| 1. |
- Collantes, Edward Ryan A., et al.
(author)
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EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma
- 2022
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In: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 43:2, s. 240-252
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Journal article (peer-reviewed)abstract
- Juvenile open-angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novel EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co-segregating with disease. Affected variant carriers (N = 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early-onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.
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| 2. |
- Le Gouellec, Valentin J. M., et al.
(author)
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The Origin of Dust Polarization in the Orion Bar
- 2023
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In: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 951:2
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Journal article (peer-reviewed)abstract
- The linear polarization of thermal dust emission provides a powerful tool to probe interstellar and circumstellar magnetic fields, because aspherical grains tend to align themselves with magnetic field lines. While the Radiative Alignment Torque (RAT) mechanism provides a theoretical framework for this phenomenon, some aspects of this alignment mechanism still need to be quantitatively tested. One such aspect is the possibility that the reference alignment direction changes from the magnetic field ("B-RAT") to the radiation field k-vector ("k-RAT") in areas of strong radiation fields. We investigate this transition toward the Orion Bar PDR, using multiwavelength SOFIA HAWC+ dust polarization observations. The polarization angle maps show that the radiation field direction is on average not the preferred grain alignment axis. We constrain the grain sizes for which the transition from B-RAT to k-RAT occurs in the Orion Bar (grains & GE; 0.1 & mu;m toward the most irradiated locations), and explore the radiatively driven rotational disruption that may take place in the high-radiation environment of the Bar for large grains. While the grains susceptible to rotational disruption should be in suprathermal rotation and aligned with the magnetic field, k-RAT aligned grains would rotate at thermal velocities. We find that the grain size at which the alignment shifts from B-RAT to k-RAT corresponds to grains too large to survive the rotational disruption. Therefore, we expect a large fraction of grains to be aligned at suprathermal rotation with the magnetic field, and to potentially be subject to rotational disruption, depending on their tensile strength.
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| 3. |
- Porth, Ann Kristin, et al.
(author)
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Standardising personalised diabetes care across European health settings: A person-centred outcome set agreed in a multinational Delphi study
- 2024
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In: Diabetic Medicine. - 0742-3071 .- 1464-5491. ; 41:5
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Journal article (peer-reviewed)abstract
- Objective: Standardised person-reported outcomes (PRO) data can contextualise clinical outcomes enabling precision diabetes monitoring and care. Comprehensive outcome sets can guide this process, but their implementation in routine diabetes care has remained challenging and unsuccessful at international level. We aimed to address this by developing a person-centred outcome set for Type 1 and Type 2 diabetes, using a methodology with prospects for increased implementability and sustainability in international health settings. Methods: We used a three-round questionnaire-based Delphi study to reach consensus on the outcome set. We invited key stakeholders from 19 countries via purposive snowball sampling, namely people with diabetes (N = 94), healthcare professionals (N = 65), industry (N = 22) and health authorities (N = 3), to vote on the relevance and measurement frequency of 64 previously identified clinical and person-reported outcomes. Subsequent consensus meetings concluded the study. Results: The list of preliminary outcomes was shortlisted via the consensus process to 46 outcomes (27 clinical outcomes and 19 PROs). Two main collection times were recommended: (1) linked to a medical visit (e.g. diabetes-specific well-being, symptoms and psychological health) and (2) annually (e.g. clinical data, general well-being and diabetes self management-related outcomes). Conclusions: PROs are often considered in a non-standardised way in routine diabetes care. We propose a person-centred outcome set for diabetes, specifically considering psychosocial and behavioural aspects, which was agreed by four international key stakeholder groups. It guides standardised collection of meaningful outcomes at scale, supporting individual and population level healthcare decision making. It will be implemented and tested in Europe as part of the H2O project.
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| 4. |
- Wang, Ying, et al.
(author)
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Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade
- 2020
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In: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 117:27, s. 15818-15826
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Journal article (peer-reviewed)abstract
- Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsoninsensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.
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