| 1. |
- Galluzzi, L, et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes.
- 2009
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 16:8, s. 1093-107
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Forskningsöversikt (refereegranskat)abstract
- Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells.
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| 2. |
- Aghakhanian, F, et al.
(författare)
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INTEGRATION OF GWAS AND EPIGENETIC STUDIES IDENTIFIES NOVEL GENES THAT ALTER EXPRESSION IN THE MINOR SALIVARY GLAND IN SJOGREN'S DISEASE
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 72-73
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Sjogren’s disease (SjD) is an autoimmune disease characterized by reduced function of exocrine glands (i.e., salivary and lacrimal glands). Epithelial cell damage resulting from lymphocytic infiltration has been implicated in SjD etiology [1]. How genetic and epigenetic changes influence epithelial-immune cell interactions in SjD pathogenesis remain understudied.ObjectivesEvaluate the role of SjD risk loci in salivary gland tissue to gain insights into the potential genes involved in salivary gland dysfunction.MethodsSNPs from 16 regions with SNP-SjD associations (P<5x10-8) in our GWAS study (3232 SjD cases) and meta-analysis of ImmunoChip data (619 SjD cases) [2] were interrogated for eQTLs using Genotype-Tissue Expression (GTEx) minor salivary gland data. Subsequent analysis identified genes that were both eQTLs in the minor salivary gland and significantly expressed in RNA-seq and ATAC-seq data from the submaxillary salivary gland epithelial cell line, A253. Pathway enrichment analysis was performed using gProfiler on the genes where coalescence of eQTL, RNA-seq, and ATAC-seq data was observed. To further validate the results, we performed transcriptome-wide association study (TWAS) analysis using GWAS summary statistics and minor salivary gland eQTL GTEx data.ResultsIn total, 5884 genome-wide significant SNPs from 16 SjD risk loci were identified as potential minor salivary gland eQTLs using two discovery thresholds: p(FDR)<0.05 provided by eQTL study (3566 SNPs) and p(FDR)>0.05 and p<0.05 in eQTL study (2318 SNPs). Further analysis revealed 10 SjD risk loci with SNPs that were minor salivary gland eQTLs for a total of 155 unique genes that had a coalescence of RNA- and ATAC-seq data in A253 cells. Many SNPs altered the expression of the nearest gene to the risk allele (i.e., index gene), such as IRF5 and TNPO3 on chromosome 7 at 128Mb; however, this locus had 12 additional genes that were eQTLs in minor salivary gland. In contrast, other loci had no reported eQTLs for the index gene, but several reported eQTLs for other genes, such TYK2 on chromosome 19 at 10Mb that showed no change in TYK2 expression but eQTLs for 8 distant genes, including ICAM1. Pathway enrichment analysis revealed an enrichment in Butyrophilin (BTN) family interactions (R-HSA-8851) (PAdj=1.564x10-5), including the BTN2A1, BTN2A2, BTN3A1, BTN3A2 and BTN3A3 gene cluster in the MHC region. In further support, TWAS of the minor salivary gland and the SjD GWAS summary statistics (after Bonferroni correction) showed association between SjD and BTN3A2 (p=1.24x10-42), as well as many other loci in the MHC region. In addition, several long non-coding (lnc) RNAs on chromosome 17 were significant, peaking at RP11-259G18.1 (p=4.43x10-10).ConclusionThis study shows that SjD-associated risk alleles influence disease by altering gene expression in immune cells and minor salivary glands. Further, our analysis suggests that altered gene expression in the minor salivary gland expands beyond effects on the index gene to several genes on each locus. Interestingly, we observed minor salivary gland eQTLs for several BTN family genes, which act as cell-surface binding partners to regulate cell-cell interactions, including interactions between epithelial cells and activated T cells [3]. Future work will assess chromatin-chromatin-interactions within the 10 SjD risk loci in salivary gland cells and tissues to map local chromatin regulatory networks that regulate gene expression. Additional transcriptional studies of SjD minor salivary gland tissues will provide further insights into how altered gene expression in the salivary gland influences SjD pathology.References[1]Verstappen. Nat Rev Rheumatol 2021;17(6):333-348.[2]Khatri, et al. Annals of Rheumatic Diseases 2020;79:30-31.[3]Arnett HA, Viney JL. Nature Reviews Immunology 2014;14:559-569.Disclosure of InterestsFarhang Aghakhanian: None declared, Mandi M Wiley: None declared, Bhuwan Khatri: None declared, Kandice L Tessneer: None declared, Astrid Rasmussen: None declared, Simon J. Bowman Consultant of: Abbvie, Galapagos, and Novartis in 2020-2021., Lida Radfar: None declared, Roald Omdal: None declared, Marie Wahren-Herlenius: None declared, Blake M Warner: None declared, Torsten Witte: None declared, Roland Jonsson: None declared, Maureen Rischmueller: None declared, Patrick M Gaffney: None declared, Judith A. James: None declared, Lars Ronnblom: None declared, R Hal Scofield: None declared, Xavier Mariette: None declared, Marta Alarcon-Riquelme: None declared, Wan Fai Ng: None declared, Kathy Sivils Employee of: Current employee of Janssen, Gunnel Nordmark: None declared, Umesh Deshmukh: None declared, A Darise Farris: None declared, Christopher Lessard: None declared
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| 3. |
- Bar, N., et al.
(författare)
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A reference map of potential determinants for the human serum metabolome
- 2020
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Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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| 4. |
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| 5. |
- Deshmukh, A. A., et al.
(författare)
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Investigating the Applicability and Limitations of Glass-Forming Criteria Based on Bond Parameters on Thermal Stability in Mg-Based Multicomponent Bulk Metallic Glasses
- 2018
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Ingår i: Transactions of the Indian Institute of Metals. - : SPRINGER INDIA. - 0972-2815 .- 0975-1645. ; 71:11, s. 2631-2634
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, correlation of thermal stability () with the bond parameters such as electronegativity (), atomic radius mismatch (), and valence electron concentration () for Mg-based multicomponent bulk metallic glasses (BMGs) have been evaluated. A statistical approach of regression analysis has been adopted to investigate correlations among these parameters. Available experimental data have been used for the systematic investigation from ternary to multicomponent Mg-based BMGs. In addition, the applicability of the criteria has been assessed for the systems with and without rare earth (RE) elements. We have found that BMG systems containing RE group elements have significant effect on width of supercooled liquid region. Results obtained from our modified empirical equation have been compared with that of earlier models and have shown better correlations.
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| 6. |
- Deshmukh, A. A., et al.
(författare)
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Understanding the effect of compositions on electronegativity, atomic radius and thermal stability of Mg-Ni-Y amorphous alloy
- 2018
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Ingår i: 2nd International Conference on Condensed Matter and Applied Physics (ICC 2017). - : American Institute of Physics (AIP). - 9780735416482
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Konferensbidrag (refereegranskat)abstract
- In the present paper, the consequences of variation in compositions on the electronegativity (ΔX), atomic radius difference (δ) and the thermal stability (ΔTx) of Mg-Ni-Y bulk metallic glasses (BMGs) are evaluated. In order to understand the effect of variation in compositions on ΔX, δ and ΔTx, regression analysis is performed on the experimentally available data. A linear correlation between both δ and ΔX with regression coefficient 0.93 is observed. Further, compositional variation is performed with δ and then it is correlated to the ΔTx by deriving subsequent equations. It is observed that concentration of Mg, Ni and Y are directly proportional to the δ with regression coefficients 0.93, 0.93 and 0.50 respectively. The positive slope of Ni and Y stated that ΔTx will increase if it has more contribution from both Ni and Y. On the other hand negative slope stated that composition of Mg should be selected in such a way that it will have more stability with Ni and Y. The results obtained from mathematical calculations are also tested by regression analysis of ΔTx with the compositions of individual elements in the alloy. These results conclude that there is a strong dependence of ΔTx of the alloy on the compositions of the constituting elements in the alloy.
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| 8. |
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| 11. |
- Wilman, H. R., et al.
(författare)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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