| 1. |
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| 2. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 3. |
- Stella, Roberto, et al.
(författare)
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Confirmation of Protein Biomarkers of Corticosteroids Treatment in Veal Calves Sampled under Field Conditions
- 2014
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 13:4, s. 1794-1799
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Tidskriftsartikel (refereegranskat)abstract
- In veal calf production, growth promoters are still illicitly used. Surveillance of misuse of such molecules is necessary to preserve human health. Methods currently adopted for their analysis are based on liquid chromatography tandem mass spectrometry, but their efficacy can be affected by undetectable residual concentrations in biological matrices due to treatments at low-dosage or based on unknown anabolic compounds. The development of screening methods to identify the indirect biological effects of administration of growth promoters can improve the efficiency of drug residue monitoring. To this purpose, an integrated approach has been used to further validate the set of protein biomarkers defined in a previous controlled study to detect the use of corticosteroids through the changes caused in muscle protein expression. The thymus morphology of 48 samples collected under field conditions was evaluated to assess the presence of potential corticosteroids treatment. Animals were divided on the basis of their thymus characteristics in negative or suspected for illegal corticosteroids treatment. Drug residue analyses were performed on the liver, giving a satisfactory correlation with the histological examination (similar to 85%). Finally, the proteomics analysis of muscle protein extracts was carried out by 2D differential in gel electrophoresis, and proteins that were differentially expressed between the two animal groups (p value <0.01) were selected for MALDI-MS/MS analysis. This approach allowed us to identify 29 different proteins, and our findings indicate that the altered protein expression pattern can be used as an indirect method for the detection of illicit corticosteroids administration. A subset of the identified proteins was already reported in a previous controlled study, proving that these biomarkers can be used to develop a screening assay to improve the tools currently available for the detection of corticosteroids abuse in bovine meat production.
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| 4. |
- Stella, Roberto, et al.
(författare)
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Protein Expression Changes in Skeletal Muscle in Response to Growth Promoter Abuse in Beef Cattle
- 2011
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 10:6, s. 2744-2757
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Tidskriftsartikel (refereegranskat)abstract
- The fraudulent treatment of cattle with growth promoting agents (GPAs) is a matter of great concern for the European Union (EU) authorities and consumers. It has been estimated that 10% of animals are being illegally treated in the EU. In contrast, only a much lower percentage of animals (< 0.5%) are actually found as being noncompliant by conventional analytical methods. Thus, it has been proposed that methods should be developed that can detect the use of the substances via the biological effects of these substances on target organs, such as the alteration of protein expression profiles. Here we present a study aimed at evaluating if a correlation exists between the treatment with GPAs and alterations in the two-dimensional electrophoresis (2DE) protein pattern obtained from the biceps brachii skeletal muscle from mixed-bred cattle. After image analysis and statistical evaluation, protein spots that differentiate between treated and control groups were selected for analysis by mass spectrometry. A set of proteins could be defined that accurately detect the use of glucocorticoids and beta(2)-agonists as growth promoters through the changes caused in muscle differentiation. As a further validation, we repeated the analysis using an independent set of samples from a strain of pure-bred cattle and verified these proteins by Western blot analysis.
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| 5. |
- Stella, Roberto, et al.
(författare)
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Proteomics for the detection of indirect markers of steroids treatment in bovine muscle
- 2015
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Ingår i: Proteomics. - : Wiley. - 1615-9861 .- 1615-9853. ; 15:13, s. 2332-2341
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Tidskriftsartikel (refereegranskat)abstract
- Despite the ban by the European Union, anabolic steroids might still be illicitly employed in bovine meat production. The surveillance of misuse of such potentially harmful molecules is necessary to guarantee consumers' health. Analytical methods for drug residue control are based on LC-MS/MS, but their efficacy can be hindered due to undetectable residual concentrations as a result of low-dosage treatments. Screening methods based on the recognition of indirect biological effects of growth promoters' administration, such as the alteration of protein expression, can improve the efficacy of surveillance. The present study was aimed at identifying modifications in the muscle protein expression pattern between bulls treated with an ear implant (Revalor-XS (R)) containing trenbolone acetate (200 mg) and estradiol (40 mg), and untreated animals. The analysis of skeletal muscle was carried out using a tandem mass tags shotgun proteomics approach. We defined 28 candidate protein markers with a significantly altered expression induced by steroids administration. A subset of 18 candidate markers was validated by SRM and allowed to build a predictive model based on partial least square discriminant analysis. Our findings confirm the effectiveness of the proteomics approach as potential tool to overcome analytical limitations of drug residue monitoring.
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| 6. |
- Stella, Roberto, et al.
(författare)
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Targeted proteomics for the indirect detection of dexamethasone treatment in bovines
- 2016
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Ingår i: Analytical and Bioanalytical Chemistry. - : Springer Science and Business Media LLC. - 1618-2642 .- 1618-2650. ; 408:29, s. 8343-8353
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Tidskriftsartikel (refereegranskat)abstract
- The illegal use of pharmacologically active compounds for growth promotion in food-producing species poses risks for consumer health and animal welfare. Surveillance relies on the quantification of drug residues in animal fluids or tissues, but the efficacy can be negatively affected due to undetectable residual concentrations in biological matrices. Consequently, techniques focusing on the indirect biological effects of exogenous compound administration have been proposed as more sensitive detection methods. The purpose of the present study is to develop a tandem mass spectrometry analytical method based on low-energy collision-induced dissociation (CID-MS/MS) using multiple reaction monitoring (MRM) for the quantification of 12 potential protein markers of skeletal muscle to detect anabolic treatments with dexamethasone. Protein markers identified in a previous study applying a 2D-DIGE proteomics approach have been quantified using the signature peptide method. A group of proteins were confirmed as reliable markers. Quantitative results enabled a predictive model to be defined based on logistic regression for the detection of treated animals. The developed model was finally cross-validated in an independent animal set. [Figure not available: see fulltext.]
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| 7. |
- Bendz, Maria, et al.
(författare)
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Quantification of Membrane Proteins Using Nonspecific Protease Digestions
- 2009
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 8:12, s. 5666-5673
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Tidskriftsartikel (refereegranskat)abstract
- We present a mass spectrometry-based method for the identification and quantification of membrane proteins using the low-specificity protease Proteinase K, at very high pH, to digest proteins isolated by a modified SDS-PAGE protocol. The resulting peptides are modified with a fragmentation-directing isotope labeled tag. We apply the method to quantify differences in membrane protein expression of Bacillus subtilis grown in the presence or absence of glucose.
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| 8. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 9. |
- Fogh, Isabella, et al.
(författare)
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A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis
- 2014
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Ingår i: Human Molecular Genetics. - Oxford : Oxford University Press. - 0964-6906 .- 1460-2083. ; 23:8, s. 2220-2231
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Tidskriftsartikel (refereegranskat)abstract
- Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (90) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P 1.11 10(8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P 8.62 10(9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P 7.69 10(9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as 12 using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
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| 10. |
- Kenna, Kevin P., et al.
(författare)
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NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1037-1042
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
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| 11. |
- Lai, Chao-Qiang, et al.
(författare)
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Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A
- 2020
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Ingår i: American Journal of Clinical Nutrition. - : OXFORD UNIV PRESS. - 0002-9165 .- 1938-3207. ; 112:5, s. 1200-1211
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitinc palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome). but the mechanism underlying these associations is unknown. Objectives: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases. Methods: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network. n = 978; Framingham Heart Study. n = 2331: and REgistre GIroni del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed metaanalysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator. Results: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation. whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with beta = 58.4 +/- 7.27, P = 8.98 x 10(-16) for CHO intake; beta = -36.4 +/- 5.95. P = 9.96 x 10(-10) for FAT intake; and beta = 3.30 +/- 0.49. P = 1.48 x 10(-11) for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases. Conclusions: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A.
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| 12. |
- Laudisio, Alice, et al.
(författare)
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Association of Pisa Syndrome With Mortality in Patients With Parkinson's Disease
- 2019
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610 .- 1538-9375. ; 20:8, s. 1037-
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: In Parkinson's disease, Pisa syndrom (PS) has been associated with disease stage and severity, combined treatment with levodopa and dopamine agonists, gait disorders, and comorbidities. Some forms of PS are potentially reversible; nevertheless, little is known about the impact of this syndrome on survival. Design: Prospective study with a median follow-up of 2 years. Setting and participants: Patients with Parkinson's disease, age 65 years and older (N = 189), attending a geriatric day hospital. Measurements: According to established criteria, PS was diagnosed in the presence of at least 10 degrees lateral flexion of the trunk reducible by passive mobilization or supine positioning. Cox regression was adopted to assess the association of PS with all-cause mortality. Results: PS was diagnosed in 40 patients (21%); over the follow-up, 21 (11%) subjects died. In Cox regression, PS was associated with higher mortality [hazard ratio (HR) 4.10; 95% confidence interval (CI) = 1.36-12.38], after adjusting; other variables associated with mortality were age (HR = 1.19, 95% CI = 1.08-1.32), beta blockers (HR = 4.35, 95% CI = 1.23-15.39), and albumin levels (HR = 0.05, 95% CI = 0.01-0.33). The association of PS with mortality remained significant also after adjusting for variables associated with this syndrome (HR = 4.04, 95% CI = 1.33-12.25). Conclusions/Implications: PS represents a risk factor for earlier mortality in Parkinson's disease; further studies are needed to ascertain the underlying causes and whether treatment of this condition might improve survival. (C) 2019 AMDA - The Society for Post-Acute and Long-Term Care Medicine.
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| 13. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 14. |
- Marques, Carolina, et al.
(författare)
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NF1 regulates mesenchymal gliblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1
- 2021
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The molecular basis underlying glioblastoma (GBM) heterogeneity and plasticity is not fully understood. Using transcriptomic data of human patient-derived brain tumor stem cell lines (BTSCs), classified based on GBM-intrinsic signatures, we identify the AP-1 transcription factor FOSL1 as a key regulator of the mesenchymal (MES) subtype. We provide a mechanistic basis to the role of the neurofibromatosis type 1 gene (NF1), a negative regulator of the RAS/MAPK pathway, in GBM mesenchymal transformation through the modulation of FOSL1 expression. Depletion of FOSL1 in NF1-mutant human BTSCs and Kras-mutant mouse neural stem cells results in loss of the mesenchymal gene signature and reduction in stem cell properties and in vivo tumorigenic potential. Our data demonstrate that FOSL1 controls GBM plasticity and aggressiveness in response to NF1 alterations.
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| 15. |
- Nava, Veronica, et al.
(författare)
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Plastic debris in lakes and reservoirs
- 2023
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 619:7969, s. 317-322
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Tidskriftsartikel (refereegranskat)abstract
- Plastic debris is thought to be widespread in freshwater ecosystems globally(1). However, a lack of comprehensive and comparable data makes rigorous assessment of its distribution challenging(2,3). Here we present a standardized cross-national survey that assesses the abundance and type of plastic debris (>250 mu m) in freshwater ecosystems. We sample surface waters of 38 lakes and reservoirs, distributed across gradients of geographical position and limnological attributes, with the aim to identify factors associated with an increased observation of plastics. We find plastic debris in all studied lakes and reservoirs, suggesting that these ecosystems play a key role in the plastic-pollution cycle. Our results indicate that two types of lakes are particularly vulnerable to plastic contamination: lakes and reservoirs in densely populated and urbanized areas and large lakes and reservoirs with elevated deposition areas, long water-retention times and high levels of anthropogenic influence. Plastic concentrations vary widely among lakes; in the most polluted, concentrations reach or even exceed those reported in the subtropical oceanic gyres, marine areas collecting large amounts of debris(4). Our findings highlight the importance of including lakes and reservoirs when addressing plastic pollution, in the context of pollution management and for the continued provision of lake ecosystem services.
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| 16. |
- Nikpay, Majid, et al.
(författare)
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A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:10, s. 1121-1121
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Tidskriftsartikel (refereegranskat)abstract
- Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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| 17. |
- Peggion, Caterina, et al.
(författare)
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Microglia in Prion Diseases : Angels or Demons?
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:20
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Forskningsöversikt (refereegranskat)abstract
- Prion diseases are rare transmissible neurodegenerative disorders caused by the accumulation of a misfolded isoform (PrPSc) of the cellular prion protein (PrP) in the central nervous system (CNS). Neuropathological hallmarks of prion diseases are neuronal loss, astrogliosis, and enhanced microglial proliferation and activation. As immune cells of the CNS, microglia participate both in the maintenance of the normal brain physiology and in driving the neuroinflammatory response to acute or chronic (e.g., neurodegenerative disorders) insults. Microglia involvement in prion diseases, however, is far from being clearly understood. During this review, we summarize and discuss controversial findings, both in patient and animal models, suggesting a neuroprotective role of microglia in prion disease pathogenesis and progression, or-conversely-a microglia-mediated exacerbation of neurotoxicity in later stages of disease. We also will consider the active participation of PrP in microglial functions, by discussing previous reports, but also by presenting unpublished results that support a role for PrP in cytokine secretion by activated primary microglia.
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| 18. |
- Ponticelli, Francesco, et al.
(författare)
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Safety and efficacy of coronary sinus narrowing in chronic refractory angina: Insights from the RESOURCE study.
- 2021
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 337, s. 29-37
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Tidskriftsartikel (refereegranskat)abstract
- Refractory angina (RA) is considered the end-stage of coronary artery disease, and often has no interventional treatment options. Coronary sinus Reducer (CSR) is a recent addition to the therapeutic arsenal, but its efficacy has only been evaluated on small populations. The RESOURCE registry provides further insights into this therapy.The RESOURCE is an observational, retrospective registry that includes 658 patients with RA from 20 centers in Europe, United Kingdom and Israel. Prespecified endpoints were the amelioration of anginal symptoms evaluated with the Canadian Cardiovascular Society (CCS) score, the rates of procedural success and complications, and MACEs as composite of all-cause mortality, acute coronary syndromes, and stroke.At a median follow-up of 502days (IQR 225-1091) after CSR implantation, 39.7% of patients improved by ≥2 CCS classes (primary endpoint), and 76% by ≥1 class. Procedural success was achieved in 96.7% of attempts, with 3% of procedures aborted mostly for unsuitable coronary sinus anatomy. Any complication occurred in 5.7% of procedures, but never required bailout surgery nor resulted in intra- or periprocedural death or myocardial infarction. One patient developed periprocedural stroke after inadvertent carotid artery puncture. At the last available follow-up, overall mortality and MACE were 10.4% and 14.6% respectively. At one, three and five years, mortality rate at Kaplan-Meier analysis was 4%, 13.7%, and 23.4% respectively.CSR implantation is safe and reduces angina in patients with refractory angina.
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| 19. |
- Puri, Rishi, et al.
(författare)
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Transcatheter aortic valve implantation in patients with small aortic annuli using a 20 mm balloon-expanding valve
- 2017
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 103, s. 148-153
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Tidskriftsartikel (refereegranskat)abstract
- Background While transcatheter aortic valve implantation (TAVI) is established for treating highoperative risk surgical aortic valve replacement candidates, until recently the smallest transcatheter heart valve (THV) measured 23 mm, posing greater risk for annular rupture and THV failure in patients with aortic stenosis (AS) with small aortic annuli (=20 mm). Objectives In the setting of a multicentre registry, we report on the safety, efficacy and early clinical outcomes of the SAPIEN XT 20 mm balloon-expanding THV. Results Among TAVI 55 recipients (n=30 for native AS, n=25 for a valve-in-valve procedure (V-in-V)), median age and Society of Thoracic Surgeons score were 85 (81 to 87) years and 7.8 (4.7 to 12.4)%, respectively. Mean and minimum annular diameters were 19±1 and 17±2 mm, respectively, in native patients with AS, and 17±1 mm (internal diameter) in V-in-V recipients. Successful device implantation rate was 96%, with no procedural-related death. Overall in-hospital-30-day death, stroke and major bleeding rates were 5%, 2% and 9%, respectively. In native AS TAVI recipients, mean transaortic gradient decreased from 54±20 to 12±5 mm Hg ( p<0.001), and from 45±17 to 24±8 mm Hg (p<0.001) in V-in-V recipients. Severe prosthesis-patient mismatch (PPM) rates were 10% and 48% in native AS and V-in-V TAVI recipients, respectively ( p=0.03). Post-TAVI, the rate of moderate aortic regurgitation was 7% and 0% in native AS and V-in-V TAVI recipients, respectively. Conclusions TAVI with the 20 mm SAPIEN XT THV appears safe and technically feasible, with acceptable short-term clinical outcomes and low rates of severe PPM in those with native AS.
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| 20. |
- Soffitta, Paolo, et al.
(författare)
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XIPE : the X-ray imaging polarimetry explorer
- 2013
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Ingår i: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 36:3, s. 523-567
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Tidskriftsartikel (refereegranskat)abstract
- X-ray polarimetry, sometimes alone, and sometimes coupled to spectral and temporal variability measurements and to imaging, allows a wealth of physical phenomena in astrophysics to be studied. X-ray polarimetry investigates the acceleration process, for example, including those typical of magnetic reconnection in solar flares, but also emission in the strong magnetic fields of neutron stars and white dwarfs. It detects scattering in asymmetric structures such as accretion disks and columns, and in the so-called molecular torus and ionization cones. In addition, it allows fundamental physics in regimes of gravity and of magnetic field intensity not accessible to experiments on the Earth to be probed. Finally, models that describe fundamental interactions (e.g. quantum gravity and the extension of the Standard Model) can be tested. We describe in this paper the X-ray Imaging Polarimetry Explorer (XIPE), proposed in June 2012 to the first ESA call for a small mission with a launch in 2017. The proposal was, unfortunately, not selected. To be compliant with this schedule, we designed the payload mostly with existing items. The XIPE proposal takes advantage of the completed phase A of POLARIX for an ASI small mission program that was cancelled, but is different in many aspects: the detectors, the presence of a solar flare polarimeter and photometer and the use of a light platform derived by a mass production for a cluster of satellites. XIPE is composed of two out of the three existing JET-X telescopes with two Gas Pixel Detectors (GPD) filled with a He-DME mixture at their focus. Two additional GPDs filled with a 3-bar Ar-DME mixture always face the Sun to detect polarization from solar flares. The Minimum Detectable Polarization of a 1 mCrab source reaches 14 % in the 2-10 keV band in 10(5) s for pointed observations, and 0.6 % for an X10 class solar flare in the 15-35 keV energy band. The imaging capability is 24 arcsec Half Energy Width (HEW) in a Field of View of 14.7 arcmin x 14.7 arcmin. The spectral resolution is 20 % at 6 keV and the time resolution is 8 mu s. The imaging capabilities of the JET-X optics and of the GPD have been demonstrated by a recent calibration campaign at PANTER X-ray test facility of the Max-Planck-Institut fur extraterrestrische Physik (MPE, Germany). XIPE takes advantage of a low-earth equatorial orbit with Malindi as down-link station and of a Mission Operation Center (MOC) at INPE (Brazil). The data policy is organized with a Core Program that comprises three months of Science Verification Phase and 25 % of net observing time in the following 2 years. A competitive Guest Observer program covers the remaining 75 % of the net observing time.
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| 21. |
- Stella, Roberto, et al.
(författare)
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Relative Quantification of Membrane Proteins in Wild-Type and Prion Protein (PrP)-Knockout Cerebellar Granule Neurons
- 2012
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 11:2, s. 523-536
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 25% of eukaryotic proteins possessing homology to at least two trans membrane domains are predicted to be embedded in biological membranes. Nevertheless, this group of proteins is not usually well represented in proteome-wide experiments due to their refractory nature. Here we present a quantitative mass spectrometry-based comparison of membrane protein expression in cerebellar granule neurons grown in primary culture that were isolated from wild-type mice and mice lacking the cellular prion protein. This protein is a cell-surface glycoprotein that is mainly expressed in the central nervous system and is involved in several neurodegenerative disorders, though its physiological role is unclear. We used a low specificity enzyme a-chymotrypsin to digest membrane proteins preparations that had been separated by SDS-PAGE. The resulting peptides were labeled with tandem mass tags and analyzed by MS. The differentially expressed proteins identified using this approach were further analyzed by multiple reaction monitoring to confirm the expression level changes.
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| 22. |
- Strollo, Rocky, et al.
(författare)
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Autoantibody and T cell responses to oxidative post-translationally modified insulin neoantigenic peptides in type 1 diabetes
- 2023
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 66:1, s. 132-146
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Antibodies specific to oxidative post-translational modifications (oxPTM) of insulin (oxPTM-INS) are present in most individuals with type 1 diabetes, even before the clinical onset. However, the antigenic determinants of such response are still unknown. In this study, we investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in type 1 diabetes. We also assessed the concordance between antibody and T cell responses to the oxPTM-INS neoantigenic peptides. Methods oxPTM-INS was generated by exposing insulin to various reactive oxidants. The insulin fragments resulting from oxPTM were fractionated by size-exclusion chromatography further to ELISA and LC-MS/MS analysis to identify the oxidised peptide neoepitopes. Immunogenic peptide candidates were produced and then modified in house or designed to incorporate in silico-oxidised amino acids during synthesis. Autoantibodies to the oxPTM-INSPs were tested by ELISA using sera from 63 participants with new-onset type 1 diabetes and 30 control participants. An additional 18 fresh blood samples from participants with recently diagnosed type 1 diabetes, five with established disease, and from 11 control participants were used to evaluate, in parallel, CD4(+) and CD8(+) T cell activation by oxPTM-INSPs. Results We observed antibody and T cell responses to three out of six LC-MS/MS-identified insulin peptide candidates: A:12-21 (SLYQLENYCN, native insulin peptide 3 [Nt-INSP-3]), B:11-30 (LVEALYLVCGERGFFYTPKT, Nt-INSP-4) and B:21-30 (ERGFFYTPKT, Nt-INSP-6). For Nt-INSP-4 and Nt-INSP-6, serum antibody binding was stronger in type 1 diabetes compared with healthy control participants (p <= 0.02), with oxidised forms of ERGFFYTPKT, oxPTM-INSP-6 conferring the highest antibody binding (83% binders to peptide modified in house by hydroxyl radical [(OH)-O-?] and >88% to in silico-oxidised peptide; p <= 0.001 vs control participants). Nt-INSP-4 induced the strongest T cell stimulation in type 1 diabetes compared with control participants for both CD4(+) (p<0.001) and CD8(+) (p=0.049). CD4(+) response to oxPTM-INSP-6 was also commoner in type 1 diabetes than in control participants (66.7% vs 27.3%; p=0.039). Among individuals with type 1 diabetes, the CD4(+) response to oxPTM-INSP-6 was more frequent than to Nt-INSP-6 (66.7% vs 27.8%; p=0.045). Overall, 44.4% of patients showed a concordant autoimmune response to oxPTM-INSP involving simultaneously CD4(+) and CD8(+) T cells and autoantibodies. Conclusions/interpretation Our findings support the concept that oxidative stress, and neoantigenic epitopes of insulin, may be involved in the immunopathogenesis of type 1 diabetes.
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| 23. |
- Wain, Louise V., et al.
(författare)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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