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- Revêchon, Gwladys
(author)
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Molecular insights into Hutchinson-Gilford progeria syndrome and age-associated disease : from mechanisms to treatment strategy
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Aging is a complex process that occurs as we grow old and is associated with a gradual decline of tissue functions. Scientists have been trying to understand the mechanisms that drive such phenomenon by studying premature aging syndromes and aging-related disorders. The Hutchinson-Gilford progeria syndrome (HGPS) is a lethal segmental genetic disease affecting children at an early age and characterized by accelerated aging-like features including alopecia, loss of subcutaneous adipose tissue and cardiovascular pathologies. This disorder primarily results from the production of a noxious protein called progerin, altering proper tissue homeostasis and functions. Strikingly, HGPS children present an accelerated vascular aging phenotype similar to that of chronic kidney disease (CKD) patients. Indeed, in addition to displaying kidney defects, CKD patients exhibit an accelerated vascular decline. Interestingly, progerin has previously been found expressed in cells and tissues from aged individuals, but its contribution to aging and aging-associated disorders remains poorly understood. Here, we investigated whether and how various levels of progerin are relevant to the development and progression of tissue pathology in HGPS, normal aging and aging-associated diseases, in order to generate a potential new treatment strategy for HGPS in particular. In paper I, to better understand the mechanisms by which progerin accumulation disrupts tissue homeostasis, a humanized HGPS mouse model with overexpression of progerin in the skin was used. We demonstrated that progerin accumulation resulted in impaired tissue homeostasis as a consequence of an aberrant increase in symmetric cell division. Further analysis suggested a potential causal role of the Wnt/β-catenin signaling, associated with mislocalization of the nuclear envelope proteins emerin and nesprin-2. In paper II, to investigate whether a small fraction of progerin-expressing cells in a tissue can lead to tissue pathology during aging, another humanized HGPS mouse model was employed. We showed that continuous expression of progerin in only a few preadipocytes and adipocytes is associated with fibrosis and lipoatrophy over time. This phenotype was combined with increased senescence, persistent DNA damage and cell death, which were found accompanied by macrophage infiltration and systemic inflammation. These results suggested that progerin, despite being expressed in only a low fraction of the cells of a tissue, has the potential to contribute to a common aging-associated phenotype. In paper III, to unravel the possible involvement of progerin expression in age-associated diseases, we used arterial biopsies and blood from CKD patients. We found that progerin was expressed at low frequencies in 70% of the CKD patients arteries (in up to 7.4% of the cells), which was associated with an increase in DNA damage. When searching for the cause of progerin expression, we identified the LMNA c.1824C>T mutation in both the blood and arteries. Our data further suggested that progerinexpressing cells might arise during vascular regeneration, by proliferation of progenitor cells. In paper IV, to examine the mechanisms associated with telomere dysfunction in HGPS, we employed various in vitro systems and a severe progeroid mouse model of skin. We demonstrated that telomere dysfunction leads to the production of non-coding RNAs, which activates the DNA damage response signaling. Treatment with telomeric sequence-specific antisense oligonucleotides not only repressed this signaling, but also significantly improved both the healthspan and lifespan of HGPS mice. This thesis provides novel findings about the complex molecular mechanisms underlying progerin expression in HGPS, and its possible contribution to aging and CKD-related early vascular aging, all of which led to the discovery of a potential new treatment approach for HGPS.
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| 2. |
- Goepfert, Caroline, et al.
(author)
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Elite cross-country skiers’ adaptations of the diagonal stride technique at different inclinations
- 2009
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Conference paper (peer-reviewed)abstract
- Introduction: Despite the equal relevance of classic and freestyle in modern cross-country skiing, the main focus of biomechanical studies has mainly been on the latter technique. Diagonal stride [DIA] as a main classical technique has further developed over the last 20 years. There is still a lack of biomechanical data describing DIA and adaptations to different inclinations. A previous study showed that skiers increased cycle rate rather than cycle length as the strategy to adapt to increasing inclinations (Bilodeau et al. 1992). However, no kinetic or joint kinematic data were presented. The aim of the present study was to identify kinetic and kinematic adaptations in DIA at different inclinations. Methods: Twelve elite XC skiers (Swedish National Team; VO2max-DIA: 72.3 ± 3.8 ml·kg-1·min-1) performed DIA roller skiing at treadmill inclinations of 3°, 6° and 9° at 11 km·h-1 for biomechanical analyses. Leg and arm joint angles (goniometers), pole force (strain gauge), both at 2000 Hz, and plantar force (Pedar Mobile) at 100 Hz were recorded. Repeated measures ANOVA were calculated in order to examine the biomechanical differences between the named inclinations. The statistical level of significance was set at P<0.05. Results: Cycle time [CT] (P<0.01) and relative (%CT) arm recovery time (P<0.05) decreased at higher inclinations. Cycle rate and relative poling time both increased (both P<0.01). No differences were found for the relative durations of leg-ground contact and leg swing. All the force values measured were greatest at the steepest inclination, including peak pole and leg forces, forefoot force in ground position and impulses of pole and leg push-off (all P<0.01). Elbow [EA], hip [HA] and knee [KA] angle minima, EA at pole plant, KA at ski plant and HAmaximum before push-off decreased (all P<0.01). The elbow extension range of motion [ROM] and knee (both P<0.01), as well as hip push-off extension ROM (P<0.05), increased with inclination. Angular push-off flexion velocity (P<0.01) decreased, along with higher angular push-off extension velocities in the ankle (P<0.05), knee and hip joints (both P<0.01) at steeper inclinations. Conclusion: Elite skiers adapt the DIA technique to increased inclinations through substantial changes in pole and leg kinetics and joint kinematics, with only minor changes in specific phase durations. Arm and leg actions show larger amplitudes, higher angular velocities, longer poling times, higher forces and impulses generated at higher frequencies. We suggest that XC skiers should use technique, endurance and strength training at different inclinations in order to train these aspects specifically.
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| 3. |
- Cricchio, Giovanni, 1968-, et al.
(author)
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Sinus bone formation and implant survival after sinus membrane elevation and implant placement: a 1- to 6-year follow-up study.
- 2011
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In: Clinical oral implants research. - Copenhagen : Wiley. - 1600-0501 .- 0905-7161. ; 22:10, s. 1200-1212
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Journal article (peer-reviewed)abstract
- Objectives: To investigate the long-term clinical and radiographic results of the maxillary sinus membrane elevation technique where implants were inserted in a void space created by the elevation of the sinus membrane without adding any graft material. Materials and methods: A total of 84 patients were subjected to 96 membrane elevation procedures and simultaneous placement of 239 implants. Changes of intra-sinus and marginal bone height in relation to the implants were measured in intraoral radiographs taken at insertion, after 6 months of healing, after 6 months of loading and then annually. Computerized tomography was performed pre-surgically and 6 months post-surgically. Resonance Frequency Analyses measurements were performed at the time of implants placement, at abutment connection and after 6 months of loading. The implant follow-up period ranged from a minimum of one to a maximum of 6 years after implants loading. Results: All implants were stable after 6 months of healing. A total of three implants were lost during the follow-up period giving a survival rate of 98.7%. Radiography demonstrated on average 5.3±2.1 mm of intra-sinus new bone formation after 6 months of healing. RFA measurements showed adequate primary stability (implant stability quotient 67.4±6.1) and small changes over time. Conclusion: Maxillary sinus membrane elevation and simultaneous placement of implants without the use of bone grafts or bone substitutes result in predictable bone formation with a high implant survival rate of 98.7% during a follow-up period of up to 6 years. The intra-sinus bone formation remained stable in the long-term follow-up. It is suggested that the secluded compartment allowed for bone formation according to the principle of guided tissue regeneration. The high implant survival rate of 98.7% indicated that the implants sufficiently supported the fixed bridges throughout the study period. This technique reduces the risks for morbidity related to harvesting of bone grafts and eliminates the costs of grafting materials.
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| 6. |
- Mills, G., et al.
(author)
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A synthesis of AOT40-based response functions and critical levels of ozone for agricultural and horticultural crops
- 2007
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In: Atmospheric Environment. - : Elsevier BV. - 1352-2310. ; 41:12, s. 2630-2643
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Journal article (peer-reviewed)abstract
- Crop-response data from over 700 published papers and conference proceedings have been analysed with the aim of establishing ozone dose-response functions for a wide range of European agricultural and horticultural crops. Data that met rigorous selection criteria (e.g. field-based, ozone concentrations within European range, full season exposure period) were used to derive AOT40-yield response functions for 19 crops by first converting the published ozone concentration data into AOT40 (AOT40 is the hourly mean ozone concentration accumulated over a threshold ozone concentration of 40ppb during daylight hours, units ppmh). For any individual crop, there were no significant differences in the linear response functions derived for experiments conducted in the USA or Europe, or for individual cultivars. Three statistically independent groups were identified: ozone sensitive crops (wheat, water melon, pulses, cotton, turnip, tomato, onion, soybean and lettuce); moderately sensitive crops (sugar beet, potato, oilseed rape, tobacco, rice, maize, grape and broccoli) and ozone resistant (barley and fruit represented by plum and strawberry). Critical levels of a 3 month AOT40 of 3 ppm It and a 3.5 month AOT40 of 6ppm h were derived from the functions for wheat and tomato, respectively. (c) 2006 Elsevier Ltd. All rights reserved.
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| 7. |
- Ferreira, Luiz Kobuti, et al.
(author)
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Functional connectivity in behavioral variant frontotemporal dementia
- 2022
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In: Brain and Behavior. - : Wiley. - 2162-3279. ; 12:12
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Research review (peer-reviewed)abstract
- Introduction: Functional connectivity (FC)—which reflects relationships between neural activity in different brain regions—has been used to explore the functional architecture of the brain in neurodegenerative disorders. Although an increasing number of studies have explored FC changes in behavioral variant frontotemporal dementia (bvFTD), there is no focused, in-depth review about FC in bvFTD. Methods: Comprehensive literature search and narrative review to summarize the current field of FC in bvFTD. Results: (1) Decreased FC within the salience network (SN) is the most consistent finding in bvFTD; (2) FC changes extend beyond the SN and affect the interplay between networks; (3) results within the Default Mode Network are mixed; (4) the brain as a network is less interconnected and less efficient in bvFTD; (5) symptoms, functional impairment, and cognition are associated with FC; and (6) the functional architecture resembles patterns of neuropathological spread. Conclusions: FC has potential as a biomarker, and future studies are expected to advance the field with multicentric initiatives, longitudinal designs, and methodological advances.
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| 9. |
- Macassa, Gloria, et al.
(author)
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Trends in infant and child mortality in Mozambique during and after a period ofconflict
- 2003
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In: Public Health. - 0033-3506 .- 1476-5616. ; 117:4, s. 221-227
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Journal article (peer-reviewed)abstract
- This study describes urban and rural trends of infant, child and under-five mortality in Mozambique (1973–1997) by mother's place of residence. A direct method of estimation was applied to the 1997 Mozambican Demographic and Health Survey data. The levels of infant, child and under-five mortality were considerably higher in rural than in urban areas. The difference in mortality between urban and rural areas increased over time until 1988–1992 and thereafter diminished. Possible causes of the different trends (e.g. the impact of civil war, drought, migration, adjustment programme and HIV/AIDS) are discussed. The increase in mortality in urban areas during the last few years before the survey may have been related to the immigration to urban areas of mothers whose children had high levels of mortality. Higher levels of infant, child and under-five mortality still prevail, particularly in rural areas. Further studies are needed to investigate the differentials of infant and child mortality by mother's place of residence.
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| 10. |
- Patel, Pankaj C., et al.
(author)
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Caste-Based Discrimination, Microfinance Credit Scores, and Microfinance Loan Approvals Among Females in India
- 2022
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In: Business & society. - : Sage Publications. - 0007-6503 .- 1552-4205. ; 61:2, s. 372-388
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Journal article (peer-reviewed)abstract
- We draw on the phenomenon of caste-based discrimination in India and signaling theory to assess whether microfinance credit scores improve the odds of female micropreneurs from a lower caste receiving loans and whether visible business characteristics further improve the odds of receiving microfinance loans. In a sample of 3,144 female microfinance loan applicants at a female-focused microloan enterprise in India, females from a lower caste, relative to those from a higher caste, have lower odds of receiving loans when their credit scores are below the mean. However, when females from a lower caste have credit scores higher than the mean, the odds of receiving a loan increase. The practical effect of size is small but meaningful. Loan applicants from a lower caste with a visible signal of business ability do not improve their chances of receiving a loan relative to those from a higher caste.
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