| 1. |
- Martin, Myriam, et al.
(författare)
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Citrullination of C1-inhibitor as a mechanism of impaired complement regulation in rheumatoid arthritis
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid arthritis (RA). Citrullination is induced by immune cell-derived peptidyl-Arg deiminases (PADs), which are overactivated in the inflamed synovium. We characterized the effect of PAD2- and PAD4-induced citrullination on the ability of the plasma-derived serpin C1-inhibitor (C1-INH) to inhibit complement and contact system activation. MethodsCitrullination of the C1-INH was confirmed by ELISA and Western blotting using a biotinylated phenylglyoxal probe. C1-INH-mediated inhibition of complement activation was analyzed by C1-esterase activity assay. Downstream inhibition of complement was studied by C4b deposition on heat-aggregated IgGs by ELISA, using pooled normal human serum as a complement source. Inhibition of the contact system was investigated by chromogenic activity assays for factor XIIa, plasma kallikrein, and factor XIa. In addition, autoantibody reactivity to native and citrullinated C1-INH was measured by ELISA in 101 RA patient samples. ResultsC1-INH was efficiently citrullinated by PAD2 and PAD4. Citrullinated C1-INH was not able to bind the serine protease C1s and inhibit its activity. Citrullination of the C1-INH abrogated its ability to dissociate the C1-complex and thus inhibit complement activation. Consequently, citrullinated C1-INH had a decreased capacity to inhibit C4b deposition via the classical and lectin pathways. The inhibitory effect of C1-INH on the contact system components factor XIIa, plasma kallikrein, and factor XIa was also strongly reduced by citrullination. In RA patient samples, autoantibody binding to PAD2- and PAD4-citrullinated C1-INH was detected. Significantly more binding was observed in anti-citrullinated protein antibody (ACPA)-positive than in ACPA-negative samples. ConclusionCitrullination of the C1-INH by recombinant human PAD2 and PAD4 enzymes impaired its ability to inhibit the complement and contact systems in vitro. Citrullination seems to render C1-INH more immunogenic, and citrullinated C1-INH might thus be an additional target of the autoantibody response observed in RA patients.
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| 2. |
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| 3. |
- Vogt, Leonie M., et al.
(författare)
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Apolipoprotein E Triggers Complement Activation in Joint Synovial Fluid of Rheumatoid Arthritis Patients by Binding C1q
- 2020
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 204:10, s. 2779-2790
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Tidskriftsartikel (refereegranskat)abstract
- We identified apolipoprotein E (ApoE) as one of the proteins that are found in complex with complement component C4d in pooled synovial fluid of rheumatoid arthritis (RA) patients. Immobilized human ApoE activated both the classical and the alternative complement pathways. In contrast, ApoE in solution demonstrated an isoform-dependent inhibition of hemolysis and complement deposition at the level of sC5b-9. Using electron microscopy imaging, we confirmed that ApoE interacts differently with C1q depending on its context; surface-bound ApoE predominantly bound C1q globular heads, whereas ApoE in a solution favored the hinge/stalk region of C1q. As a model for the lipidated state of ApoE in lipoprotein particles, we incorporated ApoE into phosphatidylcholine/phosphatidylethanolamine liposomes and found that the presence of ApoE on liposomes increased deposition of C1q and C4b from serum when analyzed using flow cytometry. In addition, posttranslational modifications associated with RA, such as citrullination and oxidation, reduced C4b deposition, whereas carbamylation enhanced C4b deposition on immobilized ApoE. Posttranslational modification of ApoE did not alter Clq interaction but affected binding of complement inhibitors factor H and C4b -binding protein. This suggests that changed ability of C4b to deposit on modified ApoE may play an important role. Our data show that posttranslational modifications of ApoE alter its interactions with complement. Moreover, ApoE may play different roles in the body depending on its solubility, and in diseased states such as RA, deposited ApoE may induce local complement activation rather than exert its typical role of inhibition.
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| 4. |
- Bauer, M. K. A., et al.
(författare)
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Role of reactive oxygen intermediates in activation-induced CD95 (APO-1/Fas) ligand expression
- 1998
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Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 273:14, s. 8048-8055
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Tidskriftsartikel (refereegranskat)abstract
- Activation-induced cell death of T lymphocytes requires the inducible expression of CD95 (APO-1/Fas) ligand, which triggers apoptosis in CD95-bearing target cells by an autocrine or paracrine mechanism. Although execution of the CD95 death pathway is largely independent of reactive oxygen intermediates, activation-induced cell death is blocked by a variety of antioxidants. In the present study, we investigated the involvement of redox processes in the regulation of CD95 ligand (CD95L) expression in Jurkat T cells. We show that various antioxidants potently inhibited the transcriptional activation of CD95L following T cell receptor litigation or stimulation of cells with phorbol ester and ionomycin. Conversely, a prooxidant such as hydrogen peroxide alone was able to increase CD95L expression. As detected by Western blot and cytotoxicity assays, functional expression of CD95L protein was likewise diminished by antioxidants. Inhibition of CD95L expression was associated with a decreased DNA binding activity of nuclear factor (NF)-kappa B, an important redox-controlled transcription factor. Moreover, inhibition of NF-kappa B activity by a transdominant I kappa B mutant attenuated CD95L expression. Our data suggest that, although reactive oxygen intermediates do not act as mediators in the execution phase of CD95-mediated apoptosis, they are involved in the transcriptional regulation of CD95L expression.
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| 5. |
- De Wit, Jan, et al.
(författare)
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Designing and Evaluating Iconic Gestures for Child-Robot Second Language Learning
- 2021
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Ingår i: Interacting with computers. - : Oxford University Press (OUP). - 0953-5438 .- 1873-7951. ; 33:6, s. 596-626
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we examine the process of designing robot-performed iconic hand gestures in the context of a long-Term study into second language tutoring with children of approximately 5 years old. We explore four factors that may relate to their efficacy in supporting second language tutoring: The age of participating children; differences between gestures for various semantic categories, e.g. measurement words, such as small, versus counting words, such as five; the quality (comprehensibility) of the robot's gestures; and spontaneous reenactment or imitation of the gestures. Age was found to relate to children's learning outcomes, with older children benefiting more from the robot's iconic gestures than younger children, particularly for measurement words. We found no conclusive evidence that the quality of the gestures or spontaneous reenactment of said gestures related to learning outcomes. We further propose several improvements to the process of designing and implementing a robot's iconic gesture repertoire.
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| 6. |
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| 7. |
- Gohritz, A, et al.
(författare)
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Ersatzoperationen bei Ausfall motorisher Funktionen an der Hand : Tendon transposition to restore muscle function in the hand
- 2007
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Ingår i: Der Unfallchirurg. - : Springer Science and Business Media LLC. - 0177-5537 .- 1433-044X. ; 110:9, s. 759-76
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Tidskriftsartikel (refereegranskat)abstract
- Nerve injuries in the upper extremity can result in severe disability. In the last three decades, progress in microsurgical techniques has improved the outcome for nerve injuries and if the prognosis is reasonably good, nerve repair should usually be performed prior to tendon transfer procedures. However, above all proximal lesions of peripheral nerves such as high radial nerve palsy still often yield unsatisfactory results, despite a technically well-executed nerve repair. Prognosis further depends on the time interval since the injury and also on the age of the patient, as the regenerative process is delayed in older patients. The indication for tendon transfers strongly depends on the personal and professional profiles of the individual patient. Tendon transfer procedures alleviate the suffering from functional hand impairment providing a superior alternative to permanent external splints. Tendon transfers are usually secondary procedures for replacing function after evaluation of the functional motor loss. Numerous transfer procedures have been described for every nerve trunk of the upper extremity, their prognosis depending mainly on the extent and pattern of nerve loss, local effects of the trauma (e.g. involvement of soft tissues, joints), and the physiological characteristics of the transferred muscle. Even if the results of the tendon transfers may finally be less satisfactory in cases of complex nerve damage than in isolated motor nerve lesions, they offer a valuable functional benefit, often being the only possibility to restore hand function. Although regrettably underused, tendon transfer improve upper extremity function in more than 70% of patients with cervical spinal cord injury. Reconstruction of key elements such as wrist extension, key grip between the thumb and the index finger, or digital flexion and extension leads to highly improved use of the tetraplegic hand and thus provides new mobility and independence from the help of others. This article presents an overview of the most common procedures to restore hand function in peripheral nerve injuries and tetraplegia in order to provide a systematic approach for decision making.
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| 8. |
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| 9. |
- Gohritz, A., et al.
(författare)
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[Nerve and muscle transfer surgery to restore paralyzed elbow function]
- 2008
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Ingår i: Unfallchirurg. - : Springer Science and Business Media LLC. - 0177-5537. ; 111:2, s. 85-101
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Tidskriftsartikel (refereegranskat)abstract
- Paralysis of elbow flexion or extension leads to major impairment of upper extremity function. Surgical reconstruction can be achieved using several procedures.If the time interval since the nerve injury is short, anatomic reconstruction by means of nerve suture or nerve transplantation should be attempted. Alternatively, nerve transposition is possible. If more than 12-18 months have elapsed, reinnervation of arm muscles can no longer be expected. In this case, muscle transposition is helpful. Restoring flexion is predominantly required following brachial plexus injury, when the function of the biceps, brachioradialis and brachialis muscles are lost. As donor muscles the latissimus dorsi, pectoralis major and triceps brachii can be used, alternatively a transfer of the flexor-pronator muscles of the forearm is possible. Latissimus dorsi transfer to reconstruct elbow flexion is also indicated in defects of the anterior upper arm muscle compartiment due to trauma, ischemia, or tumor. Patients with proximal radial nerve lesions may benefit from latissimus transfer to reachieve elbow flexion extension.In tetraplegic patients, elbow extension is restored mainly by transfer of the posterior deltoid muscle extended with a tendon graft, or by means of a biceps-to-triceps transfer.
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| 10. |
- Gohritz, A., et al.
(författare)
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Rekonstruktion der aktiven Ellbogenbeugung durch bipolare Transposition des Musculus latissimus dorsi : [Restoration of active elbow flexion by muscle transfer of the latissimus dorsi]
- 2009
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Ingår i: Operative Orthopädie und Traumatologie. - 0934-6694. ; 21:2, s. 115-25
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Reconstruction of active elbow flexion against gravity (strength grade > or =M(3)) by transfer of the latissimus dorsi muscle in order to improve the functionality of the upper extremity. INDICATIONS: Irreparable lesions of the musculocutaneous nerve (C(5)/6). Failure of regeneration after peripheral nerve reconstruction for the musculocutaneous nerve (neurolysis, suture, nerve grafting). Brachial plexus injury (lesions to the upper part, C(5)/6). Loss of biceps function due to trauma, ischemia, poliomyelitis or tumor. CONTRAINDICATIONS: Possible recovery of biceps function by reinnervation, spontaneously or after nerve reconstruction. Weakness of the latissimus dorsi muscle (strength grade < M(4)). Insufficient passive range of motion of the elbow joint (osteoarthritis, contracture). Lack of motivation, reliability, and cooperation of the patient in postoperative rehabilitation program. SURGICAL TECHNIQUE: The intact latissimus dorsi muscle is transferred with its origin and insertion ventrally and sutured with its thoracic aponeurosis into the insertion of the biceps tendon in order to act as an elbow flexor. POSTOPERATIVE MANAGEMENT: Following postoperative immobilization in an upper-arm Gilchrist bandage at 100 degrees flexion and supination (or neutral position, but not pronation) of the forearm for 6 weeks, passive motion exercises of the elbow are started. Active flexion and extension exercises begin at 8-10 weeks postoperatively. To prevent the deleterious effect of muscle and tendon elongation, an orthosis is used during the night to keep the elbow flexed at 90 degrees for 6 months. RESULTS: According to the authors' experience and the results reported in the literature, bipolar latissimus dorsi muscle transfer is a reliable method to restore functional elbow flexion regarding range of motion (> 90 degrees elbow flexion) and strength (at least antigravity strength, > or =M(3)) with acceptable donor morbidity and complication rate.
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| 11. |
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| 12. |
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| 13. |
- Hendriksen, Rene S., et al.
(författare)
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Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- © 2019, The Author(s). Antimicrobial resistance (AMR) is a serious threat to global public health, but obtaining representative data on AMR for healthy human populations is difficult. Here, we use metagenomic analysis of untreated sewage to characterize the bacterial resistome from 79 sites in 60 countries. We find systematic differences in abundance and diversity of AMR genes between Europe/North-America/Oceania and Africa/Asia/South-America. Antimicrobial use data and bacterial taxonomy only explains a minor part of the AMR variation that we observe. We find no evidence for cross-selection between antimicrobial classes, or for effect of air travel between sites. However, AMR gene abundance strongly correlates with socio-economic, health and environmental factors, which we use to predict AMR gene abundances in all countries in the world. Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR. We propose metagenomic analysis of sewage as an ethically acceptable and economically feasible approach for continuous global surveillance and prediction of AMR.
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| 14. |
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| 15. |
- Kern, Ralph, et al.
(författare)
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Coulomb Excitation of Proton-rich N = 80 Isotones at HIE-ISOLDE
- 2020
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 1555:1
-
Tidskriftsartikel (refereegranskat)abstract
- A projectile Coulomb-excitation experiment was performed at the radioactive ion beam facility HIE-ISOLDE at CERN. The radioactive 140Nd and 142Sm ions were post accelerated to the energy of 4.62 MeV/A and impinged on a 1.45 mg/cm2-thin 208Pb target. The γ rays depopulating the Coulomb-excited states were recorded by the HPGe-array MINIBALL. The scattered charged particles were detected by a double-sided silicon strip detector in forward direction. Experimental γ-ray intensities were used for the determination of electromagnetic transition matrix elements. Preliminary results for the reduced transition strength of the B(M1 23+ to 21+)=0.35(19) μN2 of 140Nd and a first estimation for 142Sm have been deduced using the Coulomb-excitation calculation software GOSIA. The 23+ states of 140Nd and 142Sm show indications of being the main fragment of the proton-neutron mixed-symmetry 21, ms+ state.
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| 16. |
- Kern, Ralph, et al.
(författare)
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Search for Isovector Valence-Shell Excitations in 140Nd and 142Sm via Coulomb excitation reactions of radioactive ion beams
- 2018
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Ingår i: International Conference on Nuclear Structure and Related Topics (NSRT18). - : EDP Sciences. - 2101-6275. ; 194
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Konferensbidrag (refereegranskat)abstract
- Projectile Coulomb excitation experiments were performed at HIE-ISOLDE at CERN with the radioactive ion beams of 140Nd and 142Sm. Ions with an energy of 4:62 MeV/A were impinging on a 1.45 mg/cm2 thick 208Pb target. The γ-rays depopulating the Coulomb-excited states were recorded by the HPGe-array MINIBALL and scattered particles were detected by a double-sided silicon strip detector. Experimental intensities were used for the determination of electromagnetic transition matrix elements. A preliminary result of the B(M1; 2+ 3 → 2+ 1) of 140Nd and an upper limit for the case of 142Sm are revealing the main fragments of the proton-neutron mixed-symmetry 2+ 1;ms states.
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| 17. |
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| 18. |
- Krylov, A, et al.
(författare)
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A shift in heavy and clay mineral provenance indicates a middle Miocene onset of a perennial sea ice cover in the Arctic Ocean
- 2008
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Ingår i: Paleoceanography. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- During the Arctic Coring Expedition (ACEX), a 428-m-thick sequence of Upper Cretaceous to Quaternary sediments was penetrated. The mineralogical composition of the upper 300 m of this sequence is presented here for the first time. Heavy and clay mineral associations indicate a major and consistent shift in provenance, from the Barents-Kara–western Laptev Sea region, characterized by presence of common clinopyroxene, to the eastern Laptev-East Siberian seas in the upper part of the section, characterized by common hornblende (amphibole). Sea ice originating from the latter source region must have survived at least one summer melt cycle in order to reach the ACEX drill site, if considering modern sea ice trajectories and velocities. This shift in mineral assemblages probably represents the onset of a perennial sea ice cover in the Arctic Ocean, which occurred at about 13 Ma, thus suggesting a coeval freeze in the Arctic and Antarctic regions.
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| 19. |
- Kurek, Magdalena, et al.
(författare)
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Spermatogonia Loss Correlates with LAMA 1 Expression in Human Prepubertal Testes Stored for Fertility Preservation
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- Fertility preservation for male childhood cancer survivors not yet capable of producing mature spermatozoa, relies on experimental approaches such as testicular explant culture. Although the first steps in somatic maturation can be observed in human testicular explant cultures, germ cell depletion is a common obstacle. Hence, understanding the spermatogonial stem cell (SSC) niche environment and in particular, specific components such as the seminiferous basement membrane (BM) will allow progression of testicular explant cultures. Here, we revealed that the seminiferous BM is established from 6 weeks post conception with the expression of laminin alpha 1 (LAMA 1) and type IV collagen, which persist as key components throughout development. With prepubertal testicular explant culture we found that seminiferous LAMA 1 expression is disrupted and depleted with culture time correlating with germ cell loss. These findings highlight the importance of LAMA 1 for the human SSC niche and its sensitivity to culture conditions.
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| 20. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 21. |
- Schulze-Osthoff, Klaus, et al.
(författare)
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Role of ICE-related and other proteases in Fas-mediated apoptosis
- 1996
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Ingår i: Cell Death and Differentiation. - 1350-9047 .- 1476-5403. ; 3:2, s. 177-184
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Forskningsöversikt (refereegranskat)abstract
- Interleukin-1 beta-converting enzyme (ICE)-like proteases comprise a novel family of unusual cysteine proteases which have been implicated in programmed cell death in both invertebrates and mammals. Current available evidence indicates a role of ICE proteases as central executioners of apoptosis triggered by the cell surface receptor Fas (APO-1). The presence of multiple mammalian ICE proteases with partially overlapping but distinct activities suggests a complex proteolytic cascade which is induced upon Fas ligation. The precise role of single members of the ICE family in Fas-mediated apoptosis, however, is still unclear. Here, we summarize the present knowledge about the relevance of ICE proteases, their potential targets, and interaction with unrelated proteases in cell death mediated by Fas and other apoptotic stimuli.
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| 22. |
- Seiboth, Frank, et al.
(författare)
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Aberration Correction for Hard X-ray Focusing at the Nanoscale
- 2017
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Ingår i: Advances in X-Ray/EUV Optics and Components XII. - : SPIE - International Society for Optical Engineering. - 9781510612303 - 9781510612297
-
Konferensbidrag (refereegranskat)abstract
- We developed a corrective phase plate that enables the correction of residual aberration in reflective, diffractive, and refractive X-ray optics. The principle is demonstrated on a stack of beryllium compound refractive lenses with a numerical aperture of 0.49 x 10(-3) at three different synchrotron radiation and x-ray free-electron laser facilities. By introducing this phase plate into the beam path, we were able to correct the spherical aberration of the optical system and improve the Strehl ratio of the optics from 0.29(7) to 0.87(5), creating a diffraction-limited, large aperture, nanofocusing optics that is radiation resistant and very compact.
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| 23. |
- Seiboth, Frank, et al.
(författare)
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Perfect X-ray focusing via fitting corrective glasses to aberrated optics
- 2017
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Due to their short wavelength, X-rays can in principle be focused down to a few nanometres and below. At the same time, it is this short wavelength that puts stringent requirements on X-ray optics and their metrology. Both are limited by today’s technology. In this work, we present accurate at wavelength measurements of residual aberrations of a refractive X-ray lens using ptychography to manufacture a corrective phase plate. Together with the fitted phase plate the optics shows diffraction-limited performance, generating a nearly Gaussian beam profile with a Strehl ratio above 0.8. This scheme can be applied to any other focusing optics, thus solving the X-ray optical problem at synchrotron radiation sources and X-ray free-electron lasers.
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| 24. |
- Smebye, Andreas, et al.
(författare)
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Biochar amendment to soil changes dissolved organic matter content and composition
- 2016
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 142, s. 100-105
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Tidskriftsartikel (refereegranskat)abstract
- Amendments of biochar, a product of pyrolysis of biomass, have been shown to increase fertility of acidic soils by enhancing soil properties such as pH, cation-exchange-capacity and water-holding-capacity. These parameters are important in the context of natural organic matter contained in soils, of which dissolved organic matter (DOM) is the mobile and most bioavailable fraction. The effect of biochar on the content and composition of DOM in soils has received little research attention. This study focuses on the effects of amendments of two different biochars to an acidic acrisol and a pH-neutral brown soil. A batch experiment showed that mixing biochar with the acrisols at a 10 wt.% dose increased the pH from 4.9 to 8.7, and this resulted in a 15-fold increase in the dissolved organic carbon concentration (from 4.5 to 69 mg L-1). The pH-increase followed the same trend as the release of DOM in the experiment, causing higher DOM solubility and desorption of DOM from mineral sites. The binding to biochar of several well-characterised reference DOM materials was also investigated and results showed a higher sorption of aliphatic DOM to biochar than aromatic DOM, with DOM-water partitioning coefficients (Kd-values) ranging from 0.2 to 590 L kg(-1). A size exclusion occurring in biochar's micropores, could result in a higher sorption of smaller aliphatic DOM molecules than larger aromatic ones. These findings indicate that biochar could increase the leaching of DOM from soil, as well as change the DOM composition towards molecules with a larger size and higher aromaticity.
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| 25. |
- Stitziel, Nathan O., et al.
(författare)
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Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
- 2016
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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| 26. |
- Tesi, Bianca, et al.
(författare)
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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.MethodsgWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.FindingsThe prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).InterpretationOverall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
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| 27. |
- Tesi, Bianca, et al.
(författare)
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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
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| 28. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 29. |
- van den Berghe, Rianne, et al.
(författare)
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Individual Differences in Children's (Language) Learning Skills Moderate Effects of Robot-Assisted Second Language Learning
- 2021
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Ingår i: Frontiers in Robotics and AI. - : Frontiers Media SA. - 2296-9144. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The current study investigated how individual differences among children affect the added value of social robots for teaching second language (L2) vocabulary to young children. Specifically, we investigated the moderating role of three individual child characteristics deemed relevant for language learning: first language (L1) vocabulary knowledge, phonological memory, and selective attention. We expected children low in these abilities to particularly benefit from being assisted by a robot in a vocabulary training. An L2 English vocabulary training intervention consisting of seven sessions was administered to 193 monolingual Dutch five-year-old children over a three- to four-week period. Children were randomly assigned to one of three experimental conditions: 1) a tablet only, 2) a tablet and a robot that used deictic (pointing) gestures (the no-iconic-gestures condition), or 3) a tablet and a robot that used both deictic and iconic gestures (i.e., gestures depicting the target word; the iconic-gestures condition). There also was a control condition in which children did not receive a vocabulary training, but played dancing games with the robot. L2 word knowledge was measured directly after the training and two to four weeks later. In these post-tests, children in the experimental conditions outperformed children in the control condition on word knowledge, but there were no differences between the three experimental conditions. Several moderation effects were found. The robot's presence particularly benefited children with larger L1 vocabularies or poorer phonological memory, while children with smaller L1 vocabularies or better phonological memory performed better in the tablet-only condition. Children with larger L1 vocabularies and better phonological memory performed better in the no-iconic-gestures condition than in the iconic-gestures condition, while children with better selective attention performed better in the iconic-gestures condition than the no-iconic-gestures condition. Together, the results showed that the effects of the robot and its gestures differ across children, which should be taken into account when designing and evaluating robot-assisted L2 teaching interventions.
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| 30. |
- van Leeuwen, F., et al.
(författare)
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Gaia Data Release 1 : Open cluster astrometry: Performance, limitations, and future prospects
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 601
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Tidskriftsartikel (refereegranskat)abstract
- Context. The first Gaia Data Release contains the Tycho-Gaia Astrometric Solution (TGAS). This is a subset of about 2 million stars for which, besides the position and photometry, the proper motion and parallax are calculated using Hipparcos and Tycho-2 positions in 1991.25 as prior information. Aims. We investigate the scientific potential and limitations of the TGAS component by means of the astrometric data for open clusters. Methods. Mean cluster parallax and proper motion values are derived taking into account the error correlations within the astrometric solutions for individual stars, an estimate of the internal velocity dispersion in the cluster, and, where relevant, the effects of the depth of the cluster along the line of sight. Internal consistency of the TGAS data is assessed. Results. Values given for standard uncertainties are still inaccurate and may lead to unrealistic unit-weight standard deviations of least squares solutions for cluster parameters. Reconstructed mean cluster parallax and proper motion values are generally in very good agreement with earlier Hipparcos-based determination, although the Gaia mean parallax for the Pleiades is a significant exception. We have no current explanation for that discrepancy. Most clusters are observed to extend to nearly 15 pc from the cluster centre, and it will be up to future Gaia releases to establish whether those potential cluster-member stars are still dynamically bound to the clusters. Conclusions. The Gaia DR1 provides the means to examine open clusters far beyond their more easily visible cores, and can provide membership assessments based on proper motions and parallaxes. A combined HR diagram shows the same features as observed before using the Hipparcos data, with clearly increased luminosities for older A and F dwarfs.
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| 31. |
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| 32. |
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| 33. |
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| 34. |
- Vogt, K C, et al.
(författare)
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The use of intravascular ultrasound as control procedure for the deployment of endovascular stented grafts
- 1997
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Ingår i: European Journal of Vascular and Endovascular Surgery. - 1532-2165. ; 13:6, s. 592-596
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess whether intravascular ultrasound (IVUS), used systematically in a series of patients with abdominal aortic aneurysms (AAA), is a feasible control procedure to ensure correct transfemoral placement of endovascular stent grafts (TPEG). DESIGN: Descriptive study. MATERIALS AND METHODS: Fourteen patients with infrarenal aortic aneurysms were treated by the placement of one tube graft, 10 aorto-uni-iliac and three aorto-bi-iliac grafts. Arteriography and IVUS were performed before, during and after deployment of the graft to ensure correct placement in relation to side branches, and proper adaptation of the stents to the aortic wall. Postoperative CT-scan and arteriography served as control procedures. RESULTS: IVUS identified both renal arteries before graft deployment in eight of 13 (62%) patients. In the remaining patients only one renal artery was visualised due to interference from guidewires or the introducer system. Imaging during stent deployment was abandoned after IVUS catheter damage in two of three cases. Postprocedural IVUS was able to evaluate the expansion of the stents and the adaptation to the aortic wall in all instances. In four (29%) cases a leak was identified. Additional intervention included deployment of a further stent (n = 2) or redilation (n = 2). Covering of the renal arteries could only be indirectly determined by IVUS. CONCLUSION: IVUS can provide important decisive information before and after stented graft deployment, with the limitations that guidewires, introducer system and stents may cause interference. Contemporary IVUS designs are unsuitable for monitoring stent deployment.
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| 35. |
- Wadensten, Elisabeth, et al.
(författare)
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Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer.
- 2023
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Ingår i: JCO Precision Oncology (JCO PO). - : American Society of Clinical Oncology. - 2473-4284. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
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| 36. |
- Wadensten, Elisabeth, et al.
(författare)
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Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer
- 2023
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Ingår i: JCO Precision Oncology. - : American Society of Clinical Oncology. - 2473-4284. ; :7
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.Methods: We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.Results: During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Conclusion: Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
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| 37. |
- Webb, Thomas R., et al.
(författare)
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Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
- 2017
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 69:7, s. 823-836
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits.CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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