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- Gustavsson, Emil K., et al.
(författare)
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The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1
- 2024
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Ingår i: Science Advances. - 2375-2548. ; 10:26, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson’s disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function—yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.
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| 2. |
- Iliodromiti, Stamatina, et al.
(författare)
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Liver, visceral and subcutaneous fat in men and women of South Asian and white European descent : a systematic review and meta-analysis of new and published data
- 2023
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 66:1, s. 44-56
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Forskningsöversikt (refereegranskat)abstract
- Aims/hypothesis South Asians have a two- to fivefold higher risk of developing type 2 diabetes than those of white European descent. Greater central adiposity and storage of fat in deeper or ectopic depots are potential contributing mechanisms. We collated existing and new data on the amount of subcutaneous (SAT), visceral (VAT) and liver fat in adults of South Asian and white European descent to provide a robust assessment of potential ethnic differences in these factors. Methods We performed a systematic review of the Embase and PubMed databases from inception to August 2021. Unpublished imaging data were also included. The weighted standardised mean difference (SMD) for each adiposity measure was estimated using random-effects models. The quality of the studies was assessed using the ROBINS-E tool for risk of bias and overall certainty of the evidence was assessed using the GRADE approach. The study was pre-registered with the OSF Registries (https://osf. io/w5bf9). Results We summarised imaging data on SAT, VAT and liver fat from eight published and three previously unpublished datasets, including a total of 1156 South Asian and 2891 white European men, and 697 South Asian and 2271 white European women. Despite South Asian men having a mean BMI approximately 0.5-0.7 kg/m(2) lower than white European men (depending on the comparison), nine studies showed 0.34 SMD (95% CI 0.12, 0.55; I-2 =83%) more SAT and seven studies showed 0.56 SMD (95% CI 0.14, 0.98; I-2 =93%) more liver fat, but nine studies had similar VAT (-0.03 SMD; 95% CI -0.24, 0.19;1 2 =85%) compared with their white European counterparts. South Asian women had an approximately 0.9 kg/m(2) lower BMI but 0.31 SMD (95% CI 0.14, 0.48; I-2=53%) more liver fat than their white European counterparts in five studies. Subcutaneous fat levels (0.03 SMD; 95% CI -0.17, 0.23; I-2 =72%) and VAT levels (0.04 SMD; 95% CI -0.16, 0.24; I-2 =71%) did not differ significantly between ethnic groups in eight studies of women. Conclusions/interpretation South Asian men and women appear to store more ectopic fat in the liver compared with their white European counterparts with similar BMI levels. Given the emerging understanding of the importance of liver fat in diabetes pathogenesis, these findings help explain the greater diabetes risks in South Asians.
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| 3. |
- Massaro, Giulia, et al.
(författare)
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Fetal gene therapy for neurodegenerative disease of infants
- 2018
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 24:9, s. 1317-1323
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Tidskriftsartikel (refereegranskat)abstract
- For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood–brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains.
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| 4. |
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| 5. |
- Watkins, Jonathan, et al.
(författare)
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Pacing Strategies and Metabolic Responses During 4-Minute Running Time-Trials
- 2017
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Ingår i: International Journal of Sports Physiology and Performance. - : Human Kinetics. - 1555-0265 .- 1555-0273. ; 12:9, s. 1143-1150
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The aim of the current study was to investigate pacing strategies and the distributionof physiological resources in best versus worst performances during a series of 4-minute, self-paced running time-trials (RunTTs). Methods: Five male and five female recreational runners(age 32 ± 7 years) completed a sub-maximal ramp test and five RunTTs on a motor-driventreadmill fitted with a speed-controlling laser system. The supramaximal V̇ O2 demand wasestimated by linear extrapolation from the sub-maximal relationship between V̇ O2 and speed,enabling computation of the accumulated oxygen deficit (AOD). Results: There were nosignificant differences between the five RunTTs for any of the performance, physiological orsubjective responses (P > 0.05). The trial-to-trial variability in pacing (i.e., separate quarters)was typically low, with an average within-athlete CV of 3.3%, being highest at the start andend of the 4 minutes. Total distance covered and distance covered over the first and last 2minutes for best and worst performances were 1137 ± 94 and 1090 ± 89 m (P < 0.001), 565 ±53 and 526 ± 40 m (P = 0.002), and 572 ± 47 and 565 ± 54 m (P = 0.346), respectively.Conclusions: Negative pacing strategies were evident during both the best and worstperformances of the RunTT. Best performances were characterised by more aggressive pacingover the first 2 minutes compared with worst performances. In addition, the relatively low trial-to-trial variability in running speed suggests that pacing strategies are similar during a seriesof 4-minute, self-paced running time-trials.
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