells. Taken together, these data are consistent with the possibility that oncogenes can induce cellular stiffness via an HDAC6-induced reorganization of the vimentin intermediate filament network.
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| 22. |
- Rönnlund, Daniel, et al.
(författare)
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Fluorescence Nanoscopy of Platelets Resolves Platelet-State Specific Storage, Release and Uptake of Proteins, Opening up Future Diagnostic Applications
- 2012
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Ingår i: Advanced Healthcare Materials. - : Wiley-Blackwell. - 2192-2640 .- 2192-2659. ; 1:6, s. 707-713
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of how platelets store, sequester and release specific proteins seems to be implicated in many disease states, including cancer. Dual-color immunofluorescence stimulated emission depletion (STED) microscopy with 40 nm resolution is used to map pro-angiogenic VEGF, anti-angiogenic PF-4 and fibrinogen in >300 individual platelets. This reveals that these proteins are stored in a segmented, zonal manner within regional clusters, significantly smaller than the size of an alpha-granule. No colocalization between the different proteins is observed. Upon platelet activation by thrombin or ADP, the proteins undergo significant spatial rearrangements, including alterations in the size and number of the protein clusters, and specific for a certain protein and the type of activation induced. Following these observations, a simple assignment procedure is used to show that the three distinct states of platelets (non-, ADP- and thrombin-activated) can be identified based on the average size, number and peripheral localization profiles of the regional protein clusters within the platelets. Thus, high-resolution spatial mapping of specific proteins is a useful procedure to detect and characterize deviations in the selective storage, release and uptake of these proteins in the platelets. Since these deviations seem to be specific for, and may even underlie, certain patophysiological states, these findings may have interesting diagnostic and therapeutic implications.
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| 23. |
- Rönnlund, Daniel, 1984-, et al.
(författare)
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Multicolor Fluorescence Nanoscopy by Photobleaching : Concept Verification and its Application to Resolve Selective Storage of Proteins in Platelets
- 2014
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Ingår i: ACS Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 8:5, s. 4358-4365
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Tidskriftsartikel (refereegranskat)abstract
- Fluorescence nanoscopy provides means to discernthe finer details of protein localization and interaction in cells by offeringan order of magnitude higher resolution than conventional optical imagingtechniques. However, these super resolution techniques put higher demands onthe optical system as well as on the fluorescent probes, making multicolorfluorescence nanoscopy a challenging task. Here we present a new and simpleprocedure which exploits the photostability and excitation spectra of dyes toincrease the number of simultaneous recordable targets in STED nanoscopy. Weuse this procedure to demonstrate four color STED imaging of platelets with ≤40 nm resolution and low crosstalk. Platelets can selectively store, sequesterand release a multitude of different proteins, and in a manner specific fordifferent physiological and disease states. By applying multicolor nanoscopy tostudy platelets, we can achieve spatial mapping of the protein organizationwith a high resolution, for multiple proteins at the same time and in the samecell. This provides a means to identify specific platelet activation states fordiagnostic purposes and to understand the underlying protein storage andrelease mechanisms. We studied the organization of the pro- and anti-angiogenicproteins VEGF and PF-4 together with fibrinogen and filamentous actin, andfound distinct features in their respective protein localization. Further,colocalization analysis revealed only minor overlap between the proteins VEGFand PF-4 indicating that they have separate storage and release mechanisms,corresponding well with their opposite rules as pro- and anti-angiogenicproteins, respectively.
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| 24. |
- Rönnlund, Daniel, et al.
(författare)
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Spatial organization of proteins in metastasizing cells
- 2013
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Ingår i: Cytometry Part A. - : John Wiley & Sons. - 1552-4922 .- 1552-4930. ; 83:9, s. 855-865
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Tidskriftsartikel (refereegranskat)abstract
- The ability of tumor cells to invade into the surrounding tissue is linked to defective adhesive and mechanical properties of the cells, which are regulated by cell surface adhesions and the intracellular filamentous cytoskeleton, respectively. With the aim to further reveal the underlying mechanisms and provide new strategies for early cancer diagnostics, we have used ultrahigh resolution stimulated emission depletion (STED) microscopy as a means to identify metastasizing cells, based on their subcellular protein distribution patterns reflecting their specific adhesive and mechanical properties. We have compared the spatial distribution of cell-matrix adhesion sites and the vimentin filamentous systems in a matched pair of primary, normal, and metastatic human fibroblast cells. We found that the metastatic cells showed significantly increased densities and more homogenous distributions of nanoscale adhesion-related particles. Moreover, they showed an increase in the number but reduced sizes of the areas of cell-matrix adhesion complexes. The organization of the vimentin intermediate filaments was also found to be significantly different in the metastasizing cells, showing an increased entanglement and loss of directionality. Image analysis procedures were established, allowing an objective detection and characterization of these features and distinction of metastatic cells from their normal counterparts. In conclusion, our results suggest that STED microscopy provides a novel tool to identify metastasizing cells from a very sparse number of cells, based on the altered spatial distribution of the cell-matrix adhesions and intermediate filaments.
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| 25. |
- Rönnlund, Daniel, 1984-
(författare)
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Super resolution optical imaging – image analysis, multicolor development and biological applications
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on super resolution STED optical imaging. STED provides a wealth of new informational content to the acquired images by using stimulated emission to surpass the diffraction limit in optical fluorescence microscopy. To further increase the informational content, a new method to perform multicolor STED imaging by exploiting differences in the photostability and excitation spectra of dyes is presented. In order to extract information from the images, computational algorithms which handle the new type of high resolution informational content are developed.We propose that multicolor super resolution imaging in combination with image analysis can reduce the amount of clinical samples required to perform accurate cancer diagnosis. To date, such diagnosis is based mainly on significant amounts of tissue samples extracted from the suspected tumor site. The sample extraction often requires anesthetics and can lead to complications such as hematoma, infections and even cancer cell ceding along the needle track. We show that by applying multicolor STED and image analysis, the information gained from single cells is greatly increased. We therefore propose that accurate diagnosis can be based on significantly less extracted tissue material, allowing for a more patient friendly sampling. This approach can also be applied when studying blood platelets, where we show how the high informational content can be used to identify platelet specific activational states. Since platelets are involved in many different types of diseases, such analysis could provide means of performing truly minimally invasive diagnostics based on a simple blood test.In addition, our data makes it possible to understand in finer detail the underlying mechanisms rendering cells metastasis competent. We combine the high resolution spatial information provided by STED with information regarding the adhesive forces of cells measured by TFM (Traction Force Microscopy) and the cell stiffness measured by AFM (Atomic Force Microscopy). Such comparisons provide a link between the specific highly resolved protein distributions and different cellular mechanics and functions.This thesis also includes STED imaging and analysis on the spatial organization of neuronal synaptic regulating proteins, implicating the speed with which neuronal signaling can be regulated.
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| 26. |
- Rönnlund, Michael, et al.
(författare)
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Effects of Perceived Long-Term Stress on Subjective and Objective Aspects of Memory and Cognitive Functioning in a Middle-Aged Population-Based Sample
- 2013
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Ingår i: The Journal of Genetic Psychology. - : Taylor & Francis Group. - 0022-1325 .- 1940-0896. ; 174:1, s. 25-41
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Tidskriftsartikel (refereegranskat)abstract
- The longitudinal effects of perceived stress on measures of memory and two other cognitive functions (word fluency, visuospatial ability) in a middle-aged sample (40–60 years, M age = 47.1 years, SD = 6.1 years; n = 192) were examined. A group describing themselves as stressed in general at baseline, and at follow-up measurement 5 and 10 years later (n = 96) was compared with a matched (age, sex) low-stress group (n = 96). The results revealed more depressive symptoms over time in the high-stress group. With regard to memory, a dissociation between subjective and objective measures was observed. Specifically, participants in the high-stress group rated their memory as worse over time as compared with controls, and reported a higher frequency of occurrence of everyday memory failures, effects partly independent of depressive symptoms. However, the groups did not differ in terms of objective episodic memory performance, word fluency or block design performance, with stable levels of performance over time regardless of perceived stress. The lack of effects of stress on cognitive performance is discussed in the light of factors such as stress level, age of the participants, and other individual difference factors.
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| 27. |
- Sörman, Daniel, 1974-, et al.
(författare)
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Blood pressure levels and longitudinal changes in relation to social network factors : [Niveles de presión arterial y cambios longitudinales en relación con factores de la red social: ¿Mejor juntos o por separado?]
- 2016
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Ingår i: Psychological Topics. - : Faculty of Arts and Sciences in Rijeka. - 1332-0742. ; 25:1, s. 59-73
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine the relationship between social network variables and levels of and longitudinal changes in blood pressure in a middle-aged/older sample. The participants (50-75 years at baseline; n=1097) responded to questions concerning social relationships at baseline and their blood pressure (diastolic, systolic) was measured. Blood pressure levels were reassessed 5, 10, and 15 years later. Latent growth models with responses to questions concerning social relationships as predictors and basic demographic factors (age, sex) as covariates, unexpectedly indicated that a more limited social network (no close friend, few visits, little contact with friends in other ways, not living with someone, and a composite index based on all questions) was associated with significantly lower diastolic blood pressure levels. For systolic blood pressure a similar result was observed for one of the variables (lack of a close friend). In general, these effects diminished over time, as indexed by the positive relationship between several of the social variables and slope. The results were little affected by inclusion of additional covariates (e.g. measures of psychological distress, smoking/alcohol habits, and BMI) suggesting that the origins of this unexpected pattern of findings must probably be sought for in other subjectrelated factors, such as, for example, increased help seeking. Future studies should consider qualitative aspects (e.g. feelings of loneliness, quality of social relationships) in addition to structural aspects to provide a better understanding of these associations.
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| 28. |
- Sörman Eriksson, Daniel, et al.
(författare)
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Social network size and cognitive functioning in middle-aged adults : cross-sectional and longitudinal associations
- 2017
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Ingår i: Journal of Adult Development. - : Springer Science and Business Media LLC. - 1068-0667 .- 1573-3440. ; 24:2, s. 77-88
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Tidskriftsartikel (refereegranskat)abstract
- The objective of the present study was to examine relations between social network size and three cognitive abilities (episodic memory, semantic memory, visuospatial ability) in middle-aged adults. We analyzed cross-sectional data on social network size and cognitive functioning that were available for 804 participants aged 40–60 years. In addition, we examined 5- and 10-year follow-up measurements of cognitive functioning that were available for 604 and 255 participants, respectively. Cross-sectional analyses revealed a positive association between social network size and each of the three cognitive abilities. Baseline network size was positively related to 5-year changes in semantic memory, and to 10-year changes in semantic as well as episodic memory, but was unrelated to changes in visuospatial performance. A minor portion of the sample (n = 131) had 10-year follow-up data on network size. Cross-lagged panel correlations revealed that baseline network size was associated with follow-up measurement in cognitive functioning (episodic memory, semantic memory), whereas baseline cognitive performance was unrelated to future network size. Together, the results demonstrate a small but positive relation between network size and declarative memory abilities, in line with models proposing a cognitive reserve built up by factors such as the increased cognitive stimulation associated with a more extensive social network.
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| 29. |
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| 30. |
- Xu, Lei, et al.
(författare)
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Effects of resolution, target density and labeling on co-localization estimates – nanoscopy and modified algorithms to suppress false positives
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Co-localization analysis of fluorescence images is an important and extensively used tool to quantify molecular interactions in cells. In recent years, fluorescence nanoscopy techniques have made great progress and approach resolutions close to molecular dimensions. Although a strong increase in image resolution evidently influences different co-localization estimates it has to date not been systematically evaluated to what extent co-localization analyses can benefit from such techniques. . In this work, we apply simulations and resolution-tunable stimulated emission depletion (STED) microscopy to evaluate how resolution, molecular density and label size for the targeted molecules, as well as intensity variation and signal-to-noise ratio influence the estimates of the most commonly used co-localization algorithms (Pearson correlation coefficient, Manders M1 & M2 coefficients, and the image cross correlation spectroscopy (ICCS) method). We investigated the practically measureable extents of co-localization when using STED microscopy with positive and negative control samples and discussed the strengths and weaknesses of using nanoscopic techniques for co-localization studies. At a typical optical resolution of a confocal microscope (200-300 nm) our results indicate that the extent of co-localization is typically over-estimated by the tested algorithms, especially at high molecular densities. Only minor effects of this kind were observed at higher resolutions (< 60 nm). Apart from higher resolution, we introduced as an additional remedy a statistical variant of Costes threshold searching algorithm to set intensity thresholds separating background noise from signals. By this variant, combined with correlation-based methods like the Pearson coefficient and the ICCS approach, false positives at confocal resolutions and high molecular densities were found to be strongly suppressed.
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| 31. |
- Xu, Lei, et al.
(författare)
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Nanoscale analysis of cell-matrix adhesions
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Cell adhesion to the extracellular matrix is required for physiological processes, such as morphogenesis and wound healing. The cell adheres to the extracellular matrix via focal adhesions, which are considered to be cell adhesion organelles that govern cell function. However, the spatial architecture and organization of focal adhesions at a nanometer scale remain unclear. Therefore, we compared the spatial distribution of focal adhesion components within and outside of focal adhesions, using STED microscopy with resolution of 40-50nm. Our results are consistent with the concept that at the nanometer scale, adhesion proteins within but not outside of focal adhesions are composed by nanoscale protein clusters that attach to the extracellular matrix.
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| 32. |
- Xu, Lei, et al.
(författare)
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Nanoscale localization of proteins within focal adhesions indicates discrete functional assemblies with selective force-dependence
- 2018
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Ingår i: The FEBS Journal. - : WILEY. - 1742-464X .- 1742-4658. ; 285:9, s. 1635-1652
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Tidskriftsartikel (refereegranskat)abstract
- Focal adhesions (FAs) are subcellular regions at the micrometer scale that link the cell to the surrounding microenvironment and control vital cell functions. However, the spatial architecture of FAs remains unclear at the nanometer scale. We used two-color and three-color super-resolution stimulated emission depletion microscopy to determine the spatial distributions and co-localization of endogenous FA components in fibroblasts. Our data indicate that adhesion proteins inside, but not outside, FAs are organized into nanometer size units of multi-protein assemblies. The loss of contractile force reduced the nanoscale co-localization between different types of proteins, while it increased this co-localization between markers of the same type. This suggests that actomyosin-dependent force exerts a nonrandom, specific, control of the localization of adhesion proteins within cell-matrix adhesions. These observations are consistent with the possibility that proteins in cell-matrix adhesions are assembled in nanoscale particles, and that force regulates the localization of the proteins therein in a protein-specific manner. This detailed knowledge of how the organization of FA components at the nanometer scale is linked to the capacity of the cells to generate contractile forces expands our understanding of cell adhesion in health and disease.
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| 33. |
- Xu, Lei, et al.
(författare)
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Resolution, target density and labeling effects in colocalization studies - suppression of false positives by nanoscopy and modified algorithms
- 2016
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Ingår i: The FEBS Journal. - : Wiley-Blackwell. - 1742-464X .- 1742-4658. ; 283:5, s. 882-898
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Tidskriftsartikel (refereegranskat)abstract
- Colocalization analyses of fluorescence images are extensively used to quantify molecular interactions in cells. In recent years, fluorescence nanoscopy has approached resolutions close to molecular dimensions. However, the extent to which image resolution influences different colocalization estimates has not been systematically investigated. In this work, we applied simulations and resolution-tunable stimulated emission depletion microscopy to evaluate how the resolution, molecular density and label size of targeted molecules influence estimates of the most commonly used colocalization algorithms (Pearson correlation coefficient, Manders' M1 and M2 coefficients), as well as estimates by the image cross-correlation spectroscopy method. We investigated the practically measureable extents of colocalization for stimulated emission depletion microscopy with positive and negative control samples with an aim to identifying the strengths and weaknesses of nanoscopic techniques for colocalization studies. At a typical optical resolution of a confocal microscope (200-300 nm), our results indicate that the extent of colocalization is typically overestimated by the tested algorithms, especially at high molecular densities. Only minor effects of this kind were observed at higher resolutions (< 60 nm). By contrast, underestimation of colocalization may occur if the resolution is close to the size of the label/affinity molecules themselves. To suppress false positives at confocal resolutions and high molecular densities, we introduce a statistical variant of Costes' threshold searching algorithm, used in combination with correlation-based methods like the Pearson coefficient and the image cross-correlation spectroscopy approach, to set intensity thresholds separating background noise from signals.
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