| 1. |
- Abbafati, Cristiana, et al.
(author)
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- 2020
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Journal article (peer-reviewed)
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| 2. |
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| 3. |
- Bacic, Luka
(author)
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Molecular mechanisms underlying the activation of ALC1 nucleosome remodeling
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Packaging DNA into chromatin represses essential DNA-based processes, such as transcription, DNA replication, and repair. To change the accessibility of DNA, cells have evolved a set of enzymes referred to as chromatin remodelers that act on the basic repeat unit of chromatin, the nucleosome. Chromatin remodelers are critical for normal cell physiology and development. Dysfunction or aberrant regulation of chromatin remodelers can lead to multisystem developmental disorders and cancers. DNA damage represents a major threat to eukaryotic cells. When DNA damage persists, the cell can enter programmed cell death. To avoid such a dramatic outcome, cells must rapidly recognize the DNA damage and trigger DNA repair pathways. An early event following DNA damage is the relaxation of chromatin. Chromatin relaxation depends on ATP consumption and ADP-ribosylation, where the site of DNA damage is marked with ADP-ribose units. ADP-ribose, in turn, can be recognized by the macro domain of the remodeler ALC1 (Amplified in Liver Cancer 1). ALC1 has therefore been implicated in the DNA damage response. In the absence of DNA damage, the macro domain of ALC1 is placed against its ATPase motor to inhibit its activity. However, it is unclear how ALC1, in its active state, engages the nucleosome. Moreover, the mechanism by which ALC1 is fully activated upon recruitment is poorly understood, and the impact of ALC1-catalyzed nucleosome sliding in the vicinity of a DNA damage site is unknown. This thesis investigates how ALC1 engages its substrate, the nucleosome, and how histone modifications can regulate ALC1 activity. Structural and biophysical approaches revealed an ALC1 regulatory segment that binds to the acidic patch, a prominent feature on the nucleosome surface. Further analysis showed that the interaction between ALC1 and the acidic patch is required to fully activate ALC1. Moreover, in vitro ADP-ribosylation of nucleosomes enabled us to form a stable complex of nucleosome-bound ALC1 amenable to structural determination by cryogenic electron microscopy. Our structural models visualize nucleosomal epitopes that play an important role in stimulating productive remodeling by ALC1, as confirmed by various biochemical approaches. Taken together, our data suggested a possible mechanism by which ALC1 could render DNA breaks more accessible to downstream repair factors. Since recent studies defined ALC1 as an attractive anti-cancer target, this thesis provides insights into the molecular mechanisms that regulate ALC1 activity as a potential starting point for structure-based drug development.
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| 4. |
- Bennett, Joanne M., et al.
(author)
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Land use and pollinator dependency drives global patterns of pollen limitation in the Anthropocene
- 2020
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Land use change, by disrupting the co-evolved interactions between plants and their pollinators, could be causing plant reproduction to be limited by pollen supply. Using a phylogenetically controlled meta-analysis on over 2200 experimental studies and more than 1200 wild plants, we ask if land use intensification is causing plant reproduction to be pollen limited at global scales. Here we report that plants reliant on pollinators in urban settings are more pollen limited than similarly pollinator-reliant plants in other landscapes. Plants functionally specialized on bee pollinators are more pollen limited in natural than managed vegetation, but the reverse is true for plants pollinated exclusively by a non-bee functional group or those pollinated by multiple functional groups. Plants ecologically specialized on a single pollinator taxon were extremely pollen limited across land use types. These results suggest that while urbanization intensifies pollen limitation, ecologically and functionally specialized plants are at risk of pollen limitation across land use categories. An insufficient amount of pollen transfer by pollinators (pollen limitation) could reduce plant reproduction in human-impacted landscapes. Here the authors conduct a global meta-analysis and find that pollen limitation is high in urban environments and depends of plant traits such as pollinator dependency.
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| 5. |
- Chen, Gefei, et al.
(author)
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Molecular basis for different substrate-binding sites and chaperone functions of the BRICHOS domain
- 2024
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In: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 33:7
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Journal article (peer-reviewed)abstract
- Proteins can misfold into fibrillar or amorphous aggregates and molecular chaperones act as crucial guardians against these undesirable processes. The BRICHOS chaperone domain, found in several otherwise unrelated proproteins that contain amyloidogenic regions, effectively inhibits amyloid formation and toxicity but can in some cases also prevent non-fibrillar, amorphous protein aggregation. Here, we elucidate the molecular basis behind the multifaceted chaperone activities of the BRICHOS domain from the Bri2 proprotein. High-confidence AlphaFold2 and RoseTTAFold predictions suggest that the intramolecular amyloidogenic region (Bri23) is part of the hydrophobic core of the proprotein, where it occupies the proposed amyloid binding site, explaining the markedly reduced ability of the proprotein to prevent an exogenous amyloidogenic peptide from aggregating. However, the BRICHOS-Bri23 complex maintains its ability to form large polydisperse oligomers that prevent amorphous protein aggregation. A cryo-EM-derived model of the Bri2 BRICHOS oligomer is compatible with surface-exposed hydrophobic motifs that get exposed and come together during oligomerization, explaining its effects against amorphous aggregation. These findings provide a molecular basis for the BRICHOS chaperone domain function, where distinct surfaces are employed against different forms of protein aggregation.
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| 6. |
- Halle-Smith, James M., et al.
(author)
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Perioperative interventions to reduce pancreatic fistula following pancreatoduodenectomy : meta-analysis
- 2022
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In: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 109:9, s. 812-821
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Journal article (peer-reviewed)abstract
- BACKGROUND: Data on interventions to reduce postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD) are conflicting. The aim of this study was to assimilate data from RCTs. METHODS: MEDLINE and Embase databases were searched systematically for RCTs evaluating interventions to reduce all grades of POPF or clinically relevant (CR) POPF after PD. Meta-analysis was undertaken for interventions investigated in multiple studies. A post hoc analysis of negative RCTs assessed whether these had appropriate statistical power. RESULTS: Among 22 interventions (7512 patients, 55 studies), 12 were assessed by multiple studies, and subjected to meta-analysis. Of these, external pancreatic duct drainage was the only intervention associated with reduced rates of both CR-POPF (odds ratio (OR) 0.40, 95 per cent c.i. 0.20 to 0.80) and all-POPF (OR 0.42, 0.25 to 0.70). Ulinastatin was associated with reduced rates of CR-POPF (OR 0.24, 0.06 to 0.93). Invagination (versus duct-to-mucosa) pancreatojejunostomy was associated with reduced rates of all-POPF (OR 0.60, 0.40 to 0.90). Most negative RCTs were found to be underpowered, with post hoc power calculations indicating that interventions would need to reduce the POPF rate to 1 per cent or less in order to achieve 80 per cent power in 16 of 34 (all-POPF) and 19 of 25 (CR-POPF) studies respectively. CONCLUSION: This meta-analysis supports a role for several interventions to reduce POPF after PD. RCTs in this field were often relatively small and underpowered, especially those evaluating CR-POPF.
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| 7. |
- Ho, Phay J., et al.
(author)
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The role of transient resonances for ultra-fast imaging of single sucrose nanoclusters
- 2020
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11
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Journal article (peer-reviewed)abstract
- Intense x-ray free-electron laser (XFEL) pulses hold great promise for imaging function in nanoscale and biological systems with atomic resolution. So far, however, the spatial resolution obtained from single shot experiments lags averaging static experiments. Here we report on a combined computational and experimental study about ultrafast diffractive imaging of sucrose clusters which are benchmark organic samples. Our theoretical model matches the experimental data from the water window to the keV x-ray regime. The large-scale dynamic scattering calculations reveal that transient phenomena driven by non-linear x-ray interaction are decisive for ultrafast imaging applications. Our study illuminates the complex interplay of the imaging process with the rapidly changing transient electronic structures in XFEL experiments and shows how computational models allow optimization of the parameters for ultrafast imaging experiments. X-ray free electron lasers provide high photon flux to explore single particle diffraction imaging of biological samples. Here the authors present dynamic electronic structure calculations and benchmark them to single-particle XFEL diffraction data of sucrose clusters to predict optimal single-shot imaging conditions.
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| 8. |
- Jiang, Wanghsu, et al.
(author)
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MrpH, a new class of metal-binding adhesin, requires zinc to mediate biofilm formation
- 2020
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In: PLoS Pathogens. - : PUBLIC LIBRARY SCIENCE. - 1553-7366 .- 1553-7374. ; 16:8
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Journal article (peer-reviewed)abstract
- Author summary Many bacteria use fimbriae to adhere to surfaces, and this function is often essential for pathogens to gain a foothold in the host. In this study, we examine the major virulence-associated fimbrial protein, MrpH, of the bacterial urinary tract pathogenProteus mirabilis. This species is particularly known for causing catheter-associated urinary tract infections, in which it forms damaging urinary stones and crystalline biofilms that can block the flow of urine through indwelling catheters. MrpH resides at the tip of mannose-resistantProteus-like (MR/P) fimbriae and is required for MR/P-dependent adherence to surfaces. Although MR/P belongs to a well-known class of adhesive fimbriae encoded by the chaperone-usher pathway, we found that MrpH has a dramatically different structure compared with other tip-located adhesins in this family. Unexpectedly, MrpH was found to bind a zinc cation, which we show is essential for MR/P-mediated biofilm formation and adherence to red blood cells. Furthermore, MR/P-mediated adherence can be modified by controlling zinc levels. These findings have the potential to aid development of better anti-biofilm urinary catheters or other methods to preventP.mirabilisinfection of the urinary tract. Proteus mirabilis, a Gram-negative uropathogen, is a major causative agent in catheter-associated urinary tract infections (CAUTI). Mannose-resistantProteus-like fimbriae (MR/P) are crucially important forP.mirabilisinfectivity and are required for biofilm formation and auto-aggregation, as well as for bladder and kidney colonization. Here, the X-ray crystal structure of the MR/P tip adhesin, MrpH, is reported. The structure has a fold not previously described and contains a transition metal center with Zn(2+)coordinated by three conserved histidine residues and a ligand. Using biofilm assays, chelation, metal complementation, and site-directed mutagenesis of the three histidines, we show that an intact metal binding site occupied by zinc is essential for MR/P fimbria-mediated biofilm formation, and furthermore, thatP.mirabilisbiofilm formation is reversible in a zinc-dependent manner. Zinc is also required for MR/P-dependent agglutination of erythrocytes, and mutation of the metal binding site rendersP.mirabilisunfit in a mouse model of UTI. The studies presented here provide important clues as to the mechanism of MR/P-mediated biofilm formation and serve as a starting point for identifying the physiological MR/P fimbrial receptor.
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| 9. |
- Knight, Sean, et al.
(author)
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Tunable cavity-enhanced terahertz frequency-domain optical Hall effect
- 2020
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In: Review of Scientific Instruments. - : AMER INST PHYSICS. - 0034-6748 .- 1089-7623. ; 91:8
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Journal article (peer-reviewed)abstract
- Presented here is the development and demonstration of a tunable cavity-enhanced terahertz (THz) frequency-domain optical Hall effect (OHE) technique. The cavity consists of at least one fixed and one tunable Fabry-Perot resonator. The approach is suitable for the enhancement of the optical signatures produced by the OHE in semi-transparent conductive layer structures with plane parallel interfaces. Tuning one of the cavity parameters, such as the external cavity thickness, permits shifting of the frequencies of the constructive interference and provides substantial enhancement of the optical signatures produced by the OHE. A cavity-tuning optical stage and gas flow cell are used as examples of instruments that exploit tuning an external cavity to enhance polarization changes in a reflected THz beam. Permanent magnets are used to provide the necessary external magnetic field. Conveniently, the highly reflective surface of a permanent magnet can be used to create the tunable external cavity. The signal enhancement allows the extraction of the free charge carrier properties of thin films and can eliminate the need for expensive superconducting magnets. Furthermore, the thickness of the external cavity establishes an additional independent measurement condition, similar to, for example, the magnetic field strength, THz frequency, and angle of incidence. A high electron mobility transistor (HEMT) structure and epitaxial graphene are studied as examples. The tunable cavity-enhancement effect provides a maximum increase of more than one order of magnitude in the change of certain polarization components for both the HEMT structure and epitaxial graphene at particular frequencies and external cavity sizes.
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| 10. |
- Kurilshikov, Alexander, et al.
(author)
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Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
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Journal article (peer-reviewed)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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| 11. |
- Lehmann, Laura C., 1991-
(author)
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Allosteric control of ALC1-catalyzed nucleosome remodeling
- 2021
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Doctoral thesis (other academic/artistic)abstract
- The genetic information of eukaryotic cells is packaged inside the nucleus as chromatin. This packaging restricts access to the DNA and therefore represents a barrier for processes such as DNA replication, repair, and gene expression. Specialized enzymes, termed ATP-dependent chromatin remodelers (remodelers), are involved in regulating the chromatin landscape by repositioning, ejecting, and altering the composition of nucleosomes, the smallest building blocks of chromatin. Remodelers are tightly regulated by post-translational modifications, nucleosomal features, as well as by their own domains and subunits. Dysregulation of remodeling activity has been implicated in severe disease states such as various types of cancer.ALC1/CHD1L (Amplified in Liver Cancer 1/Chromodomain-Helicase-DNA-binding protein 1-Like) is an oncogenic remodeler involved in DNA damage repair. This thesis investigates the molecular basis of ALC1 regulation, the role of the nucleosome and its features in ALC1 activation, as well as the role of this remodeler in DNA damage repair. The results presented in this thesis show that, without DNA damage, the catalytic domain of ALC1 adopts an inactive conformation that is stabilized through a conserved electrostatic interface with the macro domain of ALC1. Upon DNA damage, the binding of PAR chains to the macro domain displaces it from the ATPase motor of ALC1, thereby priming the remodeler for activation. Full activation additionally requires the interaction between a regulatory segment in the linker region of ALC1 and the nucleosome acidic patch. This interaction tethers the remodeler to the nucleosome and is required for coupling ATP hydrolysis to nucleosome remodeling. Additionally, investigations of ALC1 in vivo showed that the loss of ALC1 sensitizes cells to PARP inhibitors and is synthetic lethal with homologous recombination deficiency. This makes ALC1 a possible target for therapeutic drugs in combination with PARP inhibitors for cancers that are deficient in homologous recombination.
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| 12. |
- Pakharukova, Natalia, et al.
(author)
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Archaic chaperone-usher pili self-secrete into superelastic zigzag springs
- 2022
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 609:7926, s. 335-340
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Journal article (peer-reviewed)abstract
- Adhesive pili assembled via the chaperone-usher pathway (CUP) are hair-like appendages that mediate host tissue colonization and biofilm formation of Gram-negative bacteria 1-3. Archaic CUP pili, the most diverse and widespread CUP adhesins, are promising vaccine and drug targets due to their prevalence in the most troublesome multidrug-resistant (MDR) pathogens 1,4,5. However, their architecture and assembly-secretion process remain unknown. Here, we present the 3.4 Å resolution cryo-electron microscopy structure of the prototypical archaic Csu pilus that mediates biofilm formation of Acinetobacter baumannii, a notorious MDR nosocomial pathogen. In contrast to the thick helical tubes of the classical type 1 and P pili, archaic pili assemble into a conceptually novel ultrathin zigzag architecture secured by an elegant clinch mechanism. The molecular clinch provides the pilus with high mechanical stability as well as superelasticity, a property observed now for the first time in biomolecules, while enabling a more economical and faster pilus production. Furthermore, we demonstrate that clinch formation at the cell surface drives pilus secretion through the outer membrane. These findings suggest that clinch-formation inhibitors might represent a new strategy to fight MDR bacterial infections.
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| 13. |
- Pande, Rupaly, et al.
(author)
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Can trainees safely perform pancreatoenteric anastomosis? A systematic review, meta-analysis, and risk-adjusted analysis of postoperative pancreatic fistula
- 2022
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In: Surgery (United States). - : Elsevier BV. - 0039-6060. ; 172:1, s. 319-328
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Research review (peer-reviewed)abstract
- Background: The complexity of pancreaticoduodenectomy and fear of morbidity, particularly postoperative pancreatic fistula, can be a barrier to surgical trainees gaining operative experience. This meta-analysis sought to compare the postoperative pancreatic fistula rate after pancreatoenteric anastomosis by trainees or established surgeons. Methods: A systematic review of the literature was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with differences in postoperative pancreatic fistula rates after pancreatoenteric anastomosis between trainee-led versus consultant/attending surgeons pooled using meta-analysis. Variation in rates of postoperative pancreatic fistula was further explored using risk-adjusted outcomes using published risk scores and cumulative sum control chart analysis in a retrospective cohort. Results: Across 14 cohorts included in the meta-analysis, trainees tended toward a lower but nonsignificant rate of all postoperative pancreatic fistula (odds ratio: 0.77, P =.45) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.69, P =.37). However, there was evidence of case selection, with trainees being less likely to operate on patients with a pancreatic duct width <3 mm (odds ratio: 0.45, P =.05). Similarly, analysis of a retrospective cohort (N = 756 cases) found patients operated by trainees to have significantly lower predicted all postoperative pancreatic fistula (median: 20 vs 26%, P <.001) and clinically relevant postoperative pancreatic fistula (7 vs 9%, P =.020) rates than consultant/attending surgeons, based on preoperative risk scores. After adjusting for this on multivariable analysis, the risks of all postoperative pancreatic fistula (odds ratio: 1.18, P =.604) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.85, P =.693) remained similar after pancreatoenteric anastomosis by trainees or consultant/attending surgeons. Conclusion: Pancreatoenteric anastomosis, when performed by trainees, is associated with acceptable outcomes. There is evidence of case selection among patients undergoing surgery by trainees; hence, risk adjustment provides a critical tool for the objective evaluation of performance.
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| 14. |
- Pande, Rupaly, et al.
(author)
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External validation of postoperative pancreatic fistula prediction scores in pancreatoduodenectomy : a systematic review and meta-analysis
- 2022
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In: HPB. - : Elsevier BV. - 1365-182X. ; 24:3, s. 287-298
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Research review (peer-reviewed)abstract
- Background: Multiple risk scores claim to predict the probability of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy. It is unclear which scores have undergone external validation and are the most accurate. The aim of this study was to identify risk scores for POPF, and assess the clinical validity of these scores. Methods: Areas under receiving operator characteristic curve (AUROCs) were extracted from studies that performed external validation of POPF risk scores. These were pooled for each risk score, using intercept-only random-effects meta-regression models. Results: Systematic review identified 34 risk scores, of which six had been subjected to external validation, and so included in the meta-analysis, (Tokyo (N=2 validation studies), Birmingham (N=5), FRS (N=19), a-FRS (N=12), m-FRS (N=3) and ua-FRS (N=3) scores). Overall predictive accuracies were similar for all six scores, with pooled AUROCs of 0.61, 0.70, 0.71, 0.70, 0.70 and 0.72, respectively. Considerably heterogeneity was observed, with I2 statistics ranging from 52.1-88.6%. Conclusion: Most risk scores lack external validation; where this was performed, risk scores were found to have limited predictive accuracy. Consensus is needed for which score to use in clinical practice. Due to the limited predictive accuracy, future studies to derive a more accurate risk score are warranted.
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| 15. |
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| 16. |
- Sampson, Timothy R., et al.
(author)
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A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice
- 2020
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In: eLife. - 2050-084X. ; 9
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Journal article (peer-reviewed)abstract
- Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain.
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| 17. |
- Vogelezang, Suzanne, et al.
(author)
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Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
- 2020
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In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:10
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Journal article (peer-reviewed)abstract
- The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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| 18. |
- Weinstock, Joshua S, et al.
(author)
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Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
- 2023
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In: Nature. - 1476-4687. ; 616:7958, s. 755-763
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Journal article (peer-reviewed)abstract
- Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, butthis effect was not seen inclones withdriver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimentalknockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
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| 19. |
- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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| 20. |
- Tabiri, S, et al.
(author)
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- 2021
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swepub:Mat__t
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