| 1. |
- Groß, M., et al.
(författare)
-
Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity
- 2022
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 149:1, s. 388-399
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Rubella virus–induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive. Objective: This study sought to understand the defective effector mechanism allowing rubella vaccine virus persistence in granulomas. Methods: Starting from an index case with Griscelli syndrome type 2 and rubella skin granulomas, this study combined an international survey with a literature search to identify patients with cytotoxicity defects and granuloma. The investigators performed rubella virus immunohistochemistry and PCR and T-cell migration assays. Results: This study identified 21 patients with various genetically confirmed cytotoxicity defects, who presented with skin and visceral granulomas. Rubella virus was demonstrated in all 12 accessible biopsies. Granuloma onset was typically before 2 years of age and lesions persisted from months to years. Granulomas were particularly frequent in MUNC13-4 and RAB27A deficiency, where 50% of patients at risk were affected. Although these proteins have also been implicated in lymphocyte migration, 3-dimensional migration assays revealed no evidence of impaired migration of patient T cells. Notably, patients showed no evidence of reduced control of concomitantly given measles, mumps, or varicella live-attenuated vaccine or severe infections with other viruses. Conclusions: This study identified lymphocyte cytotoxicity as a key effector mechanism for control of rubella vaccine virus, without evidence for its need in control of live measles, mumps, or varicella vaccines. Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic disorders of cytotoxicity. © 2021 American Academy of Allergy, Asthma & Immunology
|
|
| 2. |
- Donkervoort, S., et al.
(författare)
-
Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
- 2020
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 107:6, s. 1078-1095
-
Tidskriftsartikel (refereegranskat)abstract
- The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.
|
|
| 3. |
- Kempf, W., et al.
(författare)
-
MUM1 expression in cutaneous CD30+ lymphoproliferative disorders : A valuable tool for the distinction between lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma
- 2008
-
Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 158:6, s. 1280-1287
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Primary cutaneous CD30+ lymphoproliferative disorders include lymphomatoid papulosis (LyP) and primary cutaneous CD30+ anaplastic large T-cell lymphoma (ALCL). Because of overlapping histological features, it is impossible to distinguish ALCL from LyP on histological grounds. MUM1 (Multiple Myeloma oncogene 1) is expressed in systemic ALCL and classical Hodgkin lymphoma. MUM1 expression has not been studied in detail in CD30+ lymphoproliferative disorders. Objectives: To examine the expression of MUM1 in CD30+ lymphoproliferative disorders and to assess its value as a diagnostic marker. Methods: Thirty-one formalin-fixed paraffin-embedded specimens of LyP (n = 15), primary cutaneous ALCL (n = 10), secondary cutaneous infiltrates of systemic ALCL (n = 4) and secondary cutaneous Hodgkin lymphoma (n = 2) were analysed by immunohistochemistry with a monoclonal antibody against MUM1. Results Results: Positive staining for MUM1 was observed in 13 cases of LyP (87%), two cases of primary cutaneous ALCL (20%), four cases of secondary cutaneous ALCL (100%) and two cases of secondary cutaneous Hodgkin lymphoma (100%). In 11 of 13 LyP cases (85%), MUM1 was displayed by the majority, i.e. 50-90%, of the tumour cells. In contrast to LyP and secondary cutaneous ALCL, only two cases of primary cutaneous ALCL (20%) harboured MUM1-positive tumour cells. There was a statistically significant difference in the expression of MUM1 between LyP and primary cutaneous ALCL (P = 0.002) and between primary cutaneous ALCL and secondary cutaneous ALCL (P = 0.015). Conclusions: MUM1 expression is a valuable tool for the distinction of LyP and ALCL and thus represents a novel adjunctive diagnostic marker in CD30+ lymphoproliferative disorders. © 2008 The Authors.
|
|
| 4. |
- Mitteldorf, C., et al.
(författare)
-
Expression of programmed death-1 (CD279) in primary cutaneous B-cell lymphomas with correlation to lymphoma entities and biological behaviour
- 2013
-
Ingår i: British Journal of Dermatology. - : Blackwell Publishing Ltd. - 0007-0963 .- 1365-2133. ; 169:6, s. 1212-1218
-
Tidskriftsartikel (refereegranskat)abstract
- Background Programmed death-1 (PD-1/CD279) is a cell-surface protein expressed in activated T cells and a subset of T lymphocytes including follicular helper T cells (TFH). The interaction between PD-1 and its ligands plays a role in immune response and evasion of malignancies. In nodal follicular lymphoma, the number of intratumoral PD-1-positive lymphocytes is associated with overall survival. Objectives To investigate 28 cases of primary cutaneous B-cell lymphoma, including the subtypes PCFCL (n = 10), PCMZL (n = 10) and DLBCL-LT (n = 8) for the number and density of PD-1-positive cells. Methods Immunohistochemical staining and a computerized morphometric analysis for evaluation were applied. The results were correlated with the clinical outcome. To distinguish between activated T cells and TFH we performed PD-1/bcl-6 double staining and compared these results with CXCL-13 staining. Double staining for PD-1 and PAX-5 was used to investigate whether tumour cells were positive for PD-1. Results The PD-1-positive cells represented tumour-infiltrating T cells (TILs). Only a minor subset was represented by TFH. Patients with DLBCL-LT had a significantly lower number of PD-1-positive TILs than those with PCMZL (P = 0·012) and PCFCL (P = 0·002) or both (P = 0·001). The difference between PCMZL and PCFCL did not reach significance (P = 0·074). The tumour cells were negative for PD-1. Conclusions A higher number of PD-1-expressing cells was found in indolent PCMZL and PCFCL than in high-malignant DLBCL-LT. The PD-1-positive cells represented not only TFH, but also other activated T cells as a part of the tumour microenvironment. The tumour cells in all investigated types of PCBCL did not show aberrant PD-1 expression. What’s already known about this topic? In nodal follicular lymphoma, the number of intratumoral programmed death (PD)-1-positive lymphocytes is associated with overall survival. No data exist for primary cutaneous B-cell lymphoma (PCBCL). What does this study add? A higher number of PD-1-expressing cells was found in indolent primary cutaneous marginal zone lymphoma and primary cutaneous follicle centre lymphoma, in contrast to the more aggressive diffuse large B-cell lymphoma, leg type. PD-1-positive cells do not represent only follicular helper T cells. The tumour cells in all investigated types of PCBCL did not show aberrant PD-1 expression. © 2013 British Association of Dermatologists.
|
|
| 5. |
- Abercrombie, Daniel, et al.
(författare)
-
Dark Matter benchmark models for early LHC Run-2 Searches : Report of the ATLAS/CMS Dark Matter Forum
- 2020
-
Ingår i: Physics of the Dark Universe. - : Elsevier BV. - 2212-6864. ; 27
-
Tidskriftsartikel (refereegranskat)abstract
- This document is the final report of the ATLAS-CMS Dark Matter Forum, a forum organized by the ATLAS and CMS collaborations with the participation of experts on theories of Dark Matter, to select a minimal basis set of dark matter simplified models that should support the design of the early LHC Run-2 searches. A prioritized, compact set of benchmark models is proposed, accompanied by studies of the parameter space of these models and a repository of generator implementations. This report also addresses how to apply the Effective Field Theory formalism for collider searches and present the results of such interpretations.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Herold, Nikolas, et al.
(författare)
-
Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
-
Tidskriftsartikel (refereegranskat)abstract
- The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
|
|
| 9. |
- Kohnke, B, et al.
(författare)
-
Gromex : A scalable and versatile fast multipole method for biomolecular simulation
- 2020
-
Ingår i: Lecture Notes in Computational Science and Engineering. - Cham : Springer. ; , s. 517-543
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Atomistic simulations of large biomolecular systems with chemical variability such as constant pH dynamic protonation offer multiple challenges in high performance computing. One of them is the correct treatment of the involved electrostatics in an efficient and highly scalable way. Here we review and assess two of the main building blocks that will permit such simulations: (1) An electrostatics library based on the Fast Multipole Method (FMM) that treats local alternative charge distributions with minimal overhead, and (2) A λ-dynamics module working in tandem with the FMM that enables various types of chemical transitions during the simulation. Our λ-dynamics and FMM implementations do not rely on third-party libraries but are exclusively using C++ language features and they are tailored to the specific requirements of molecular dynamics simulation suites such as GROMACS. The FMM library supports fractional tree depths and allows for rigorous error control and automatic performance optimization at runtime. Near-optimal performance is achieved on various SIMD architectures and on GPUs using CUDA. For exascale systems, we expect our approach to outperform current implementations based on Particle Mesh Ewald (PME) electrostatics, because FMM avoids the communication bottlenecks caused by the parallel fast Fourier transformations needed for PME.
|
|
| 10. |
- Kutzner, C., et al.
(författare)
-
Scaling of the GROMACS 4.6 molecular dynamics code on SuperMUC
- 2014
-
Ingår i: Advances in Parallel Computing. - 0927-5452 .- 1879-808X. ; 25, s. 722-727
-
Tidskriftsartikel (refereegranskat)abstract
- Here we report on the performance of GROMACS 4.6 on the SuperMUC cluster at the Leibniz Rechenzentrum in Garching. We carried out benchmarks with three biomolecular systems consisting of eighty thousand to twelve million atoms in a strong scaling test each. The twelve million atom simulation system reached a performance of 49 nanoseconds per day on 32,768 cores.
|
|
