45 results on '"Ramadani, F"'
Search Results
2. Ontogeny of human IgE-expressing B cells and plasma cells
- Author
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Ramadani, F., Bowen, H., Upton, N., Hobson, P. S., Chan, Y.-C., Chen, J.-B., Chang, T. W., McDonnell, J. M., Sutton, B. J., Fear, D. J., and Gould, H. J.
- Published
- 2017
- Full Text
- View/download PDF
3. Advantages of simultaneous radial nerve and tendon reconstruction – a case report.
- Author
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Kempný, T., Votruba, T., Xani, Z., Ramadani, F., Lipový, B., Dvořák, Z., Holoubek, J., and Bartková, J.
- Published
- 2023
4. Visualisierung lokaler kortikaler Defekte im Charcot-Fuß mittels Mikrocomputertomographie
- Author
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Senck, S., Plank, B., Kastner, J., Ramadani, F., Trieb, K., and Hofstaetter, S.G.
- Published
- 2015
- Full Text
- View/download PDF
5. Konservative Behandlung des Charcot-Fußes mittels Vollkontaktgips
- Author
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Trieb, K., Ramadani, F., and Hofstaetter, S.G.
- Published
- 2015
- Full Text
- View/download PDF
6. Komplexe Rekonstruktionen mit winkelstabiler interner Plattenfixation bei Charcot-Arthropathie
- Author
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Ramadani, F., Härägus, H., Radu, P., Trieb, K., and Hofstaetter, S.
- Published
- 2015
- Full Text
- View/download PDF
7. Intrinsic properties of germinal center-derived B cells promote their enhanced class switching to IgE
- Author
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Ramadani, F., Upton, N., Hobson, P., Chan, Y.-C., Mzinza, D., Bowen, H., Kerridge, C., Sutton, B. J., Fear, D. J., and Gould, H. J.
- Published
- 2015
- Full Text
- View/download PDF
8. Measuring corneal clouding in patients suffering from mucopolysaccharidosis with the Pentacam densitometry programme
- Author
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Elflein, H M, Hofherr, T, Berisha-Ramadani, F, Weyer, V, Lampe, C, Beck, M, and Pitz, S
- Published
- 2013
- Full Text
- View/download PDF
9. Arthroskopie des oberen Sprungelenks Eine retrospektive Analyse der Komplikationen: Eine retrospektive Analyse der Komplikationen
- Author
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Unger, F., Lajtai, G., Ramadani, F., Aitzetmüller, G., and Orthner, E.
- Published
- 2000
- Full Text
- View/download PDF
10. Results of anterior cruciate ligament reconstruction and the use of absorbable interference screws (minimum 2.5-year follow-up): Verwendung resorbierbarer Interferenzschrauben (minimum Follow-up 2,5 Jahre)
- Author
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Lajtai, G., Humer, K., Aitzetmüller, G., Unger, F., Ramadani, F., and Orthner, E.
- Published
- 1999
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11. Ontogeny of human IgE‐expressing B cells and plasma cells
- Author
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Ramadani, F., Bowen, H., Upton, N., Hobson, P. S., Chan, Y.‐C., Chen, J.‐B., Chang, T. W., McDonnell, J. M., Sutton, B. J., Fear, D. J., and Gould, H. J.
- Subjects
B-Lymphocytes ,plasma cell ,IgE class switching ,Plasma Cells ,Gene Expression ,Cell Differentiation ,Immunoglobulin E ,allergy ,Germinal Center ,Immunoglobulin Class Switching ,Immunophenotyping ,Phenotype ,human B cells ,Experimental Allergy and Immunology ,Immunoglobulin G ,Humans ,Original Article ,ORIGINAL ARTICLES ,germinal centre ,Biomarkers ,Cells, Cultured - Abstract
Background IgE‐expressing (IgE+) plasma cells (PCs) provide a continuous source of allergen‐specific IgE that is central to allergic responses. The extreme sparsity of IgE+ cells in vivo has confined their study almost entirely to mouse models. Objective To characterize the development pathway of human IgE+ PCs and to determine the ontogeny of human IgE+ PCs. Methods To generate human IgE+ cells, we cultured tonsil B cells with IL‐4 and anti‐CD40. Using FACS and RT‐PCR, we examined the phenotype of generated IgE+ cells, the capacity of tonsil B‐cell subsets to generate IgE+ PCs and the class switching pathways involved. Results We have identified three phenotypic stages of IgE+ PC development pathway, namely (i) IgE+germinal centre (GC)‐like B cells, (ii) IgE+ PC‐like ‘plasmablasts’ and (iii) IgE+ PCs. The same phenotypic stages were also observed for IgG1+ cells. Total tonsil B cells give rise to IgE+ PCs by direct and sequential switching, whereas the isolated GC B‐cell fraction, the main source of IgE+ PCs, generates IgE+ PCs by sequential switching. PC differentiation of IgE+ cells is accompanied by the down‐regulation of surface expression of the short form of membrane IgE (mIgES), which is homologous to mouse mIgE, and the up‐regulation of the long form of mIgE (mIgEL), which is associated with an enhanced B‐cell survival and expressed in humans, but not in mice. Conclusion Generation of IgE+ PCs from tonsil GC B cells occurs mainly via sequential switching from IgG. The mIgEL/mIgES ratio may be implicated in survival of IgE+ B cells during PC differentiation and allergic disease.
- Published
- 2016
12. Epiphysiolysis Type Salter I of the Medial Clavicle with Posterior Displacement: A Case Series and Review of the Literature
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Siebenmann, C., Ramadani, F., Barbier, G., Gautier, E., and Vial, P.
- Subjects
Article Subject - Abstract
Physeal fractures of the medial clavicle with posterior displacement of the metaphysis are very rare injuries, but additional injuries can be life-threatening. Due to the specific clavicular ossification process, skeletally immature patients present usually not true sternoclavicular joint (SCJ) dislocations accordingly to adults but rather displaced physeal fractures. There is no consensus in the current literature on the best treatment of this lesion. Conservative treatment is not resulting in good outcome; closed reduction is often not successful, and open reduction with internal fixation is finally required. Several methods are described for stabilizing these physeal fractures. We treated three osseous immature patients with this lesion. Due to the small dimension of the medial clavicular epiphysis, we performed in one case a transosseous figure-of-eight suture of the clavicular metaphysis towards the sternum, and in the two other cases, a transosseous suture from the clavicular metaphysis on the anterior clavicular periosteum. The latter technique avoids harm to the small epiphysis or the SCJ and minimizes the risk of retrosternal complications.
- Published
- 2018
- Full Text
- View/download PDF
13. Sistem Informasi Perpustakaan Online di Man Kota Solok
- Author
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Maulana, Ilham Tri, primary, Suardinata, Suardinata, additional, and Ramadani, F, additional
- Published
- 2019
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14. EXPLORING THE SPEAKING ANXIETY OF ELEMENTARY LEVEL PRIVATE UNIVERSITY STUDENTS OF SOUTH KALIMANTAN AND ATTEMPTS TO SOLVE
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Arbain, M., primary, Ramadani, F., additional, and Novika, H., additional
- Published
- 2018
- Full Text
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15. Structure of extended IgE-Fc in complex with two anti-IgE Fabs
- Author
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Chen, J.B., primary, Ramadani, F., additional, Pang, M.O.Y., additional, Beavil, R.L., additional, Holdom, M.D., additional, Mitropoulou, A.N., additional, Beavil, A.J., additional, Gould, H.J., additional, Chang, T.W., additional, Sutton, B.J., additional, McDonnell, J.M., additional, and Davies, A.M., additional
- Published
- 2018
- Full Text
- View/download PDF
16. Structure of the 8D6 (anti-IgE) Fab
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Chen, J.B., primary, Ramadani, F., additional, Pang, M.O.Y., additional, Beavil, R.L., additional, Holdom, M.D., additional, Mitropoulou, A.N., additional, Beavil, A.J., additional, Gould, H.J., additional, Chang, T.W., additional, Sutton, B.J., additional, McDonnell, J.M., additional, and Davies, A.M., additional
- Published
- 2018
- Full Text
- View/download PDF
17. Ontogeny of human IgE-expressing B cells and plasma cells.
- Author
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Ramadani, F, Bowen, H, Upton, N, Hobson, PS, Chan, Y-C, Chen, J-B, Chang, TW, McDonnell, JM, Sutton, BJ, Fear, DJ, Gould, HJ, Ramadani, F, Bowen, H, Upton, N, Hobson, PS, Chan, Y-C, Chen, J-B, Chang, TW, McDonnell, JM, Sutton, BJ, Fear, DJ, and Gould, HJ
- Abstract
BACKGROUND: IgE-expressing (IgE+ ) plasma cells (PCs) provide a continuous source of allergen-specific IgE that is central to allergic responses. The extreme sparsity of IgE+ cells in vivo has confined their study almost entirely to mouse models. OBJECTIVE: To characterize the development pathway of human IgE+ PCs and to determine the ontogeny of human IgE+ PCs. METHODS: To generate human IgE+ cells, we cultured tonsil B cells with IL-4 and anti-CD40. Using FACS and RT-PCR, we examined the phenotype of generated IgE+ cells, the capacity of tonsil B-cell subsets to generate IgE+ PCs and the class switching pathways involved. RESULTS: We have identified three phenotypic stages of IgE+ PC development pathway, namely (i) IgE+ germinal centre (GC)-like B cells, (ii) IgE+ PC-like 'plasmablasts' and (iii) IgE+ PCs. The same phenotypic stages were also observed for IgG1+ cells. Total tonsil B cells give rise to IgE+ PCs by direct and sequential switching, whereas the isolated GC B-cell fraction, the main source of IgE+ PCs, generates IgE+ PCs by sequential switching. PC differentiation of IgE+ cells is accompanied by the down-regulation of surface expression of the short form of membrane IgE (mIgES ), which is homologous to mouse mIgE, and the up-regulation of the long form of mIgE (mIgEL ), which is associated with an enhanced B-cell survival and expressed in humans, but not in mice. CONCLUSION: Generation of IgE+ PCs from tonsil GC B cells occurs mainly via sequential switching from IgG. The mIgEL /mIgES ratio may be implicated in survival of IgE+ B cells during PC differentiation and allergic disease.
- Published
- 2017
18. Intrinsic properties of germinal center-derived B cells promote their enhanced class switching to IgE.
- Author
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Ramadani, F, Upton, N, Hobson, P, Chan, Y-C, Mzinza, D, Bowen, H, Kerridge, C, Sutton, BJ, Fear, DJ, Gould, HJ, Ramadani, F, Upton, N, Hobson, P, Chan, Y-C, Mzinza, D, Bowen, H, Kerridge, C, Sutton, BJ, Fear, DJ, and Gould, HJ
- Abstract
BACKGROUND: Research on the origins and development of human IgE-expressing (IgE(+) ) cells is required for understanding the pathogenesis of allergy and asthma. These studies have been thwarted by the rarity of IgE(+) cells in vivo and the low frequency of class switch recombination (CSR) to IgE ex vivo. To determine the main source of IgE(+) cells, we investigated the relation between the phenotypic composition of tonsil B cells and the CSR to IgE ex vivo. METHODS: Human tonsil B cells were analyzed by flow cytometry (FACS) and cultured with IL-4 and anti-CD40 to induce CSR to IgE. Naïve, germinal center (GC), early GC (eGC), and memory tonsil B cells were isolated by FACS, and their capacities for IL-4 and anti-CD40 signaling, cell proliferation, and de novo class switching to IgE were analyzed by RT-PCR and FACS. RESULTS: B cells from different tonsils exhibited varying capacities for CSR to IgE ex vivo. This was correlated with the percentage of eGC B cells in the tonsil at the outset of the culture. Despite relatively poor cell viability, eGC and GC B-cell cultures produced the highest yields of IgE(+) cells compared to naïve and memory B-cell cultures. The main factors accounting for this result were the strength of IL-4R and CD40 signaling and relative rates of cell proliferation. CONCLUSIONS: This study shows that the maturation state of tonsil B cells determines their capacity to undergo class switching to IgE ex vivo, with the GC-derived B cells yielding the highest percentage of IgE(+) cells.
- Published
- 2015
19. Komplexe Rekonstruktionen mit winkelstabiler interner Plattenfixation bei Charcot-Arthropathie
- Author
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Ramadani, F., primary, Härägus, H., additional, Radu, P., additional, Trieb, K., additional, and Hofstaetter, S., additional
- Published
- 2014
- Full Text
- View/download PDF
20. Konservative Behandlung des Charcot-Fußes mittels Vollkontaktgips
- Author
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Trieb, K., primary, Ramadani, F., additional, and Hofstaetter, S.G., additional
- Published
- 2014
- Full Text
- View/download PDF
21. Visualisierung lokaler kortikaler Defekte im Charcot-Fuß mittels Mikrocomputertomographie
- Author
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Senck, S., primary, Plank, B., additional, Kastner, J., additional, Ramadani, F., additional, Trieb, K., additional, and Hofstaetter, S.G., additional
- Published
- 2014
- Full Text
- View/download PDF
22. IDENTIFIKASI DAN KARAKTERISASI POTENSI AIR TANAH UNTUK PENGEMBANGAN IRIGASI SUPLEMENTER DI PABRIK GULA RENDENG DAN TRANGKIL JAWA TENGAH (IDENTIFICATION AND CHARACTERIZATION OF GROUND WATER POTENTIAL FOR DEVELOPING SUPLEMENTARY IRRIGATION IN ...
- Author
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Rejekiningrum, P., primary, Ramadani, F., additional, Apriyana, Y., additional, and Haryono, ., additional
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- 2005
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- View/download PDF
23. Determination of heavy metals in soil, water wells and wastes after the technological process in the factory battery in Gjilan, with AAS method
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Skender Demaku, Ramadani, F., Krasniqi, I., Bekolli, A., and Shehu, I.
24. The p110β isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110γ
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Klaus Okkenhaug, Stephen Meek, Antonio Bilancio, Julie Guillermet-Guibert, Faruk Ramadani, Cristiano Gonella, Bart Vanhaesebroeck, Ashreena Salpekar, Andrew J.H. Smith, Katja Bjorklof, Guillermet Guibert, J, Bjorklof, K, Salpekar, A, Gonella, C, Ramadani, F, Bilancio, Antonio, Meek, S, Smith, Aj, Okkenhaug, K, and Vanhaesebroeck, B.
- Subjects
Class I Phosphatidylinositol 3-Kinases ,Complement C5a ,Ligands ,Receptors, G-Protein-Coupled ,Mice ,Phosphatidylinositol 3-Kinases ,Animals ,Protein kinase B ,G protein-coupled receptor ,Multidisciplinary ,Phosphoinositide 3-kinase ,biology ,Kinase ,Macrophage Colony-Stimulating Factor ,Macrophages ,Genetic Complementation Test ,Biological Sciences ,Fibroblasts ,Mice, Mutant Strains ,Cell biology ,Isoenzymes ,Biochemistry ,biology.protein ,Signal transduction ,Tyrosine kinase ,Proto-Oncogene Proteins c-akt ,Platelet-derived growth factor receptor ,Proto-oncogene tyrosine-protein kinase Src ,Signal Transduction - Abstract
The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110alpha, p110beta, and p110delta) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110alpha and p110delta to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110gamma class IB PI3K lack SH2 domains and instead couple p110gamma to G protein-coupled receptors (GPCRs). Here, we show, using small-molecule inhibitors with selectivity for p110beta and cells derived from a p110beta-deficient mouse line, that p110beta is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110beta and p110gamma contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110beta but not p110gamma, p110beta mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1-phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110gamma in these cells reduced the contribution of p110beta to GPCR signaling. Taken together, these data show that p110beta and p110gamma can couple redundantly to the same GPCR agonists. p110beta, which shows a much broader tissue distribution than the leukocyte-restricted p110gamma, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110gamma expression is low or absent.
- Published
- 2008
25. Height Restoration for Vertebra Plana Using a Mechanical Lamellar Vertebral Body Reduction Device: 2-Dimensional Operative Video.
- Author
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Ramadani F, Valsecchi D, Goga C, Otten P, and Maestretti G
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- Humans, Male, Female, Lumbar Vertebrae surgery, Vertebral Body surgery, Vertebral Body diagnostic imaging
- Published
- 2024
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26. Inhibition of PI3K p110δ activity reduces IgE production in IL-4 and anti-CD40 stimulated human B cell cultures.
- Author
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Cutrina-Pons A, De Sa A, Fear DJ, Gould HJ, and Ramadani F
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- Humans, Mice, Animals, Immunoglobulin E, CD40 Antigens genetics, CD40 Antigens metabolism, Immunoglobulin G, Cell Culture Techniques, Phosphatidylinositol 3-Kinases, Interleukin-4 metabolism
- Abstract
Phosphoinositide 3-kinase (PI3K) p110δ signalling negatively regulates the production of mouse IgE. However, there are disparities between the mouse and human IgE biology, and the role of PI3K p110δ in the production of human IgE is yet to be determined. To investigate the effect of PI3K p110δ inhibition in the production of human IgE we isolated human B cells from tonsil tissue and stimulated them with IL-4 and anti-CD40 antibody to induce class switching to IgE and IgG1 in the presence or absence of IC87114, a small molecule inhibitor of PI3K p110δ. Using FACS, RT-PCR and ELISA we examined the effect of PI3K p110δ inhibition on IgE production and determined the mechanisms involved. Unlike in mice, we observed that PI3K p110δ inhibition significantly reduces the number of IgE
+ switched cells and the amounts of secreted IgE in IL4 and anti-CD40 cultures. However, the number of IgG1+ cells and secreted IgG1 were largely unaffected by PI3K p110δ inhibition. The expression levels of AID, ε and γ1 germinal transcripts or other factors involved in the regulation of CSR to IgE and IgG1 were also unaffected by IC87114. However, we found that IC87114 significantly decreases the proliferation of tonsil B cells stimulated with IL-4 and anti-CD40, specifically reducing the frequency of cells that had undergone 4 divisions or more. In addition, PI3K p110δ inhibition reduced the levels of IRF4 expression in IgE+ germinal centre-like B cells leading to a block in plasma cell differentiation. In conclusion, PI3K p110δ signalling is required for the production of human IgE, which makes it a pharmacological target for the treatment of allergic disease., (© 2023 The Authors. Immunology published by John Wiley & Sons Ltd.)- Published
- 2023
- Full Text
- View/download PDF
27. Perceived sustainability of psychosocial treatment in low- and middle-income countries in South-Eastern Europe - CORRIGENDUM.
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Ribic E, Sikira H, Dzubur Kulenovic A, Pemovska T, Russo M, Jovanovic N, Radojicic T, Repisti S, Milutinović M, Blazevska B, Konjufca J, Ramadani F, Jerotic S, and Savic B
- Published
- 2023
- Full Text
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28. The relations between socio-demographic information and negative symptoms, mental health, and quality of life: a latent profile analysis with psychotic patients in Kosovo.
- Author
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Uka F, Konjufca J, Ramadani F, Arënliu A, Bërxulli D, Jovanović N, and Russo M
- Abstract
The current study aims to identify meaningful psychotic patients' profiles by examining certain combinations of patient's demographic and socio-economic variables (sex, age, marital status, number of children, cohabitant and level of education). Moreover, we aim to assess whether there is any significant effect of class membership (profile) on negative symptoms, health state, and quality of life among psychotic patients. A convenience sample of 103 patients (age: M = 22 , SD = 1.75), was drawn from the clinical populations of Kosovo. Demographic and socio-economic data was obtained through individual interviews, meanwhile a battery of questionnaires was used to assess negative symptoms, mental health, and quality of life of patients. The 4-class solution was selected as the best fitting model and used in subsequent analyses. Results indicated a significant effect of class membership on health state, quality of life and negative symptoms. Practical implications are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Uka, Konjufca, Ramadani, Arënliu, Bërxulli, Jovanović and Russo.)
- Published
- 2023
- Full Text
- View/download PDF
29. Advantages of simultaneous radial nerve and tendon reconstruction - a case report.
- Author
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Kempný T, Votruba T, Xani Z, Ramadani F, Lipový B, Dvořák Z, Holoubek J, and Bartková J
- Subjects
- Male, Humans, Young Adult, Adult, Forearm, Upper Extremity, Tendons, Radial Nerve surgery, Plastic Surgery Procedures
- Abstract
Transection of the radial nerve is frequently associated with humeral shaft fractures that are part of a very complex upper extremity injury. In the presented case, a 19-year-old man with a 10-cm radial nerve defect with a need for nerve grafting to recover complete sensory and motor deficit of the radial nerve. In our case, at the same time we provided the tendon transfer of musculus (m.) pronator teres to m. extensor carpi radialis brevis, m. flexor carpi ulnaris to m. extensor digitorum communis, m. palmaris longus to m. extensor pollicis longus, and long sural nerve graft because of an extensive zone of the injury. The assumption was that if these two procedures are performed in one surgery, it will accelerate overall recovery, restore the functionality of the upper limb more quickly, and thus enable a faster recovery.
- Published
- 2023
- Full Text
- View/download PDF
30. Perceived sustainability of psychosocial treatment in low- and middle-income countries in South-Eastern Europe.
- Author
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Ribic E, Sikira H, Dzubur Kulenovic A, Pemovska T, Russo M, Jovanovic N, Radojicic T, Repisti S, Milutinović M, Blazevska B, Konjufca J, Ramadani F, Jerotic S, and Savic B
- Abstract
Background: DIALOG+ is an evidence-based, generic, cost-saving and easily deliverable psychosocial intervention, adaptable to clinicians' personal manner of interaction with patients. It was implemented in mental health services in five low- and middle-income countries in South-Eastern Europe during a 12-month randomised-controlled trial (IMPULSE) to improve the effectiveness of out-patient treatment for people with psychotic disorders., Aims: To investigate barriers and facilitators to the perceived sustainability of DIALOG+ that has been successfully implemented as a part of the IMPULSE project., Method: Three months after the IMPULSE trial's end, perceived sustainability of the DIALOG+ intervention was assessed via a short survey of clinicians and patients who took part in the trial. Quantitative data collected from the survey were analysed using descriptive statistics; content analysis assessed qualitative survey data. The views and experiences of key informants (patients, clinicians and healthcare policy influencers) regarding the sustainability and scale-up of DIALOG+ were further explored through semi-structured interviews. These data were explored using framework analysis., Results: Clinicians mostly appreciated the comprehensiveness of DIALOG+, and patients described DIALOG+ meetings as empowering and motivating. The barrier most commonly identified by key informants was availability of financial resources; the most important facilitators were the clinically relevant structure and comprehensiveness of the DIALOG+ intervention., Conclusions: Participants showed a willingness to sustain the implementation of DIALOG+. It is important to maintain collaboration with healthcare policy influencers to improve implementation of DIALOG+ across different levels of healthcare systems and ensure availability of resources for implementing psychosocial interventions such as DIALOG+.
- Published
- 2022
- Full Text
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31. Osteoarticular vascular corrosion casting using industrial polyurethane for the 3D representation of the vascular tree on human knee.
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Ramadani F, Petek D, Tannast M, and Filgueira L
- Subjects
- Animals, Corrosion Casting, Femur, Humans, Knee Joint, Knee, Polyurethanes
- Abstract
Vascular casting is a widely used method for the representation of body vascularization. Many different injection materials have been described throughout the time to enhance the arterial vascular supply within a specifically defined anatomical location. The use of industrial polyurethane has been recently evaluated and applied to animal and human anatomy. The aim of this study was to confirm the safe and reliable use of industrial polyurethane in knee specimen in order to obtain a three-dimensional vascular tree of the distal femur. 10 fresh-frozen knees (mid-thigh to mid tibia) were used to assess the vascularity around the femoral condyles. Industrial polyurethane foam (Soudal™ foam) was diluted with acetone in order to obtain a runny fluid, easy to inject. After injection, the knees were bathed in a 10% NaOH solution, heated at 30°. The corrosion process took from 20 to 24h and allowed all the soft tissue surrounding the knee to be subsided, leaving only the bone with polyurethane vascular architecture. After soft tissue corrosion, the vascular network around the knees was easily identified underlying the relation of the vessels to the bone. Even small arterioles (diameter<1mm) were distinguished with a good resistance to breakage. Corrosion casting remains an easy and reliable alternative to dissection for the understanding of tissue perfusion as the handling of the polyurethane is easy and has low costs. The described author's method can be used osteo-articular specimen as well as in other organs. The protocol of injection and corrosion needs however to be adapted to the different specimen and anatomical location. Polyurethane associated to acetone can safely be used as injection material in order to demonstrate the vascularity of a specimen and remains easy to use., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2022
- Full Text
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32. Transcriptional Analysis of the Human IgE-Expressing Plasma Cell Differentiation Pathway.
- Author
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Ramadani F, Bowen H, Gould HJ, and Fear DJ
- Subjects
- Apoptosis genetics, Cells, Cultured, Early Growth Response Protein 1 genetics, Gene Expression Regulation, Gene Regulatory Networks, Germinal Center immunology, Humans, Hypersensitivity metabolism, Immunoglobulin G metabolism, Interferon Regulatory Factors genetics, Palatine Tonsil pathology, Phenotype, Cell Differentiation genetics, Immunoglobulin E metabolism, Plasma Cells metabolism, Transcriptome genetics
- Abstract
IgE is secreted by plasma cells (PCs) and is central to allergic disease. Using an ex vivo tonsil B cell culture system, which mimics the Th2 responses in vivo , we have recently characterized the development pathway of human IgE-expressing PCs. In this system, as in mice, we reported the predisposition of IgE-expressing B cells to differentiate into PCs. To gain a comprehensive understanding of the molecular events involved in the differentiation of human IgE
+ B cells into PCs we have used the Illumina HumanHT-12 v4 Expression BeadChip array to analyse the gene expression profile of ex vivo generated human IgE+ B cells at various stages of their differentiation into PCs. We also compared the transcription profiles of IgE+ and IgG1+ cells to discover isotype-specific patterns. Comparisons of IgE+ and IgG1+ cell transcriptional profiles revealed molecular signatures specific for IgE+ cells, which diverge from their IgG1+ cell counterparts upon differentiation into PCs. At the germinal center (GC) stage of development, unlike in some mouse studies of IgE biology, we observed similar rates of apoptosis and no significant differences in the expression of apoptosis-associated genes between the IgE+ and IgG1+ B cells. We identified a gene interaction network associated with early growth response 1 ( EGR1 ) that, together with the up-regulated IRF4, may account for the predisposition of IgE+ B cells to differentiate into PCs. However, despite their swifter rates of PC differentiation, the transcription profile of IgE+ PCs is more closely related to IgE+ and IgG1+ plasmablasts (PBs) than to IgG1+ PCs, suggesting that the terminal differentiation of IgE+ cells is impeded. We also show that IgE+ PCs have increased levels of apoptosis suggesting that the IgE+ PCs generated in our in vitro tonsil B cell cultures, as in mice, are short-lived. We identified gene regulatory networks as well as cell cycle and apoptosis signatures that may explain the diverging PC differentiation programme of these cells. Overall, our study provides a detailed analysis of the transcriptional pathways underlying the differentiation of human IgE-expressing B cells and points to molecular signatures that regulate IgE+ PC differentiation and function.- Published
- 2019
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33. Peanut allergen-specific antibodies go public.
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Gould HJ and Ramadani F
- Subjects
- B-Lymphocytes, Humans, Immunoglobulin E, Plant Proteins, Transcriptome, Allergens, Arachis immunology
- Published
- 2018
- Full Text
- View/download PDF
34. miR-29b directly targets activation-induced cytidine deaminase in human B cells and can limit its inappropriate expression in naïve B cells.
- Author
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Recaldin T, Hobson PS, Mann EH, Ramadani F, Cousins DJ, Lavender P, and Fear DJ
- Subjects
- 3' Untranslated Regions genetics, Base Sequence, Enzyme Activation, Gene Knockdown Techniques, Genome, Human, HEK293 Cells, Humans, Immunoglobulin Class Switching, Immunoglobulin E metabolism, MicroRNAs genetics, Palatine Tonsil cytology, Recombination, Genetic genetics, B-Lymphocytes enzymology, Cytidine Deaminase metabolism, MicroRNAs metabolism
- Abstract
Class-switch recombination (CSR) is an essential B cell process that alters the isotype of antibody produced by the B cell, tailoring the immune response to the nature of the invading pathogen. CSR requires the activity of the mutagenic enzyme AID (encoded by AICDA) to generate chromosomal lesions within the immunoglobulin genes that initiate the class switching recombination event. These AID-mediated mutations also participate in somatic-hypermutation of the immunoglobulin variable region, driving affinity maturation. As such, AID poses a significant oncogenic threat if it functions outside of the immunoglobulin locus. We found that expression of the microRNA, miR-29b, was repressed in B cells isolated from tonsil tissue, relative to circulating naïve B cells. Further investigation revealed that miR-29b was able to directly initiate the degradation of AID mRNA. Enforced overexpression of miR-29b in human B cells precipitated a reduction in overall AID protein and a corresponding diminution in CSR to IgE. Given miR-29b's ability to potently target AID, a mutagenic molecule that can initiate chromosomal translocations and "off-target" mutations, we propose that miR-29b acts to silence premature AID expression in naïve B cells, thus reducing the likelihood of inappropriate and potentially dangerous deamination activity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
- Full Text
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35. Structural basis for selective inhibition of immunoglobulin E-receptor interactions by an anti-IgE antibody.
- Author
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Chen JB, Ramadani F, Pang MOY, Beavil RL, Holdom MD, Mitropoulou AN, Beavil AJ, Gould HJ, Chang TW, Sutton BJ, McDonnell JM, and Davies AM
- Subjects
- B-Lymphocytes immunology, Crystallography, X-Ray, HEK293 Cells, Humans, Immunoglobulin Fab Fragments chemistry, Immunoglobulin Fab Fragments metabolism, Immunoglobulin Fc Fragments chemistry, Immunoglobulin Fc Fragments metabolism, Mast Cells immunology, Protein Binding, Protein Conformation, Antibodies, Anti-Idiotypic chemistry, Antibodies, Anti-Idiotypic metabolism, Immunoglobulin E chemistry, Immunoglobulin E metabolism, Receptors, IgE metabolism
- Abstract
Immunoglobulin E (IgE) antibodies play a central role in the allergic response: interaction with FcεRI on mast cells and basophils leads to immediate hypersensitivity reactions upon allergen challenge, while interaction with CD23/FcεRII, expressed on a variety of cells, regulates IgE synthesis among other activities. The receptor-binding IgE-Fc region has recently been found to display remarkable flexibility, from acutely bent to extended conformations, with allosteric communication between the distant FcεRI and CD23 binding sites. We report the structure of an anti-IgE antibody Fab (8D6) bound to IgE-Fc through a mixed protein-carbohydrate epitope, revealing further flexibility and a novel extended conformation with potential relevance to that of membrane-bound IgE in the B cell receptor for antigen. Unlike the earlier, clinically approved anti-IgE antibody omalizumab, 8D6 inhibits binding to FcεRI but not CD23; the structure reveals how this discrimination is achieved through both orthosteric and allosteric mechanisms, supporting therapeutic strategies that retain the benefits of CD23 binding.
- Published
- 2018
- Full Text
- View/download PDF
36. [Complex reconstruction with internal locking plate fixation for Charcot arthropathy].
- Author
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Ramadani F, Härägus H, Radu P, Trieb K, and Hofstaetter S
- Subjects
- Arthropathy, Neurogenic diagnosis, Diabetic Foot diagnosis, Equipment Failure Analysis, Female, Humans, Male, Prosthesis Design, Plastic Surgery Procedures methods, Retrospective Studies, Treatment Outcome, Arthropathy, Neurogenic surgery, Bone Plates, Diabetic Foot surgery, Internal Fixators, Plastic Surgery Procedures instrumentation
- Abstract
Background: Osteosynthesis and reposition of the Charcot foot is challenging with respect to choice of a proper implant. There is currently no international consensus regarding the optimal implant., Objectives: Locking plates seem to be an innovative and stable method for reconstruction. The aim of this work is to analyze bone fusion, complications, pseudoarthrosis, and patient satisfaction., Methods: This paper presents a retrospective analysis of 63 consecutive Charcot feet treated between 2004 and 2014. The mean follow-up time was 2.4 years., Results: All Charcot feet treated between 2004 and 2014 were Sanders type II or III. A bony fusion was achieved in 50 % of the cases, 26 % had a functional pseudoarthrosis with intact implants and pain-free mobility, and 22 % showed no healing with broken implants. Conclusion Internal fixation with locking plates is superior to screw fixation only with regard to biomechanics. We prefer internal fixation plates to external fixation because of stability even in the case of pseudoathrosis and because of the learning curve.
- Published
- 2015
- Full Text
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37. IgE responses in mouse and man and the persistence of IgE memory.
- Author
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Gould HJ and Ramadani F
- Subjects
- Animals, Antibody Affinity immunology, B-Lymphocytes metabolism, Disease Models, Animal, Humans, Hypersensitivity genetics, Hypersensitivity immunology, Hypersensitivity metabolism, Immunoglobulin Class Switching, Immunoglobulin E genetics, Immunoglobulin E metabolism, Mice, Somatic Hypermutation, Immunoglobulin, B-Lymphocytes immunology, Immunoglobulin E immunology, Immunologic Memory
- Abstract
Rapid and robust recall or 'memory' responses are an essential feature of adaptive immunity. They constitute a defense against reinfection by pathogens, yet arguably do more harm than good in allergic disease. Immunoglobulin (Ig)E antibodies mediate the allergic reaction characterized by immediate hypersensitivity, a manifestation of IgE memory. The origin of IgE memory remains obscure, mainly due to the low proportion of IgE-expressing B cells in the total B cell population. The recent development of ultrasensitive methods for tracking these cells in vivo has overcome this obstacle, and their use has revealed unexpected pathways to IgE memory in the mouse. Here, we review these findings and consider their bearing on our understanding of IgE memory and allergic disease in man., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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38. [Full contact plaster cast for conservative treatment of Charcot foot].
- Author
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Trieb K, Ramadani F, and Hofstaetter SG
- Subjects
- Arthropathy, Neurogenic diagnosis, Diabetic Foot diagnosis, Humans, Prosthesis Fitting methods, Treatment Outcome, Arthropathy, Neurogenic therapy, Casts, Surgical, Diabetic Foot therapy, Immobilization methods
- Abstract
Background: The gold standard for treatment of early stages of Charcot foot are immobilization with a full contact plaster cast, whereby different periods and loading concepts are described in the literature., Objectives: The etiology, disease course and preparation for an early conservative therapy are described and a key point is a full contact plaster cast., Methods: An overview of the etiology, pathogenesis and indications for correct evaluation of the wound situation is given. The correct technique for the total cast is described and illustrated step by step with pictures., Results: If treatment of Charcot foot is initiated in the early stages prevention or healing of ulcers can be achieved; therefore, the correct indications and technique are necessary and the cast should be changed periodically which is a key point of the healing process. Healing results in a reduction of redness, temperature and swelling which should be measured and documented., Conclusions: Treatment of Charcot foot by full contact cast and immobilization should be initiated as soon as possible.
- Published
- 2015
- Full Text
- View/download PDF
39. "Auto-anti-IgE": naturally occurring IgG anti-IgE antibodies may inhibit allergen-induced basophil activation.
- Author
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Chan YC, Ramadani F, Santos AF, Pillai P, Ohm-Laursen L, Harper CE, Fang C, Dodev TS, Wu SY, Ying S, Corrigan CJ, and Gould HJ
- Subjects
- Allergens immunology, Animals, Antibodies, Anti-Idiotypic blood, Antigens, Plant immunology, Asthma blood, Autoantibodies blood, Calcium-Binding Proteins immunology, Cell Line, Humans, Immunoglobulin E immunology, Immunoglobulin G blood, Phleum immunology, Rats, Receptors, IgE immunology, Antibodies, Anti-Idiotypic immunology, Asthma immunology, Autoantibodies immunology, Basophils immunology, Immunoglobulin G immunology
- Abstract
Background: Naturally occurring IgE-specific IgG autoantibodies have been identified in patients with asthma and other diseases, but their spectrum of functions is poorly understood., Objective: Address the hypothesis that: (i) IgG anti-IgE autoantibodies are detectable in the serum of all subjects but elevated in asthmatic patients regardless of atopic status as compared with controls; (ii) some activate IgE-sensitized basophils; and (iii) some inhibit allergen-induced basophil activation., Methods: IgE-specific IgG autoantibodies were detected and quantified in sera using ELISA. Sera were examined for their ability to activate IgE-sensitized human blood basophils in the presence and absence of allergen using a basophil activation test, and to inhibit allergen binding to specific IgE on a rat basophilic cell line stably expressing human FcεRI., Results: IgG autoantibodies binding to both free and FcεRI-bound IgE were detected in patients with atopic and non-atopic asthma, as well as controls. While some were able to activate IgE-sensitised basophils, others inhibited allergen-induced basophil activation, at least partly by inhibiting binding of IgE to specific allergen., Conclusion: Naturally occurring IgG anti-IgE autoantibodies may inhibit, as well as induce, basophil activation. They act in a manner distinct from therapeutic IgG anti-IgE antibodies such as omalizumab. They may at least partly explain why atopic subjects who make allergen-specific IgE never develop clinical symptoms, and why omalizumab therapy is of variable clinical benefit in severe atopic asthma., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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40. The who, where, and when of IgE in allergic airway disease.
- Author
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Dullaers M, De Bruyne R, Ramadani F, Gould HJ, Gevaert P, and Lambrecht BN
- Subjects
- Animals, Cell Differentiation, Cell Movement, Humans, Molecular Targeted Therapy, Respiratory Hypersensitivity therapy, Immunoglobulin E immunology, Plasma Cells immunology, Respiratory Hypersensitivity immunology
- Abstract
Allergic asthma and allergic rhinitis/conjunctivitis are characterized by a T(H)2-dominated immune response associated with increased serum IgE levels in response to inhaled allergens. Because IgE is a key player in the induction and maintenance of allergic inflammation, it represents a prime target for therapeutic intervention. However, our understanding of IgE biology remains fragmentary. This article puts together our current knowledge on IgE in allergic airway diseases with a special focus on the identity of IgE-secreting cells ("who"), their location ("where"), and the circumstances in which they are induced ("when"). We further consider the therapeutic implications of the insights gained., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)
- Published
- 2012
- Full Text
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41. PI3Kβ plays a critical role in neutrophil activation by immune complexes.
- Author
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Kulkarni S, Sitaru C, Jakus Z, Anderson KE, Damoulakis G, Davidson K, Hirose M, Juss J, Oxley D, Chessa TA, Ramadani F, Guillou H, Segonds-Pichon A, Fritsch A, Jarvis GE, Okkenhaug K, Ludwig R, Zillikens D, Mocsai A, Vanhaesebroeck B, Stephens LR, and Hawkins PT
- Subjects
- Animals, B-Lymphocytes immunology, B-Lymphocytes metabolism, Blotting, Western, CD2 Antigens genetics, CD2 Antigens metabolism, Class Ia Phosphatidylinositol 3-Kinase genetics, Enzyme Inhibitors pharmacology, Female, Flow Cytometry, Gene Rearrangement, B-Lymphocyte genetics, Immunoglobulin Heavy Chains genetics, Immunoglobulin Heavy Chains metabolism, Immunoglobulin Joining Region genetics, Immunoglobulin Joining Region metabolism, Immunoglobulin Variable Region genetics, Immunoglobulin Variable Region metabolism, In Situ Hybridization, Fluorescence, Male, Mice, Mice, Knockout, Mice, Transgenic, Neutrophils metabolism, Phosphoinositide-3 Kinase Inhibitors, Reactive Oxygen Species metabolism, Receptors, IgG metabolism, Receptors, Leukotriene B4 metabolism, Signal Transduction drug effects, Signal Transduction immunology, Antigen-Antibody Complex immunology, Class Ia Phosphatidylinositol 3-Kinase metabolism, Neutrophil Activation immunology, Neutrophils immunology
- Abstract
Neutrophils are activated by immunoglobulin G (IgG)-containing immune complexes through receptors that recognize the Fc portion of IgG (FcγRs). Here, we used genetic and pharmacological approaches to define a selective role for the β isoform of phosphoinositide 3-kinase (PI3Kβ) in FcγR-dependent activation of mouse neutrophils by immune complexes of IgG and antigen immobilized on a plate surface. At low concentrations of immune complexes, loss of PI3Kβ alone substantially inhibited the production of reactive oxygen species (ROS) by neutrophils, whereas at higher doses, similar suppression of ROS production was achieved only by targeting both PI3Kβ and PI3Kδ, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3Kβ by immune complexes involved cooperation between FcγRs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B₄. Coincident activation by a tyrosine kinase-coupled receptor (FcγR) and a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (BLT1) may provide a rationale for the preferential activation of the β isoform of PI3K. PI3Kβ-deficient mice were highly protected in an FcγR-dependent model of autoantibody-induced skin blistering and were partially protected in an FcγR-dependent model of inflammatory arthritis, whereas combined deficiency of PI3Kβ and PI3Kδ resulted in near-complete protection in the latter case. These results define PI3Kβ as a potential therapeutic target in inflammatory disease.
- Published
- 2011
- Full Text
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42. The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development.
- Author
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Ramadani F, Bolland DJ, Garcon F, Emery JL, Vanhaesebroeck B, Corcoran AE, and Okkenhaug K
- Subjects
- Analysis of Variance, Animals, B-Lymphocytes immunology, Blotting, Western, Class I Phosphatidylinositol 3-Kinases, DNA Primers genetics, DNA-Binding Proteins metabolism, Flow Cytometry, Gene Expression Profiling, Immunohistochemistry, In Situ Hybridization, Fluorescence, Mice, Mice, Mutant Strains, Specific Pathogen-Free Organisms, B-Lymphocytes cytology, Phosphatidylinositol 3-Kinases immunology, Pre-B Cell Receptors metabolism, Signal Transduction immunology
- Abstract
B cell development is controlled by a series of checkpoints that ensure that the immunoglobulin (Ig)-encoding genes produce a functional B cell receptor (BCR) and antibodies. As part of this process, recombination-activating gene (Rag) proteins regulate the in-frame assembly of the Ig-encoding genes. The BCR consists of Ig proteins in complex with the immunoreceptor tyrosine-based activation motif (ITAM)-containing Igalpha and Igbeta chains. Whereas the activation of the tyrosine kinases Src and Syk is essential for BCR signaling, the pathways that act downstream of these kinases are incompletely defined. Previous work has revealed a key role for the p110delta isoform of phosphatidylinositol 3-kinase (PI3K) in agonist-induced BCR signaling; however, early B cell development and mature B cell survival, which depend on agonist-independent or "tonic" BCR signaling, are not substantially affected by a deficiency in p110delta. Here, we show that p110alpha, but not p110beta, compensated in the absence of p110delta to promote early B cell development in the bone marrow and B cell survival in the spleen. In the absence of both p110alpha and p110delta activities, pre-BCR signaling failed to suppress the production of Rag proteins and to promote developmental progression of B cell progenitors. Unlike p110delta, however, p110alpha did not contribute to agonist-induced BCR signaling. These studies indicate that either p110alpha or p110delta can mediate tonic signaling from the BCR, but only p110delta can contribute to antigen-dependent activation of B cells.
- Published
- 2010
- Full Text
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43. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span.
- Author
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Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, and Withers DJ
- Subjects
- AMP-Activated Protein Kinases metabolism, Adipose Tissue, White metabolism, Animals, Bone Density, Caloric Restriction, Female, Gene Deletion, Gene Expression, Gene Expression Regulation, Insulin metabolism, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Motor Activity, Muscle, Skeletal metabolism, Protein Kinases metabolism, Ribosomal Protein S6 Kinases, 90-kDa genetics, T-Lymphocyte Subsets immunology, TOR Serine-Threonine Kinases, Transcription, Genetic, Aging physiology, Longevity physiology, Ribosomal Protein S6 Kinases, 90-kDa metabolism, Signal Transduction
- Abstract
Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging.
- Published
- 2009
- Full Text
- View/download PDF
44. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma.
- Author
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Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, and Vanhaesebroeck B
- Subjects
- Animals, Class I Phosphatidylinositol 3-Kinases, Complement C5a pharmacology, Fibroblasts enzymology, Genetic Complementation Test, Isoenzymes genetics, Isoenzymes metabolism, Ligands, Macrophage Colony-Stimulating Factor pharmacology, Macrophages enzymology, Mice, Mice, Mutant Strains, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins c-akt metabolism, Receptors, G-Protein-Coupled agonists, Signal Transduction, Phosphatidylinositol 3-Kinases metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110alpha, p110beta, and p110delta) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110alpha and p110delta to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110gamma class IB PI3K lack SH2 domains and instead couple p110gamma to G protein-coupled receptors (GPCRs). Here, we show, using small-molecule inhibitors with selectivity for p110beta and cells derived from a p110beta-deficient mouse line, that p110beta is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110beta and p110gamma contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110beta but not p110gamma, p110beta mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1-phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110gamma in these cells reduced the contribution of p110beta to GPCR signaling. Taken together, these data show that p110beta and p110gamma can couple redundantly to the same GPCR agonists. p110beta, which shows a much broader tissue distribution than the leukocyte-restricted p110gamma, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110gamma expression is low or absent.
- Published
- 2008
- Full Text
- View/download PDF
45. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice.
- Author
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Selman C, Lingard S, Choudhury AI, Batterham RL, Claret M, Clements M, Ramadani F, Okkenhaug K, Schuster E, Blanc E, Piper MD, Al-Qassab H, Speakman JR, Carmignac D, Robinson IC, Thornton JM, Gems D, Partridge L, and Withers DJ
- Subjects
- Animals, Biomarkers analysis, Female, Insulin Receptor Substrate Proteins, Insulin Resistance genetics, Intracellular Signaling Peptides and Proteins genetics, Mice, Mice, Knockout, Phosphoproteins genetics, Signal Transduction genetics, Adaptor Proteins, Signal Transducing genetics, Longevity genetics
- Abstract
Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS receptors. Our provisional results indicate that female Irs1-/- mice are long-lived. Furthermore, they displayed resistance to a range of age-sensitive markers of aging including skin, bone, immune, and motor dysfunction. These improvements in health were seen despite mild, lifelong insulin resistance. Thus, enhanced insulin sensitivity is not a prerequisite for IIS mutant longevity. Irs1-/- female mice also displayed normal anterior pituitary function, distinguishing them from long-lived somatotrophic axis mutants. In contrast, Irs2-/- mice were short-lived, whereas Irs1+/- and Irs2+/- mice of both sexes showed normal life spans. Our results therefore suggest that IRS1 signaling is an evolutionarily conserved pathway regulating mammalian life span and may be a point of intervention for therapies with the potential to delay age-related processes.
- Published
- 2008
- Full Text
- View/download PDF
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