| 1. |
- Al-Khalili, Lubna, et al.
(författare)
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Profiling of human myotubes reveals an intrinsic proteomic signature associated with type 2 diabetes
- 2014
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Ingår i: Translational Proteomics. - : Elsevier BV. - 2212-9634 .- 2212-9626. ; 2:1, s. 25-38
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Tidskriftsartikel (refereegranskat)abstract
- The development of insulin resistance and type 2 diabetes (T2D) involves a complex array of metabolic defects in skeletal muscle. An in vitro cell culture system excludes the acute effects of external systemic factors existing in vivo. Thus, we aimed to determine whether intrinsic differences in the protein profile exist in cultured myotubes derived from T2D versus normal glucose tolerant (NGT) healthy people. Applying two dimensional difference gel electrophoresis technology (2-D DIGE), the abundance of 47 proteins differed in myotubes derived from T2D patients versus NGT donors. Proteins involved in fatty acid and amino acid metabolism, TCA cycle, mitochondrial function, mRNA processing, DNA repair and cell survival showed higher abundance, while proteins associated with redox signaling (PARK7; Parkinson disease 7), glutathione metabolism (glutathione S-transferase, GST, isoforms T1, P1 and M2), and protein dynamics (heat shock protein, HSP, isoform B1 and 90A) showed reduced abundance in myotubes derived from T2D versus NGT donors. Consistent with our proteome analysis results, the level of total glutathione was reduced in myotubes obtained from T2D versus NGT donors. Taken together, our data provide evidence for intrinsic differences in the profile of proteins involved in energy metabolism, cellular oxidative stress, protein dynamics and gene regulation in myotubes derived from T2D patients. These differences thereby suggest a genetic or epigenetic influence on protein content level, which can be further investigated to understand the molecular underpinnings of T2D progression and lead to new therapeutic approaches.
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| 2. |
- Al-Khalili, L, et al.
(författare)
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Proteasome inhibition in skeletal muscle cells unmasks metabolic derangements in type 2 diabetes
- 2014
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Ingår i: American journal of physiology. Cell physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 307:9, s. C774-C787
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Tidskriftsartikel (refereegranskat)abstract
- Two-dimensional difference gel electrophoresis (2-D DIGE)-based proteome analysis has revealed intrinsic insulin resistance in myotubes derived from type 2 diabetic patients. Using 2-D DIGE-based proteome analysis, we identified a subset of insulin-resistant proteins involved in protein turnover in skeletal muscle of type 2 diabetic patients, suggesting aberrant regulation of the protein homeostasis maintenance system underlying metabolic disease. We then validated the role of the ubiquitin-proteasome system (UPS) in myotubes to investigate whether impaired proteasome function may lead to metabolic arrest or insulin resistance. Myotubes derived from muscle biopsies obtained from people with normal glucose tolerance (NGT) or type 2 diabetes were exposed to the proteasome inhibitor bortezomib (BZ; Velcade) without or with insulin. BZ exposure increased protein carbonylation and lactate production yet impaired protein synthesis and UPS function in myotubes from type 2 diabetic patients, marking the existence of an insulin-resistant signature that was retained in cultured myotubes. In conclusion, BZ treatment further exacerbates insulin resistance and unmasks intrinsic features of metabolic disease in myotubes derived from type 2 diabetic patients. Our results highlight the existence of a confounding inherent abnormality in cellular protein dynamics in metabolic disease, which is uncovered through concurrent inhibition of the proteasome system.
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| 3. |
- BarboSá, D., et al.
(författare)
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A sustainable approach to large ICT science based infrastructures: The case for radio astronomy
- 2014
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Ingår i: 2014 IEEE International Energy Conference, ENERGYCON 2014; Dubrovnik; Croatia; 13 May 2014 through 16 May 2014. - 9781479924493 ; , s. 668-674
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Konferensbidrag (refereegranskat)abstract
- Large sensor-based infrastructures for radio astronomy will be among the most intensive data-driven projects in the world, facing very high power demands. The geographically wide distribution of these infrastructures and their associated processing High Performance Computing (HPC) facilities require Green Information and Communications Technologies (ICT): a combination is needed of low power computing, power and byte efficient data storage, local data services, Smart Grid power management, and inclusion of Renewable Energies. Here we outline the major characteristics and innovation approaches to address power efficiency and long-term power sustainability for radio astronomy projects, focusing on Green ICT for science.
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| 4. |
- Pinto, Dalila, et al.
(författare)
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Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.
- 2014
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Ingår i: American journal of human genetics. - : Elsevier BV. - 1537-6605 .- 0002-9297. ; 94:5, s. 677-694
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Tidskriftsartikel (refereegranskat)abstract
- Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0× 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7× 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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| 5. |
- Zemp, D. C., et al.
(författare)
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On the importance of cascading moisture recycling in South America
- 2014
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 14:23, s. 13337-13359
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Tidskriftsartikel (refereegranskat)abstract
- Continental moisture recycling is a crucial process of the South American climate system. In particular, evapotranspiration from the Amazon basin contributes substantially to precipitation regionally as well as over other remote regions such as the La Plata basin. Here we present an in-depth analysis of South American moisture recycling mechanisms. In particular, we quantify the importance of cascading moisture recycling (CMR), which describes moisture transport between two locations on the continent that involves re-evaporation cycles along the way. Using an Eulerian atmospheric moisture tracking model forced by a combination of several historical climate data sets, we were able to construct a complex network of moisture recycling for South America. Our results show that CMR contributes about 9-10% to the total precipitation over South America and 17-18% over the La Plata basin. CMR increases the fraction of total precipitation over the La Plata basin that originates from the Amazon basin from 18-23 to 24-29% during the wet season. We also show that the south-western part of the Amazon basin is not only a direct source of rainfall over the La Plata basin, but also a key intermediary region that distributes moisture originating from the entire Amazon basin towards the La Plata basin during the wet season. Our results suggest that land use change in this region might have a stronger impact on downwind rainfall than previously thought. Using complex network analysis techniques, we find the eastern side of the sub-tropical Andes to be a key region where CMR pathways are channeled. This study offers a better understanding of the interactions between the vegetation and the atmosphere on the water cycle, which is needed in a context of land use and climate change in South America.
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| 6. |
- Barbosa, S., et al.
(författare)
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Workshop on Engaging the Human-Computer Interaction Community with Public Policymaking Internationally : Extended Abstract
- 2013
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Ingår i: Proceeding CHI EA '13 CHI '13 Extended Abstracts on Human Factors in Computing Systems. - New York, NY, USA : Association for Computing Machinery (ACM). - 9781450318990 ; , s. 3279-3282
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Konferensbidrag (refereegranskat)abstract
- There is an increasing interest in the intersection of human-computer interaction and public policy. This day-long workshop will examine successes and challenges related to public policy and human computer interaction, in order to provide a forum to create a baseline of examples and to start the process of writing a white paper on the topic.
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| 7. |
- Barbosa, Edna J L, 1961, et al.
(författare)
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Extracellular water and blood pressure in adults with growth hormone (GH) deficiency: a genotype-phenotype association study.
- 2014
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Growth hormone deficiency (GHD) in adults is associated with decreased extracellular water volume (ECW). In response to GH replacement therapy (GHRT), ECW increases and blood pressure (BP) reduces or remains unchanged. Our primary aim was to study the association between polymorphisms in genes related to renal tubular function with ECW and BP before and 1 year after GHRT. The ECW measures using bioimpedance analysis (BIA) and bioimpedance spectroscopy (BIS) were validated against a reference method, the sodium bromide dilution method (Br(-)).
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| 8. |
- Barbosa, Edna J L, 1961, et al.
(författare)
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Genotypes associated with lipid metabolism contribute to differences in serum lipid profile of GH-deficient adults before and after GH replacement therapy.
- 2012
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X .- 0804-4643. ; 167:3, s. 353-62
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Tidskriftsartikel (refereegranskat)abstract
- bjective: GH deficiency (GHD) in adults is associated with an altered serum lipid profile that responds to GH replacement therapy (GHRT). This study evaluated the influence of polymorphisms in genes related to lipid metabolism on serum lipid profile before and after 1 year of GHRT in adults. Design and methods: In 318 GHD patients, total cholesterol (TC) serum concentrations, LDL-C, HDL-C, and triglycerides (TG) were assessed. Using a candidate gene approach, 20 single nucleotide polymorphisms (SNPs) were genotyped. GH dose was individually titrated to obtain normal serum IGF1 concentrations. Results: At baseline, the minor alleles of cholesteryl ester transfer protein (CETP) gene SNPs rs708272 and rs1800775 were associated with higher serum TC and apolipoprotein E (APOE) gene SNP rs7412 with lower TC concentrations; CETP SNPs rs708272, rs1800775, and rs3764261 and apolipoprotein B (APOB) gene SNP rs693 with higher serum HDL-C; APOE SNP rs7412, peroxisome proliferator-activated receptor gamma (PPARG) gene SNP rs10865710 with lower LDL-C, and CETP SNP rs1800775 with higher LDL-C; and APOE/C1/C4/C2 cluster SNP rs35136575 with lower serum TG. After treatment, APOB SNP rs676210 GG genotype was associated with larger reductions in TC and LDL-C and PPARG SNP rs10865710 CC genotype with greater TC reduction. All associations remained significant when adjusted for age, sex, and BMI. Conclusions: In GHD adults, multiple SNPs in genes related to lipid metabolism contributed to individual differences in baseline serum lipid profile. The GH treatment response in TC and LDL-C was influenced by polymorphisms in the APOB and PPARG genes.
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| 9. |
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| 10. |
- Barbosa, Edna J L, 1961
(författare)
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Prediction Models and Pharmacogenomics in Adult Growth Hormone Deficiency
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to study clinical and genetic factors that influence response to growth hormone replacement therapy (GHRT) in GH deficient (GHD) adults. The patients were part of a cohort of adults with hypopituitarism and severe GHD who were studied before and after 12 months of GHRT. The dose regimen was individualized in order to attain normal IGF-I levels. Logistic regression (LR) analysis was used to identify good and poor responders to GHRT. The candidate gene approach was used to study single nucleotide polymorphisms (SNPs) in the GH receptor (GHR) gene, in genes related to GH signaling pathways, lipid metabolism and renal tubular function. Changes in IGF-I levels, body composition (BC), lipid profile and extracellular water (ECW) were analyzed as the GHRT outcomes. We identified gender and insulin levels at baseline as predictors for changes in IGF-I levels, and gender, height and lean body mass (LBM) at baseline as predictors for changes in BC. The accuracy of the equations obtained by LR to predict whether a patient will be a GR or PR was 70% for IGF-I and 80% for BC responses. The d3 allele polymorphism in the GHR gene did not influence IGF-I levels and BF at baseline and their changes after GHRT. At baseline, distinct SNPs of the cholesteryl ester transfer protein (CETP) gene were associated with higher total cholesterol (TC), HDL-C and LDL-C, those of the apolipoprotein E (APOE) gene with lower TC and LDL-C, APOB gene with higher serum HDL-C, and those of the peroxisome proliferator-activated receptor gamma (PPARG) gene with lower LDL-C and the APOE/C1/C4/C2 cluster with lower tryglicerides (TG). After GHRT, greater reductions in TC and LDL-C were associated with SNPs in the APOB and PPARG, explaining 5% of the variation. SNPs in the signal transducer and activator of transcription 5B (STAT5B), in the phosphoinositide-3-kinase, catalytic, beta polypeptide (PIK3CB) and in the sodium/potassium/chloride transporter member 1 (SLC12A1) genes were associated with differences in ECW in GHD patients. We conclude that gender, body height, LBM and insulin levels were the best predictors of IGF-I and BC responses to GHRT in GHD adults. The presence of the d3-GHR allele did not influence responses to GHRT, but we found that some SNPs in genes related to lipid metabolism, GH signaling pathways and water balance impact the baseline characteristics of GHD and their response to GHRT.
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