| 1. |
- Karlberg, Tobias, et al.
(författare)
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14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Pseudomonas are a common cause of hospital-acquired infections that may be lethal. ADP-ribosyltransferase activities of Pseudomonas exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, an amphipathic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3 beta: ExoS and -ExoT complexes presented here reveal an extensive hydrophobic interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the amphipathic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the amphipathic C-terminus with a fragment from Vibrio Vis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the amphipathic C-terminal segment.
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| 2. |
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| 3. |
- Andersson, C David, et al.
(författare)
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Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:17, s. 7706-7718
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Tidskriftsartikel (refereegranskat)abstract
- The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyses the transfer of ADP-ribose units onto substrate proteins, using nicotinamide adenine dinucleotide (NAD(+)) as a co-substrate. They have a documented role in chromatin remodelling and DNA repair; and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. Using virtual screening we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.
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| 4. |
- Aw, S T, et al.
(författare)
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Individual semicircular canal function in superior and inferior vestibular neuritis
- 2001
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Ingår i: Neurology. - 1526-632X. ; 57:5, s. 768-774
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the concept of selective superior and inferior vestibular nerve involvement in vestibular neuritis by studying the distribution of semicircular canal (SCC) involvement in such patients. BACKGROUND: Vestibular neuritis was traditionally thought to involve the superior and inferior vestibular nerves. Recent work suggests that in some patients, only the superior nerve is involved. So far there are no reported cases of selective involvement of the inferior vestibular nerve. METHODS: The authors measured the vestibuloocular reflex from individual SCC at natural head accelerations using the head impulse test. The authors studied 33 patients with acute unilateral peripheral vestibulopathy, including 29 with classic vestibular neuritis and 4 with simultaneous ipsilateral hearing loss, 18 healthy subjects and 15 surgical unilateral vestibular deafferented patients. RESULTS: In patients with preserved hearing, eight had deficits in all three SCC, suggesting involvement of the superior and inferior vestibular nerves. Twenty-one had a lateral SCC deficit or a combined lateral and anterior SCC deficit consistent with selective involvement of the superior vestibular nerve. Two patients with ipsilateral hearing loss had normal caloric responses and an isolated posterior SCC deficit on impulsive testing. The authors propose that these two patients had a selective loss of inferior vestibular nerve function. CONCLUSION: Vestibular neuritis can affect the superior and inferior vestibular nerves together or can selectively affect the superior vestibular nerve.
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| 5. |
- Betts, G A, et al.
(författare)
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Neck muscle vibration alters visually-perceived roll after unilateral vestibular loss
- 2000
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Ingår i: NeuroReport. - 1473-558X. ; 11:12, s. 2659-2662
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Tidskriftsartikel (refereegranskat)abstract
- Unilateral sternocleidomastoid muscle vibration was applied to 21 normal and six unilateral vestibular deafferented (uVD) human subjects at head erect and during 30 degrees left and right whole body roll-tilt. In normal subjects, neck vibration had no effect upon the settings of a visual bar to subjective visual horizontal (SVH) in any roll-tilt condition. In uVD subjects settings to SVH were significantly altered by neck vibration, with ipsilesional neck vibration increasing the SVH bias at head erect. Further, during contralesional roll-tilt, ipsilesional neck vibration in uVD subjects significantly increased the E-effect. These results suggest that compensation after vestibular loss allows cervical signals to influence visual perception of roll-tilt.
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| 6. |
- Ekblad, Torun, et al.
(författare)
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Towards small molecule inhibitors of mono-ADP-ribosyltransferases
- 2015
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 95, s. 546-551
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Tidskriftsartikel (refereegranskat)abstract
- Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.
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| 7. |
- Fransson, Per-Anders, et al.
(författare)
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Direction of galvanically-induced vestibulo-postural responses during active and passive neck torsion
- 2000
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 120:4, s. 500-503
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Tidskriftsartikel (refereegranskat)abstract
- The direction of a postural response induced by galvanic vestibular stimulation depends on the head and trunk position. The relative importance of afferent information (proprioception) and efferent motor command/corollary discharge is unknown. We studied the direction of body sway evoked by galvanic vestibular stimulation in 9 healthy subjects during active and passive head positioning at 0 degrees frontal position, 35 degrees to the left, and 75 degrees to the right, using a custom-built collar. At 0 degrees and 75 degrees there were no significant differences in sway direction between active and passive head positioning. The galvanic stimulation invoked sway toward the anode, mainly in the inter-aural direction. The sway direction differed significantly between active and passive positioning at 35 degrees to the side (p < 0.05). When the head was actively kept in this position, the body sway was mainly in an inter-aural direction. The sway shifted to a naso-occipital direction when the head was passively positioned at 35 degrees. Our results indicate that the afferent proprioceptive information has the largest influence on the direction of the galvanically-induced postural response, although some dependence on efferent motor commands and non-linear cervical proprioception cannot be ruled out entirely.
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| 8. |
- Fransson, Per-Anders, et al.
(författare)
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Postural Control Adaptation during Galvanic Vestibular and Vibratory Proprioceptive Stimulation
- 2003
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Ingår i: IEEE Transactions on Biomedical Engineering. - 1558-2531. ; 50:12, s. 1310-1319
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Tidskriftsartikel (refereegranskat)abstract
- he objective for this study was to investigate whether the adaptation of postural control was similar during galvanic vestibular stimulation and during vibratory proprioceptivestimulation of the calf muscles. Healthy subjects were tested during erect stance with eyes open or closed. An analysis method designed to consider the adaptive adjustments was used to evaluate the motion dynamics and the evoked changes of posture and stimulation response.Galvanic vestibular stimulation induced primarily lateral body movements and vibratory proprioceptive stimulation induced anteroposterior movements. The lateral body sway generated by the galvanic stimulation was proportionally smaller and contained more high-frequency movements (0.1 Hz) than the anteroposterior body sway induced by the vibratory stimulation. The adaptive adjustments of the body sway to the stimulation had similar time course and magnitude during galvanic and vibratory stimulation. The perturbations induced by stimulation were gradually reduced within the same time range (15–20 s) and both kinds of stimulation induced a body leaning whose direction was dependent on stimulus. The similarities in the adjustmentpatterns suggest that postural control operates in the same way independent of the receptor systems affected by the disturbance and irrespective of whether the motion responses were induced in a lateral or anteroposterior direction.
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| 9. |
- Gorcenco, Sorina, et al.
(författare)
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Ataxia-pancytopenia syndrome with SAMD9L mutations
- 2017
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Ingår i: Neurology: Genetics. - 2376-7839. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations.METHODS: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed.RESULTS: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC.CONCLUSIONS: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial.
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| 10. |
- Groenheit, Ramona, et al.
(författare)
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High Prevalence of SARS-CoV-2 Omicron Infection Despite High Seroprevalence, Sweden, 2022
- 2023
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Ingår i: Emerging Infectious Diseases. - : CENTERS DISEASE CONTROL & PREVENTION. - 1080-6040 .- 1080-6059. ; 29:6
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Tidskriftsartikel (refereegranskat)abstract
- We performed 2 surveys during 2022 to estimate point prevalences of SARS-CoV-2 infection compared with overall viral seroprevalence in Sweden. Point prevalence was 1.4% in March and 1.5% in September. Estimated seroprevalence was >80%, including among unvaccinated children. Continued SARS-CoV-2 surveillance is necessary for detecting emerging, possibly more pathogenic variants.
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