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- Elsaid, K., et al.
(författare)
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Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia
- 2023
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 75:5, s. 794-805
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Tidskriftsartikel (refereegranskat)abstract
- Objective In gout, hyperuricemia promotes urate crystal deposition, which stimulates the NLRP3 inflammasome and interleukin-1 beta (IL-1 beta)-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis in a young female patient with normouricemia diagnosed as having sufficient and weighted classification criteria for gout according to the American College of Rheumatology (ACR)/EULAR gout classification criteria (the proband).Methods We conducted whole-genome sequencing, quantitative proteomics, whole-blood RNA-sequencing analysis using serum samples from the proband. We used a mouse model of IL-1 beta-induced knee synovitis to characterize proband candidate genes, biomarkers, and pathogenic mechanisms of gout.Results Lubricin level was attenuated in human proband serum and associated with elevated acute-phase reactants and inflammatory whole-blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of inter-alpha trypsin inhibitor heavy chain 3, an inhibitor of lubricin-degrading cathepsin G. Changes in the proband's serum protein interactome network supported enhanced lubricin degradation, with cathepsin G activity increased relative to its inhibitors, SERPINB6 and thrombospondin 1. Activation of Toll-like receptor 2 (TLR-2) suppressed levels of lubricin mRNA and lubricin release in cultured human synovial fibroblasts (P < 0.01). Lubricin blunted urate crystal precipitation and IL-1 beta induction of xanthine oxidase and urate in cultured macrophages (P < 0.001). In lubricin-deficient mice, injection of IL-1 beta in knees increased xanthine oxidase-positive synovial resident M1 macrophages (P < 0.05).Conclusion Our findings linked normouricemic erosive gout to attenuated lubricin, with impaired control of cathepsin G activity, compounded by deleterious NLRP3 variants. Lubricin suppressed monosodium urate crystallization and blunted IL-1 beta-induced increases in xanthine oxidase and urate in macrophages. The collective activities of articular lubricin that could limit incident and erosive gouty arthritis independently of hyperuricemia are subject to disruption by inflammation, activated cathepsin G, and synovial fibroblast TLR-2 signaling.
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- Laine, Christine M., et al.
(författare)
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WNT1 Mutations in Early-Onset Osteoporosis and Osteogenesis Imperfecta
- 2013
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 368:19, s. 1809-1816
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Tidskriftsartikel (refereegranskat)abstract
- This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T -> G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C -> A, p.Ser295(star). In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.
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| 12. |
- Verberne, EA, et al.
(författare)
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DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:14
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Tidskriftsartikel (refereegranskat)abstract
- JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.
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- Agelidis, Alex, et al.
(författare)
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Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival
- 2021
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Ingår i: JCI Insight. - : American Society For Clinical Investigation. - 2379-3708. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we followed heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late-stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.
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- Campeau, Audrey, et al.
(författare)
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Patterns in CH4 and CO2 concentrations across boreal rivers : Major drivers and implications for fluvial greenhouse emissions under climate change scenarios
- 2014
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 20:4, s. 1075-1088
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Tidskriftsartikel (refereegranskat)abstract
- It is now widely accepted that boreal rivers and streams are regionally significant sources of carbon dioxide (CO2), yet their role as methane (CH4) emitters, as well as the sensitivity of these greenhouse gas (GHG) emissions to climate change, are still largely undefined. In this study, we explore the large-scale patterns of fluvial CO2 and CH4 partial pressure (pCO(2),pCH(4)) and gas exchange (k) relative to a set of key, climate-sensitive river variables across 46 streams and rivers in two distinct boreal landscapes of Northern Quebec. We use the resulting models to determine the direction and magnitude of C-gas emissions from these boreal fluvial networks under scenarios of climate change. River pCO(2) and pCH(4) were positively correlated, although the latter was two orders of magnitude more variable. We provide evidence that in-stream metabolism strongly influences the dynamics of surface water pCO(2) and pCH(4), but whereas pCO(2) is not influenced by temperature in the surveyed streams and rivers, pCH(4) appears to be strongly temperature-dependent. The major predictors of ambient gas concentrations and exchange were water temperature, velocity, and DOC, and the resulting models indicate that total GHG emissions (C-CO2 equivalent) from the entire network may increase between by 13 to 68% under plausible scenarios of climate change over the next 50years. These predicted increases in fluvial GHG emissions are mostly driven by a steep increase in the contribution of CH4 (from 36 to over 50% of total CO2-equivalents). The current role of boreal fluvial networks as major landscape sources of C is thus likely to expand, mainly driven by large increases in fluvial CH4 emissions.
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| 15. |
- Campeau, Audrey, et al.
(författare)
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Regional contribution of CO2 and CH4 fluxes from the fluvial network in a lowland boreal landscape of Quebec
- 2014
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Ingår i: Global Biogeochemical Cycles. - 0886-6236 .- 1944-9224. ; 28:1, s. 57-69
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Tidskriftsartikel (refereegranskat)abstract
- Boreal rivers and streams are known as hot spots of CO2 emissions, yet their contribution to CH4 emissions has traditionally been assumed to be negligible, due to the spatially fragmented data and lack of regional studies addressing both gases simultaneously. Here we explore the regional patterns in river CO2 and CH4 concentrations (pCO(2) and pCH(4)), gas exchange coefficient (k), and the resulting emissions in a lowland boreal region of Northern Quebec. Rivers and streams were systematically supersaturated in both gases, with both pCO(2) and pCH(4) declining along the river continuum. The k was on average low and increased with stream order, consistent with the hydrology of this flat landscape. The smallest streams (order 1), which represent <20% of the total river surface, contributed over 35% of the total fluvial greenhouse gas (GHG) emissions. The end of winter and the spring thaw periods, which are rarely included in annual emission budgets, contributed on average 21% of the annual GHG emissions. As a whole, the fluvial network acted as significant source of both CO2 and CH4, releasing on average 1.5 tons of C (CO2 eq) yr(-1)km(-2) of landscape, of which CH4 emissions contributed approximately 34%. We estimate that fluvial CH4 emissions represent 41% of the regional aquatic (lakes, reservoirs, and rivers) CH4 emissions, despite the relatively small riverine surface (4.3% of the total aquatic surface). We conclude that these fluvial networks in boreal lowlands play a disproportionately large role as hot spots for CO2 and more unexpectedly for CH4 emissions. Key Points pCO(2) and pCH(4) decrease, whereas the k600 increases with increasing stream order Small streams and spring thaw period play a large role in regional C balance Rivers are significant sources of CO2 and unexpectedly large sources of CH4
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| 16. |
- Campeau, A., et al.
(författare)
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Stable Carbon Isotopes Reveal Soil-Stream DIC Linkages in Contrasting Headwater Catchments
- 2018
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Ingår i: Journal of Geophysical Research-Biogeosciences. - : American Geophysical Union (AGU). - 2169-8953 .- 2169-8961. ; 123:1, s. 149-167
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Tidskriftsartikel (refereegranskat)abstract
- Large CO2 evasion to the atmosphere occurs as dissolved inorganic carbon (DIC) is transported from soils to streams. While this physical process has been the focus of multiple studies, less is known about the underlying biogeochemical transformations that accompany this transfer of C from soils to streams. Here we used patterns in stream water and groundwater C-13-DIC values within three headwater catchments with contrasting land cover to identify the sources and processes regulating DIC during its transport. We found that although considerable CO2 evasion occurs as DIC is transported from soils to streams, there were also other processes affecting the DIC pool. Methane production and mixing of C sources, associated with different types and spatial distribution of peat-rich areas within each catchment, had a significant influence on the C-13-DIC values in both soils and streams. These processes represent an additional control on C-13-DIC values and the catchment-scale cycling of DIC across different northern landscape types. The results from this study demonstrate that the transport of DIC from soils to streams results in more than just rapid CO2 evasion to the atmosphere but also represents a channel of C transformation, which questions some of our current conceptualizations of C cycling at the landscape scale. Plain Language Summary Large carbon dioxide emission to the atmosphere occurs as rainwater percolates through soils and into streams. This physical process is important for the global carbon cycle and has been the focus of multiple studies. However, less is known about the underlying processes that accompanies this transfer of carbon dioxide from soils to streams. Here we analyze the stable isotope composition of soil and stream carbon dioxide and demonstrate that methane production and mixing of carbon sources also occur in soils and streams. These processes were linked to different types and configurations of peat-rich areas, for example, bogs, fens, and riparian zones, found within each of the three studied catchments. Our results therefore demonstrate that the export of carbon dioxide from soils to streams not only results in emissions to the atmosphere but also represents a channel of transformation. This questions some of our current conceptualization of the catchment-scale cycling of carbon dioxide.
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| 17. |
- Johnstone, Devon L., et al.
(författare)
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Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ : Report of seven new subjects and review of the literature
- 2020
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 43:6, s. 1321-1332
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Tidskriftsartikel (refereegranskat)abstract
- We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ.
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| 18. |
- Muralidharan, Somsundar Veppil, et al.
(författare)
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BET bromodomain inhibitors synergize with ATR inhibitors in melanoma in melanoma.
- 2017
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Ingår i: Cell Death & Disease. - 2041-4889. ; 8:8, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.
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| 19. |
- Palmer, Elizabeth E., et al.
(författare)
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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
- 2023
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Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; 28:2, s. 668-697
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Tidskriftsartikel (refereegranskat)abstract
- Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
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| 20. |
- Wallin, Marcus, 1979-, et al.
(författare)
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Carbon dioxide and methane emissions of Swedish low-order streams : a national estimate and lessons learnt from more than a decade of observations
- 2018
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Ingår i: Limnology and Oceanography Letters. - : John Wiley & Sons. - 2378-2242. ; 3:3, s. 156-167
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Tidskriftsartikel (refereegranskat)abstract
- Low-order streams are suggested to dominate the atmospheric CO2 source of all inland waters. Yet, many large-scale stream estimates suffer from methods not designed for gas emission determination and rarely include other greenhouse gases such as CH4. Here, we present a compilation of directly measured CO2 and CH4 concentration data from Swedish low-order streams (> 1600 observations across > 500 streams) covering large climatological and land-use gradients. These data were combined with an empirically derived gas transfer model and the characteristics of a ca. 400,000 km stream network covering the entire country. The total stream CO2 and CH4 emission corresponded to 2.7 Tg C yr(-1) (95% confidence interval: 2.0-3.7) of which the CH4 accounted for 0.7% (0.02 Tg C yr(-1)). The study highlights the importance of low-order streams, as well as the critical need to better represent variability in emissions and stream areal extent to constrain future stream C emission estimates.
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