| 1. |
- Freitag, Daniel F., et al.
(author)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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In: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Journal article (peer-reviewed)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 2. |
- Guo, Jingtao, et al.
(author)
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The Dynamic Transcriptional Cell Atlas of Testis Development during Human Puberty
- 2020
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In: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 26:2, s. 262-
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Journal article (peer-reviewed)abstract
- The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To characterize this understudied process, we profiled and analyzed single-cell transcriptomes of similar to 10,000 testicular cells from four boys spanning puberty and compared them to those of infants and adults. During puberty, undifferentiated spermatogonia sequentially expand and differentiate prior to the initiation of gametogenesis. Notably, we identify a common pre-pubertal progenitor for Leydig and myoid cells and delineate candidate factors controlling pubertal differentiation. Furthermore, pre-pubertal Sertoli cells exhibit two distinct transcriptional states differing in metabolic profiles before converging to an alternative single mature population during puberty. Roles for testosterone in Sertoli cell maturation, antimicrobial peptide secretion, and spermatogonial differentiation are further highlighted through single-cell analysis of testosterone-suppressed transfemale testes. Taken together, our transcriptional atlas of the developing human testis provides multiple insights into developmental changes and key factors accompanying male puberty.
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| 3. |
- Giwercman, Aleksander, et al.
(author)
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Aging, DNA damage, and reproductive outcome
- 2010
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In: Paternal Influences on Human Reproductive Success. - 9781107024489 - 9781139169349 ; , s. 82-92
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Book chapter (peer-reviewed)abstract
- Due to increasing life expectancy and a number of social factors, at least in the Western world, an increasing proportion of men who are considered to belong to an “older age group” have the wish of becoming fathers. One of the reasons is that many women postpone their first pregnancy, which automatically leads to higher age of the potential fathers. Furthermore, divorce and building new families has become more frequent, which also affects the paternal age. For those reasons, from a social and a medical point of view, the issue of age-dependent changes in reproductive capacity of the males is receiving increasing attention. Aging might not only lead to reduced fertility but also to an increase in the occurrence of sperm DNA defects, which potentially might be transmitted to the offspring. Understanding the mechanisms linking paternal age to reproductive outcome is, therefore, crucial not only for understanding this process, but first of all in order to prevent possible negative impact of male aging on fertility and health of the offspring. In this chapter we will focus on the available information regarding age and numerical or structural changes in the DNA. The issue of epigenetic effects will be covered in a separate chapter.
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| 4. |
- Guo, Jingtao, et al.
(author)
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Chromatin and Single-Cell RNA- Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development
- 2017
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In: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 21:4, s. 533-546
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Journal article (peer-reviewed)abstract
- Human adult spermatogonial stem cells (hSSCs) must balance self-renewal and differentiation. To understand how this is achieved, we profiled DNA methylation and open chromatin (ATAC-seq) in SSEA4(+) hSSCs, analyzed bulk and single-cell RNA transcriptomes (RNA-seq) in SSEA4+ hSSCs and differentiating c-KIT+ spermatogonia, and performed validation studies via immunofluorescence. First, DNA hypomethylation at embryonic developmental genes supports their epigenetic "poising'' in hSSCs for future/embryonic expression, while core pluripotency genes (OCT4 and NANOG) were transcriptionally and epigenetically repressed. Interestingly, open chromatin in hSSCs was strikingly enriched in binding sites for pioneer factors (NFYA/B, DMRT1, and hormone receptors). Remarkably, single-cell RNA-seq clustering analysis identified four cellular/developmental states during hSSC differentiation, involving major transitions in cell-cycle and transcriptional regulators, splicing and signaling factors, and glucose/mitochondria regulators. Overall, our results outline the dynamic chromatin/transcription landscape operating in hSSCs and identify crucial molecular pathways that accompany the transition from quiescence to proliferation and differentiation.
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| 5. |
- Guo, Jingtao, et al.
(author)
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The adult human testis transcriptional cell atlas
- 2018
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In: Cell Research. - : INST BIOCHEMISTRY & CELL BIOLOGY. - 1001-0602 .- 1748-7838. ; 28, s. 1141-1157
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Journal article (peer-reviewed)abstract
- Human adult spermatogenesis balances spermatogonial stem cell (SSC) self-renewal and differentiation, alongside complex germ cell-niche interactions, to ensure long-term fertility and faithful genome propagation. Here, we performed single-cell RNA sequencing of similar to 6500 testicular cells from young adults. We found five niche/somatic cell types (Leydig, myoid, Sertoli, endothelial, macrophage), and observed germline-niche interactions and key human-mouse differences. Spermatogenesis, including meiosis, was reconstructed computationally, revealing sequential coding, non-coding, and repeat-element transcriptional signatures. Interestingly, we identified five discrete transcriptional/developmental spermatogonial states, including a novel early SSC state, termed State 0. Epigenetic features and nascent transcription analyses suggested developmental plasticity within spermatogonial States. To understand the origin of State 0, we profiled testicular cells from infants, and identified distinct similarities between adult State 0 and infant SSCs. Overall, our datasets describe key transcriptional and epigenetic signatures of the normal adult human testis, and provide new insights into germ cell developmental transitions and plasticity.
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| 6. |
- Rajpert-De Meyts, Ewa, et al.
(author)
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Marking the first decade of Andrology : — Conception and early development of the journal
- 2022
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In: Andrology. - : Wiley. - 2047-2919 .- 2047-2927. ; 10:S2, s. 139-143
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Journal article (peer-reviewed)abstract
- The European Academy of Andrology (EAA) celebrates its 30th anniversary in 2022. An important part of the Academy's history is its scientific publishing activity, which started with the International Journal of Andrology (Int J Androl), and continued with Andrology, the journal created and overseen jointly by the EAA and the American Society of Andrology (ASA). The year 2022 marks the first decade of existence of Andrology, which opened for submissions in the spring of 2012 and published its first issue in December 2012—in time to be presented at the 7th European Congress of Andrology in Berlin, Germany. The 10th volume of the journal is close to completion, and the past and current Chief Editors use this opportunity to look back at the first decade of Andrology.
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