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- Rosenhahn, Erik, et al.
(författare)
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Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications
- 2022
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Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 109:8, s. 1421-1435
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Tidskriftsartikel (refereegranskat)abstract
- PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.
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- Edgar, Rebecca J., et al.
(författare)
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Discovery of glycerol phosphate modification on streptococcal rhamnose polysaccharides
- 2019
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Ingår i: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 15:5, s. 463-
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Tidskriftsartikel (refereegranskat)abstract
- Cell wall glycopolymers on the surface of Gram-positive bacteria are fundamental to bacterial physiology and infection biology. Here we identify gacH, a gene in the Streptococcus pyogenes group A carbohydrate (GAC) biosynthetic cluster, in two independent transposon library screens for its ability to confer resistance to zinc and susceptibility to the bactericidal enzyme human group IIA-secreted phospholipase A(2). Subsequent structural and phylogenetic analysis of the GacH extracellular domain revealed that GacH represents an alternative class of glycerol phosphate transferase. We detected the presence of glycerol phosphate in the GAC, as well as the serotype c carbohydrate from Streptococcus mutans, which depended on the presence of the respective gacH homologs. Finally, nuclear magnetic resonance analysis of GAC confirmed that glycerol phosphate is attached to approximately 25% of the GAC N-acetylglucosamine side-chains at the C6 hydroxyl group. This previously unrecognized structural modification impacts host-pathogen interaction and has implications for vaccine design.
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- Hernández‑Morcillo, Monica, et al.
(författare)
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Scanning the solutions for the sustainable supply of forest ecosystem services in Europe
- 2022
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Ingår i: Sustainability Science. - : Springer Science and Business Media LLC. - 1862-4057 .- 1862-4065. ; 17:5, s. 2013-2029
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Tidskriftsartikel (refereegranskat)abstract
- Forests are key components of European multifunctional landscapes and supply numerous forest ecosystem services (FES) fundamental to human well-being. The sustainable provision of FES has the potential to provide responses to major societal challenges, such as climate change, biodiversity loss, or rural development. To identify suitable strategies for the future sustenance of FES, we performed a solution scanning exercise with a group of transdisciplinary forest and FES experts from diferent European regions. We identifed and prioritized ffteen major challenges hindering the balanced provision of multiple FES and identifed a series of potential solutions to tackle each of them. The most prominent challenges referred to the increased frequency and impacts of extreme weather events and the normative mindset regarding forest management. The respective solutions pointed to the promotion of forest resilience via climate-smart forestry and mainstreaming FES-orientedmanagement through a threefold strategy focusing on education, awareness raising, and networking. In a subsequent survey,most solutions were assessed as highly efective, transferable, monitorable, and with potential for being economically efcient. The implementation of the solutions could have synergistic efects when applying the notion of leverage points. Sevenemerging pathways towards the sustainable supply of FES have been identifed. These pathways build on each other and areorganized based on their potential for transformation: (1) shifting forest management paradigms towards pluralistic ecosystem valuation; (2) using integrated landscape approaches; (3) increasing forest resilience; (4) coordinating actions betweenforest-related actors; (5) increasing participation in forest planning and management; (6) continuous, open, and transparentknowledge integration; and (7) using incentive-based instruments to support regulating and cultural FES. These pathwayscan contribute to the implementation of the new EU Forestry Strategy to support the balanced supply of multiple FES.
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- Sherk, Adam, et al.
(författare)
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The public-private decision for alcohol retail systems : Examining the economic, health, and social impacts of alternative systems in Finland
- 2023
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Ingår i: Nordic Studies on Alcohol and Drugs. - : SAGE Publications. - 1455-0725 .- 1458-6126. ; 40:3, s. 218-232
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Tidskriftsartikel (refereegranskat)abstract
- Background: Organising alcohol retail systems with more or less public ownership has implications for health and the economy. The aim of the present study was to estimate the economic, health, and social impacts of alcohol use in Finland in 2018 (baseline), and in two alternative scenarios in which current partial public ownership of alcohol retail sales is either increased or fully privatised.Methods: Baseline alcohol-attributable harms and costs were estimated across five categories of death, disability, and criminal justice. Two alternate alcohol retail systems were defined as privately owned stores selling: (1) only low strength alcoholic beverages (public ownership scenario, similar to Sweden); or (2) all beverages (private ownership scenario). Policy analyses were conducted to estimate changes in alcohol use per capita. Health and economic impacts were modelled using administrative data and epidemiological modelling.Results: In Finland in 2018, alcohol use was estimated to be responsible for €1.51 billion (95% Uncertainty Estimates: €1.43 billion, €1.58 billion) in social cost, 3,846 deaths, and 270,652 criminal justice events. In the public ownership scenario, it was estimated that alcohol use would decline by 15.8% (11.8%, 19.7%) and social cost by €384.3 million (€189.5 million, €559.2 million). Full privatisation was associated with an increase in alcohol use of 9.0% (6.2%, 11.8%) and an increase in social cost of €289.7 million (€140.8 million, €439.5 million).Conclusion: The outcome from applying a novel analytical approach suggests that more public ownership of the alcohol retail system may lead to significant decreases in alcohol-caused death, disability, crime, and social costs. Conversely, full privatisation of the ownership model would lead to increased harm and costs.
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- van Hensbergen, Vincent P., et al.
(författare)
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Streptococcal Lancefield polysaccharides are critical cell wall determinants for human Group IIA secreted phospholipase A2 to exert its bactericidal effects
- 2018
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 14:10, s. 1007348-1007348
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Tidskriftsartikel (refereegranskat)abstract
- Human Group IIA secreted phospholipase A2 (hGIIA) is an acute phase protein with bactericidal activity against Gram-positive bacteria. Infection models in hGIIA transgenic mice have suggested the importance of hGIIA as an innate defense mechanism against the human pathogens Group A Streptococcus (GAS) and Group B Streptococcus (GBS). Compared to other Gram-positive bacteria, GAS is remarkably resistant to hGIIA activity. To identify GAS resistance mechanisms, we exposed a highly saturated GAS M1 transposon library to recombinant hGIIA and compared relative mutant abundance with library input through transposon-sequencing (Tn-seq). Based on transposon prevalence in the output library, we identified nine genes, including dltA and lytR, conferring increased hGIIA susceptibility. In addition, seven genes conferred increased hGIIA resistance, which included two genes, gacH and gacI that are located within the Group A Carbohydrate (GAC) gene cluster. Using GAS 5448 wild-type and the isogenic gacI mutant and gacI-complemented strains, we demonstrate that loss of the GAC N-acetylglucosamine (GlcNAc) side chain in the ΔgacI mutant increases hGIIA resistance approximately 10-fold, a phenotype that is conserved across different GAS serotypes. Increased resistance is associated with delayed penetration of hGIIA through the cell wall. Correspondingly, loss of the Lancefield Group B Carbohydrate (GBC) rendered GBS significantly more resistant to hGIIA-mediated killing. This suggests that the streptococcal Lancefield antigens, which are critical determinants for streptococcal physiology and virulence, are required for the bactericidal enzyme hGIIA to exert its bactericidal function.
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- van Sorge, Nina M., et al.
(författare)
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Bacterial protein domains with a novel Ig-like fold target human CEACAM receptors
- 2021
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Ingår i: EMBO Journal. - : Wiley-VCH Verlagsgesellschaft. - 0261-4189 .- 1460-2075. ; 40
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus agalactiae, also known as group B Streptococcus (GBS), is the major cause of neonatal sepsis in humans. A critical step to infection is adhesion of bacteria to epithelial surfaces. GBS adhesins have been identified to bind extracellular matrix components and cellular receptors. However, several putative adhesins have no host binding partner characterised. We report here that surface-expressed β protein of GBS binds to human CEACAM1 and CEACAM5 receptors. A crystal structure of the complex showed that an IgSF domain in β represents a novel Ig-fold subtype called IgI3, in which unique features allow binding to CEACAM1. Bioinformatic assessment revealed that this newly identified IgI3 fold is not exclusively present in GBS but is predicted to be present in adhesins from other clinically important human pathogens. In agreement with this prediction, we found that CEACAM1 binds to an IgI3 domain found in an adhesin from a different streptococcal species. Overall, our results indicate that the IgI3 fold could provide a broadly applied mechanism for bacteria to target CEACAMs.
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