| 1. |
- Santangelo, James S., et al.
(författare)
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Global urban environmental change drives adaptation in white clover
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
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Tidskriftsartikel (refereegranskat)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 2. |
- Falster, Daniel, et al.
(författare)
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AusTraits, a curated plant trait database for the Australian flora
- 2021
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Ingår i: Scientific Data. - : Nature Portfolio. - 2052-4463. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- We introduce the AusTraits database - a compilation of values of plant traits for taxa in the Australian flora (hereafter AusTraits). AusTraits synthesises data on 448 traits across 28,640 taxa from field campaigns, published literature, taxonomic monographs, and individual taxon descriptions. Traits vary in scope from physiological measures of performance (e.g. photosynthetic gas exchange, water-use efficiency) to morphological attributes (e.g. leaf area, seed mass, plant height) which link to aspects of ecological variation. AusTraits contains curated and harmonised individual- and species-level measurements coupled to, where available, contextual information on site properties and experimental conditions. This article provides information on version 3.0.2 of AusTraits which contains data for 997,808 trait-by-taxon combinations. We envision AusTraits as an ongoing collaborative initiative for easily archiving and sharing trait data, which also provides a template for other national or regional initiatives globally to fill persistent gaps in trait knowledge.
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| 3. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 4. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 5. |
- Bass, Joseph J., et al.
(författare)
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Overexpression of the vitamin D receptor (VIM) induces skeletal muscle hypertrophy
- 2020
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Ingår i: Molecular Metabolism. - : Elsevier. - 2212-8778. ; 42
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The Vitamin D receptor (VDR) has been positively associated with skeletal muscle mass, function and regeneration. Mechanistic studies have focused on the loss of the receptor, with in vivo whole-body knockout models demonstrating reduced myofibre size and function and impaired muscle development. To understand the mechanistic role upregulation of the VDR elicits in muscle mass/health, we studied the impact of VDR over-expression (OE) in vivo before exploring the importance of VDR expression upon muscle hypertrophy in humans.Methods: Wistar rats underwent in vivo electrotransfer (IVE) to overexpress the VDR in the Tibialis anterior (TA) muscle for 10 days, before comprehensive physiological and metabolic profiling to characterise the influence of VDR-OE on muscle protein synthesis (MPS), anabolic signalling and satellite cell activity. Stable isotope tracer (D2O) techniques were used to assess sub-fraction protein synthesis, alongside RNA-Seq analysis. Finally, human participants underwent 20 wks of resistance exercise training, with body composition and transcriptomic analysis.Results: Muscle VDR-OE yielded total protein and RNA accretion, manifesting in increased myofibre area, i.e., hypertrophy. The observed increases in MPS were associated with enhanced anabolic signalling, reflecting translational efficiency (e.g., mammalian target of rapamycin (mTOR-signalling), with no effects upon protein breakdown markers being observed. Additionally, RNA-Seq illustrated marked extracellular matrix (ECM) remodelling, while satellite cell content, markers of proliferation and associated cell-cycled related gene-sets were upregulated. Finally, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise type training.Conclusion: VDR-OE stimulates muscle hypertrophy ostensibly via heightened protein synthesis, translational efficiency, ribosomal expansion and upregulation of ECM remodelling-related gene-sets. Furthermore, VDR expression is a robust marker of the hypertrophic response to resistance exercise in humans. The VDR is a viable target of muscle maintenance through testable Vitamin D molecules, as active molecules and analogues. (C) 2020 The Author(s). Published by Elsevier GmbH.
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| 6. |
- Bass, Joseph J., et al.
(författare)
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The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo
- 2021
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Ingår i: Journal of Physiology. - : John Wiley & Sons. - 0022-3751 .- 1469-7793. ; 599:3, s. 963-979
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Tidskriftsartikel (refereegranskat)abstract
- KEY POINTS:Reduced vitamin D receptor (VDR) expression prompts skeletal muscle atrophy.Atrophy occurs through catabolic processes, namely the induction of autophagy, while anabolism remains unchanged.In response to VDR-KD mitochondrial function and related gene-set expression is impaired.In vitro VDR knockdown induces myogenic dysregulation occurring through impaired differentiation.These results highlight the autonomous role the VDR has within skeletal muscle mass regulation.Objective: Vitamin-D deficiency is estimated to affect ∼40% of the world's population and has been associated with impaired muscle maintenance. Vitamin-D exerts its actions through the Vitamin-D-receptor (VDR), the expression of which was recently confirmed in skeletal muscle, and its down-regulation is linked to reduced muscle mass and functional decline. To identify potential mechanisms underlying muscle atrophy, we studied the impact of VDR knockdown (KD) on mature skeletal muscle in vivo, and myogenic regulation in vitro in C2C12 cells.Methods: Male Wistar rats underwent in vivo electrotransfer (IVE) to knock down the VDR in hind-limb tibialis anterior (TA) muscle for 10 days. Comprehensive metabolic and physiological analysis was undertaken to define the influence loss of the VDR on muscle fibre composition, protein synthesis, anabolic and catabolic signalling, mitochondrial phenotype, and gene expression. Finally, in vitro lentiviral transfection was used to induce sustained VDR-KD in C2C12 cells to analyse myogenic regulation.Results: Muscle VDR-KD elicited atrophy through a reduction in total protein content, resulting in lower myofibre area. Activation of autophagic processes was observed, with no effect upon muscle protein synthesis or anabolic signalling. Furthermore, RNA-Seq analysis identified systematic down-regulation of multiple mitochondrial respiration related protein and genesets. Finally, in vitro VDR-knockdown impaired myogenesis (cell cycling, differentiation and myotube formation).Conclusion: Taken together, these data indicate a fundamental regulatory role of the VDR in the regulation of myogenesis and muscle mass; whereby it acts to maintain muscle mitochondrial function and limit autophagy.
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| 7. |
- Gonzalez-Robles, Cristina, et al.
(författare)
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Embedding Patient Input in Outcome Measures for Long-Term Disease-Modifying Parkinson Disease Trials
- 2024
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Ingår i: Movement Disorders. - 0885-3185 .- 1531-8257. ; 39:2, s. 433-438
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. Objectives: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. Methods: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. Results: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. Conclusions: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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| 8. |
- Gonzalez-Robles, Cristina, et al.
(författare)
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Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative
- 2023
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Ingår i: JOURNAL OF PARKINSONS DISEASE. - 1877-7171 .- 1877-718X. ; 13:6, s. 1013-1035
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. Objective: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. Methods: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. Results: An extensive inventory ofOMwas created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. Conclusion: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.
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| 9. |
- Brook, Matthew S, et al.
(författare)
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Neither myonuclear accretion nor a myonuclear domain size ceiling is a feature of the attenuated hypertrophic potential of aged human skeletal muscle
- 2023
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Ingår i: GeroScience. - : Springer. - 2509-2715 .- 2509-2723. ; 45, s. 451-462
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Tidskriftsartikel (refereegranskat)abstract
- Ageing limits growth capacity of skeletal muscle (e.g. in response to resistance exercise), but the role of satellite cell (SC) function in driving this phenomenon is poorly defined. Younger (Y) (~ 23 years) and older (O) men (~ 69 years) (normal-weight BMI) underwent 6 weeks of unilateral resistance exercise training (RET). Muscle biopsies were taken at baseline and after 3-/6-week training. We determined muscle size by fibre CSA (and type), SC number, myonuclei counts and DNA synthesis (via D2O ingestion). At baseline, there were no significant differences in fibre areas between Y and O. RET increased type I fibre area in Y from baseline at both 3 weeks and 6 weeks (baseline: 4509 ± 534 µm2, 3 weeks; 5497 ± 510 µm2 P < 0.05, 6 weeks; 5402 ± 352 µm2 P < 0.05), whilst O increased from baseline at 6 weeks only (baseline 5120 ± 403 µm2, 3 weeks; 5606 ± 620 µm2, 6 weeks; 6017 ± 482 µm2 P < 0.05). However, type II fibre area increased from baseline in Y at both 3 weeks and 6 weeks (baseline: 4949 ± 459 µm2, 3 weeks; 6145 ± 484 µm2 (P < 0.01), 6 weeks; 5992 ± 491 µm2 (P < 0.01), whilst O showed no change (baseline 5210 ± 410 µm2, 3 weeks; 5356 ± 535 µm2 (P = 0.9), 6 weeks; 5857 ± 478 µm2 (P = 0.1). At baseline, there were no differences in fibre myonuclei number between Y and O. RET increased type I fibre myonuclei number from baseline in both Y and O at 3 weeks and 6 weeks with RET (younger: baseline 2.47 ± 0.16, 3 weeks; 3.19 ± 0.16 (P < 0.001), 6 weeks; 3.70 ± 0.29 (P < 0.0001); older: baseline 2.29 ± 0.09, 3 weeks; 3.01 ± 0.09 (P < 0.001), 6 weeks; 3.65 ± 0.18 (P < 0.0001)). Similarly, type II fibre myonuclei number increased from baseline in both Y and O at 3 weeks and 6 weeks (younger: baseline 2.49 ± 0.14, 3 weeks; 3.31 ± 0.21 (P < 0.001), 6 weeks; 3.86 ± 0.29 (P < 0.0001); older: baseline 2.43 ± 0.12, 3 weeks; 3.37 ± 0.12 (P < 0.001), 6 weeks; 3.81 ± 0.15 (P < 0.0001)). DNA synthesis rates %.d-1 exhibited a main effect of training but no age discrimination. Declines in myonuclei addition do not underlie impaired muscle growth capacity in older humans, supporting ribosomal and proteostasis impairments as we have previously reported.
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| 10. |
- Gharahdaghi, Nima, et al.
(författare)
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Pharmacological hypogonadism impairs molecular transducers of exercise-induced muscle growth in humans
- 2022
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Ingår i: Journal of Cachexia, Sarcopenia and Muscle. - : John Wiley & Sons. - 2190-5991 .- 2190-6009. ; 13:2, s. 1134-1150
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The relative role of skeletal muscle mechano-transduction in comparison with systemic hormones, such as testosterone (T), in regulating hypertrophic responses to exercise is contentious. We investigated the mechanistic effects of chemical endogenous T depletion adjuvant to 6 weeks of resistance exercise training (RET) on muscle mass, function, myogenic regulatory factors, and muscle anabolic signalling in younger men.METHODS: Non-hypogonadal men (n = 16; 18-30 years) were randomized in a double-blinded fashion to receive placebo (P, saline n = 8) or the GnRH analogue, Goserelin [Zoladex (Z), 3.6 mg, n = 8], injections, before 6 weeks of supervised whole-body RET. Participants underwent dual-energy X-ray absorptiometry (DXA), ultrasound of m. vastus lateralis (VL), and VL biopsies for assessment of cumulative muscle protein synthesis (MPS), myogenic gene expression, and anabolic signalling pathway responses.RESULTS: Zoladex suppressed endogenous T to within the hypogonadal range and was well tolerated; suppression was associated with blunted fat free mass [Z: 55.4 ± 2.8 to 55.8 ± 3.1 kg, P = 0.61 vs. P: 55.9 ± 1.7 to 57.4 ± 1.7 kg, P = 0.006, effect size (ES) = 0.31], composite strength (Z: 40 ± 2.3% vs. P: 49.8 ± 3.3%, P = 0.03, ES = 1.4), and muscle thickness (Z: 2.7 ± 0.4 to 2.69 ± 0.36 cm, P > 0.99 vs. P: 2.74 ± 0.32 to 2.91 ± 0.32 cm, P < 0.0001, ES = 0.48) gains. Hypogonadism attenuated molecular transducers of muscle growth related to T metabolism (e.g. androgen receptor: Z: 1.2 fold, P > 0.99 vs. P: 1.9 fold, P < 0.0001, ES = 0.85), anabolism/myogenesis (e.g. IGF-1Ea: Z: 1.9 fold, P = 0.5 vs. P: 3.3 fold, P = 0.0005, ES = 0.72; IGF-1Ec: Z: 2 fold, P > 0.99 vs. P: 4.7 fold, P = 0.0005, ES = 0.68; myogenin: Z: 1.3 fold, P > 0.99 vs. P: 2.7 fold, P = 0.002, ES = 0.72), RNA/DNA (Z: 0.47 ± 0.03 to 0.53 ± 0.03, P = 0.31 vs. P: 0.50 ± 0.01 to 0.64 ± 0.04, P = 0.003, ES = 0.72), and RNA/ASP (Z: 5.8 ± 0.4 to 6.8 ± 0.5, P > 0.99 vs. P: 6.5 ± 0.2 to 8.9 ± 1.1, P = 0.008, ES = 0.63) ratios, as well as acute RET-induced phosphorylation of growth signalling proteins (e.g. AKTser473 : Z: 2.74 ± 0.6, P = 0.2 vs. P: 5.5 ± 1.1 fold change, P < 0.001, ES = 0.54 and mTORC1ser2448 : Z: 1.9 ± 0.8, P > 0.99 vs. P: 3.6 ± 1 fold change, P = 0.002, ES = 0.53). Both MPS (Z: 1.45 ± 0.11 to 1.50 ± 0.06%·day-1 , P = 0.99 vs. P: 1.5 ± 0.12 to 2.0 ± 0.15%·day-1 , P = 0.01, ES = 0.97) and (extrapolated) muscle protein breakdown (Z: 93.16 ± 7.8 vs. P: 129.1 ± 13.8 g·day-1 , P = 0.04, ES = 0.92) were reduced with hypogonadism result in lower net protein turnover (3.9 ± 1.1 vs. 1.2 ± 1.1 g·day-1 , P = 0.04, ES = 0.95).CONCLUSIONS: We conclude that endogenous T sufficiency has a central role in the up-regulation of molecular transducers of RET-induced muscle hypertrophy in humans that cannot be overcome by muscle mechano-transduction alone.
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