| 61. |
- Wilder, Aryn P., et al.
(författare)
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The contribution of historical processes to contemporary extinction risk in placental mammals
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643
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Tidskriftsartikel (refereegranskat)abstract
- Species persistence can be influenced by the amount, type, and distribution of diversity across the genome, suggesting a potential relationship between historical demography and resilience. In this study, we surveyed genetic variation across single genomes of 240 mammals that compose the Zoonomia alignment to evaluate how historical effective population size (Ne) affects heterozygosity and deleterious genetic load and how these factors may contribute to extinction risk. We find that species with smaller historical Ne carry a proportionally larger burden of deleterious alleles owing to long-term accumulation and fixation of genetic load and have a higher risk of extinction. This suggests that historical demography can inform contemporary resilience. Models that included genomic data were predictive of species' conservation status, suggesting that, in the absence of adequate census or ecological data, genomic information may provide an initial risk assessment.
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| 62. |
- Xue, James R., et al.
(författare)
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The functional and evolutionary impacts of human-specific deletions in conserved elements
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643
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Tidskriftsartikel (refereegranskat)abstract
- Conserved genomic sequences disrupted in humans may underlie uniquely human phenotypic traits. We identified and characterized 10,032 human-specific conserved deletions (hCONDELs). These short (average 2.56 base pairs) deletions are enriched for human brain functions across genetic, epigenomic, and transcriptomic datasets. Using massively parallel reporter assays in six cell types, we discovered 800 hCONDELs conferring significant differences in regulatory activity, half of which enhance rather than disrupt regulatory function. We highlight several hCONDELs with putative human-specific effects on brain development, including HDAC5, CPEB4, and PPP2CA. Reverting an hCONDEL to the ancestral sequence alters the expression of LOXL2 and developmental genes involved in myelination and synaptic function. Our data provide a rich resource to investigate the evolutionary mechanisms driving new traits in humans and other species.
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| 63. |
- Yang, K., et al.
(författare)
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Novel somatic mutations in the VHL gene in Swedish archived sporadic renal cell carcinomas
- 1999
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Ingår i: Cancer Letters. - Clare, Ireland : Elsevier. - 0304-3835 .- 1872-7980. ; 141:1-2, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Frequent loss-of-function somatic mutations of the VHL gene have been detected in sporadic renal cell carcinoma (RCC), indicating that inactivation of the VHL gene plays a critical role in RCC. In this study, we collected 35 archived Swedish sporadic RCCs identified from an epidemiological study on occupational exposure and kidney cancer to test how well stored pathological specimens could be retrieved and analyzed for VHL mutations. Thirty specimens were successfully analyzed with PCR-SSCP and sequencing. Aberrant SSCP bands were detected in 16 out of the 30 samples (53%). Sequencing analysis of the aberrant bands revealed seven deletions, one insertion, one base substitution on a splicing site, six missense mutations, one silent mutation and several base substitutions in the 5' non-coding region and intron 1. Most were novel somatic mutations that have not been reported in sporadic RCC. The mutations were found in three types of non-papillary RCC cases, i.e. 14 clear cells, one granular chromophilic and one sarcomatoid RCC. Interesting multiple mutations were found in three cases (5, 3, 2 mutations, respectively).
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| 64. |
- Zander, C, et al.
(författare)
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Multivariate analysis of factors influencing repeat expansion detection
- 1998
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 8:10, s. 1085-1094
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Tidskriftsartikel (refereegranskat)abstract
- Repeat expansion detection (RED) is a powerful tool for detection of expanded repeat sequences in the genome. In RED, DNA serves as a template for a repeat-specific oligonucleotide. A thermostable ligase is used to ligate oligonucleotides that have annealed at adjacent positions, creating multimers in a thermal cycling procedure. The products are visualized after gel electrophoresis, transfered to a membrane and subsequently hybridized. Multiple linear regression (MLR) and partial least square (PLS) techniques were used to reveal the most influential factors in the amplification reaction and to identify possible interacting factors. Ligation temperature proved to be the most important factor in the reaction: Temperatures far below the melting point of the oligonucleotide increased the yield considerably. Higher cycle number resulted in a continuous rise in intensity, indicating that the ligase remained active even after 700 cycles or 12 hr of cycling. In addition, the concentration of ligase was found to be important. Using optimal parameters, a 5.5- and 3.2-fold increase in the yield of 180- and 360-nucleotide products respectively was obtained. The improved sensitivity makes the method more robust and facilitates detection of repeat expansions. This improvement may be particularly useful in development of RED for diagnostic purposes as well as for nonradioactive detection of RED products. Based on these results, a new protocol for the RED method was developed taking into account the risk of introducing artifacts with increased enzyme concentrations and lowered annealing temperatures.
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| 65. |
- Abu-samha, M, et al.
(författare)
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The local structure of small water clusters : imprints on the core-level photoelectron spectrum
- 2009
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Ingår i: Journal of Physics B. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 42:5, s. 055201-
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Tidskriftsartikel (refereegranskat)abstract
- We report on an O 1s photoelectron-spectroscopy study of small neutral water clusters produced by adiabatic expansion. The photoelectron spectra were acquired under two different experimental conditions. At intermediate resolution, the cluster signal was characterized by a very broad O 1s peak with a flat top. In the second set of measurements, resolution was significantly increased at the cost of lower count rates. The cluster signal was now partly resolved into a bimodal structure. Extensive theoretical calculations were undertaken to facilitate an interpretation of the spectrum. These results suggest that the bimodal feature may be ascribed to ionization of water molecules in different hydrogen-bonding configurations, more specifically, molecules characterized by donation of either one or both hydrogen atoms in H-bonding.
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| 66. |
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| 67. |
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| 68. |
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| 69. |
- Andersson, Karin, 1972, et al.
(författare)
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Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment.
- 2015
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Ingår i: Molecular medicine (Cambridge, Mass.). - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 21, s. 536-43
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Tidskriftsartikel (refereegranskat)abstract
- T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF ). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF ) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.
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| 70. |
- Andrews, Gregory, et al.
(författare)
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Mammalian evolution of human cis-regulatory elements and transcription factor binding sites
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element-derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.
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