| 1. |
- Baumgartner, Stefan
(författare)
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Revisiting bicoid function : complete inactivation reveals an additional fundamental role in Drosophila egg geometry specification
- 2024
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Ingår i: Hereditas. - 0018-0661. ; 161:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The bicoid (bcd) gene in Drosophila has served as a paradigm for a morphogen in textbooks for decades. Discovered in 1986 as a mutation affecting anterior development in the embryo, its expression pattern as a protein gradient later confirmed the prediction from transplantation experiments. These experiments suggested that the protein fulfills the criteria of a true morphogen, with the existence of a homeodomain crucial for activation of genes along the anterior-posterior axis, based on the concentration of the morphogen. The bcd gene undergoes alternative splicing, resulting in, among other isoforms, a small and often neglected isoform with low abundance, which lacks the homeodomain, termed small bicoid (smbcd). Most importantly, all known classical strong bcd alleles used in the past to determine bcd function apparently do not affect the function of this isoform. Results: To overcome the uncertainty regarding which isoform regulates what, I removed the bcd locus entirely using CRISPR technology. bcdCRISPR eggs exhibited a short and round appearance. The phenotype could be ascribed to smbcd because all bcd alleles affecting the function of the major transcript, termed large bicoid (lgbcd) showed normally sized eggs. Several patterning genes for the embryo showed expression in the oocyte, and their expression patterns were altered in bcdCRISPR oocytes. In bcdCRISPR embryos, all downstream segmentation genes showed altered expression patterns, consistent with the expression patterns in “classical” alleles; however, due to the altered egg geometry resulting in fewer blastoderm nuclei, additional constraints came into play, further affecting their expression patterns. Conclusions: This study unveils a novel and fundamental role of bcd in shaping the egg’s geometry. This discovery demands a comprehensive revision of our understanding of this important patterning gene and prompts a reevaluation of past experiments conducted under the assumption that bcd mutants were bcdnull-mutants.
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| 2. |
- Sturma, Agnes, et al.
(författare)
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LONG-TERM FUNCTIONAL AND CLINICAL OUTCOME OF COMBINED TARGETED MUSCLE REINNERVATION AND OSSEOINTEGRATION FOR FUNCTIONAL BIONIC RECONSTRUCTION IN TRANSHUMERAL AMPUTEES: A CASE SERIES
- 2024
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Ingår i: JOURNAL OF REHABILITATION MEDICINE. - 1650-1977 .- 1651-2081. ; 56
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe and evaluate the combination of osseointegration and nerve transfers in 3 transhumeral amputees. Design: Case series. Patients: Three male patients with a unilateral traumatic transhumeral amputation. Methods: Patients received a combination of osseointegration and targeted muscle reinnervation surgery. Rehabilitation included graded weight training, range of motion exercises, biofeedback, table -top prosthesis training, and controlling the actual device. The impairment in daily life, health -related quality of life, and pain before and after the intervention was evaluated in these patients. Their shoulder range of motion, prosthesis embodiment, and function were documented at a 2- to 5 -year follow-up. Results: All 3 patients attended rehabilitation and used their myoelectric prosthesis on a daily basis. Two patients had full shoulder range of motion with the prosthesis, while the other patient had 55 degrees of abduction and 45 degrees of anteversion. They became more independent in their daily life activities after the intervention and incorporated their prosthesis into their body scheme to a high extent. Conclusion: These results indicate that patients can benefit from the combined procedure. However, the patients' perspective, risks of the surgical procedures, and the relatively long rehabilitation procedure need to be incorporated in the decision -making.
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| 3. |
- Baumgartner, Ruth, et al.
(författare)
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Impact of post-hepatectomy liver failure on morbidity and short- and long-term survival after major hepatectomy
- 2022
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Ingår i: BJS Open. - : Oxford University Press. - 2474-9842. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- Background Post-hepatectomy liver failure (PHLF) is one of the most serious postoperative complications after hepatectomy. The aim of this study was to assess the impact of the International Study Group of Liver Surgery (ISGLS) definition of PHLF on morbidity and short- and long-term survival after major hepatectomy. Methods This was a retrospective review of all patients who underwent major hepatectomy (three or more liver segments) for various liver tumours between 2010 and 2018 at two Swedish tertiary centres for hepatopancreatobiliary surgery. Descriptive statistics, regression models, and survival analyses were used. Results A total of 799 patients underwent major hepatectomy, of which 218 patients (27 per cent) developed ISGLS-defined PHLF, including 115 patients (14 per cent) with ISGLS grade A, 76 patients (10 per cent) with grade B, and 27 patients (3 per cent) with grade C. The presence of cirrhosis, perihilar cholangiocarcinoma, and gallbladder cancer, right-sided hemihepatectomy and trisectionectomy all significantly increased the risk of clinically relevant PHLF (grades B and C). Clinically relevant PHLF increased the risk of 90-day mortality and was associated with impaired long-term survival. ISGLS grade A had more major postoperative complications compared with no PHLF but failed to be an independent predictor of both 90-day mortality and long-term survival. The impact of PHLF grade B/C on long-term survival was no longer present in patients surviving the first 90 days after surgery. Conclusions The presently used ISGLS definition for PHLF should be reconsidered regarding mortality as only PHLF grade B/C was associated with a negative impact on short-term survival; however, even ISGLS grade A had clinical implications. The aim was to assess the ISGLS criteria for post-hepatectomy liver failure (PHLF) in a cohort of patients with major hepatectomy. The presently used ISGLS definition for PHLF should be reconsidered regarding mortality as only PHLF grade B/C was associated with a negative impact on short-term survival.
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| 4. |
- Fenstermacher, M.E., et al.
(författare)
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DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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| 5. |
- Gilg, Stefan, et al.
(författare)
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Molecular adsorbent recirculating system treatment in patients with post-hepatectomy liver failure : Long-term results of a pilot study
- 2022
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Ingår i: Scandinavian Journal of Surgery. - : SAGE Publications. - 1457-4969 .- 1799-7267. ; 111:3, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- Background: Post-hepatectomy liver failure (PHLF) is the leading cause of postoperative mortality following major liver resection. Between December 2012 and May 2015, 10 consecutive patients with PHLF (according to the Balzan criteria) following major/extended hepatectomy were included in a prospective treatment study with the molecular adsorbent recirculating system (MARS). Sixty- and 90-day mortality rates were 0% and 10%, respectively. Of the nine survivors, four still had liver dysfunction at 90 days postoperatively. One-year overall survival (OS) of the MARS-PHLF cohort was 50%. The present study aims to assess long-term outcome of this cohort compared to a historical control cohort.Methods: To compare long-term outcome of the MARS-PHLF treatment cohort with PHLF patients not treated with MARS, the present study includes all 655 patients who underwent major hepatectomy at Karolinska University Hospital between 2010 and 2018. Patients with PHLF were identified according to the Balzan criteria.Results: The cohort was split into three time periods: pre-MARS period (n = 192), MARS study period (n = 207), and post-MARS period (n = 256). The 90-day mortality of patients with PHLF was 55% (6/11) in the pre-MARS period, 14% during the MARS study period (2/14), and 50% (3/6) in the post-MARS period (p = 0.084). Median OS (95% confidence interval (CI)) was 37.8 months (29.3–51.7) in the pre-MARS cohort, 57 months (40.7–75.6) in the MARS cohort, and 38.8 months (31.4–51.2) in the post-MARS cohort. The 5-year OS of 10 patients included in the MARS study was 40% and the median survival 11.6 months (95% CI: 3 to not releasable). In contrast, for the remaining 21 patients fulfilling the Balzan criteria during the study period but not treated with MARS, the 5-year OS and median survival were 9.5% and 7.3 months (95% CI, 0.5–25.9), respectively (p = 0.138)).Conclusions: MARS treatment may contribute to improved outcome of patients with PHLF. Further studies are needed.The initial pilot study was registered at ClinicalTrials.gov (NCT03011424).
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| 6. |
- Maier, Hannes, et al.
(författare)
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Consensus Statement on Bone Conduction Devices and Active Middle Ear Implants in Conductive and Mixed Hearing Loss
- 2022
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Ingår i: Otology and Neurotology. - : Lippincott, Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 43:5, s. 513-529
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Tidskriftsartikel (refereegranskat)abstract
- Nowadays, several options are available to treat patients with conductive or mixed hearing loss. Whenever surgical intervention is not possible or contra-indicated, and amplification by a conventional hearing device (e.g., behind-the-ear device) is not feasible, then implantable hearing devices are an indispensable next option. Implantable bone-conduction devices and middle-ear implants have advantages but also limitations concerning complexity/invasiveness of the surgery, medical complications, and effectiveness. To counsel the patient, the clinician should have a good overview of the options with regard to safety and reliability as well as unequivocal technical performance data. The present consensus document is the outcome of an extensive iterative process including ENT specialists, audiologists, health-policy scientists, and representatives/technicians of the main companies in this field. This document should provide a first framework for procedures and technical characterization to enhance effective communication between these stakeholders, improving health care.
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| 7. |
- Tseng, Chen-Yuan, et al.
(författare)
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chinmo-mutant spermatogonial stem cells cause mitotic drive by evicting non-mutant neighbors from the niche
- 2022
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Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807. ; 57:1, s. 7-94
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Tidskriftsartikel (refereegranskat)abstract
- Niches maintain a finite pool of stem cells via restricted space and short-range signals. Stem cells compete for limited niche resources, but the mechanisms regulating competition are poorly understood. Using the Drosophila testis model, we show that germline stem cells (GSCs) lacking the transcription factor Chinmo gain a competitive advantage for niche access. Surprisingly, chinmo-/- GSCs rely on a new mechanism of competition in which they secrete the extracellular matrix protein Perlecan to selectively evict non-mutant GSCs and then upregulate Perlecan-binding proteins to remain in the altered niche. Over time, the GSC pool can be entirely replaced with chinmo-/- cells. As a consequence, the mutant chinmo allele acts as a gene drive element; the majority of offspring inherit the allele despite the heterozygous genotype of the parent. Our results suggest that the influence of GSC competition may extend beyond individual stem cell niche dynamics to population-level allelic drift and evolution.
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| 8. |
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| 9. |
- Cai, Xiaoli, et al.
(författare)
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Modulating the bicoid gradient in space and time
- 2021
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Ingår i: Hereditas. - : Springer Science and Business Media LLC. - 1601-5223. ; 158, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Background: The formation of the Bicoid (Bcd) gradient in the early Drosophila is one of the most fascinating observations in biology and serves as a paradigm for gradient formation, yet its mechanism is still not fully understood. Two distinct models were proposed in the past, the SDD and the ARTS model.Results: We define novel cis- and trans-acting factors that are indispensable for gradient formation. The first one is the poly A tail length of the bcd mRNA where we demonstrate that it changes not only in time, but also in space. We show that posterior bcd mRNAs possess a longer poly tail than anterior ones and this elongation is likely mediated by wispy (wisp), a poly A polymerase. Consequently, modulating the activity of Wisp results in changes of the Bcd gradient, in controlling downstream targets such as the gap and pair-rule genes, and also in influencing the cuticular pattern. Attempts to modulate the Bcd gradient by subjecting the egg to an extra nuclear cycle, i.e. a 15th nuclear cycle by means of the maternal haploid (mh) mutation showed no effect, neither on the appearance of the gradient nor on the control of downstream target. This suggests that the segmental anlagen are determined during the first 14 nuclear cycles. Finally, we identify the Cyclin B (CycB) gene as a trans-acting factor that modulates the movement of Bcd such that Bcd movement is allowed to move through the interior of the egg.Conclusions: Our analysis demonstrates that Bcd gradient formation is far more complex than previously thought requiring a revision of the models of how the gradient is formed.
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| 10. |
- Khalili, Dilan, et al.
(författare)
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Anti-Fibrotic Activity of an Antimicrobial Peptide in a Drosophila Model
- 2021
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 13:6, s. 376-390
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Tidskriftsartikel (refereegranskat)abstract
- Fibrotic lesions accompany several pathological conditions, including tumors. We show that expression of a dominant-active form of the Ras oncogene in Drosophila salivary glands (SGs) leads to redistribution of components of the basement membrane (BM) and fibrotic lesions. Similar to several types of mammalian fibrosis, the disturbed BM attracts clot components, including insect transglutaminase and phenoloxidase. SG epithelial cells show reduced apicobasal polarity accompanied by a loss of secretory activity. Both the fibrotic lesions and the reduced cell polarity are alleviated by ectopic expression of the antimicrobial peptide drosomycin (Drs), which also restores the secretory activity of the SGs. In addition to extracellular matrix components, both Drs and F-actin localize to fibrotic lesions.
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