Refine
H-BRS Bibliography
- yes (11) (remove)
Departments, institutes and facilities
- Fachbereich Informatik (11) (remove)
Document Type
- Article (11) (remove)
Year of publication
- 2019 (11) (remove)
Language
- English (11)
Has Fulltext
- no (11) (remove)
Keywords
- ACPYPE (1)
- Antifuse memory (1)
- Augmented reality (1)
- Ball tracking (1)
- CIBERSORT (1)
- Carbohydrate (1)
- Chip ID (1)
- Counterfeit protection (1)
- Drosophila (1)
- EM leakage (1)
Herein we report an update to ACPYPE, a Python3 tool that now properly converts AMBER to GROMACS topologies for force fields that utilize nondefault and nonuniform 1–4 electrostatic and nonbonded scaling factors or negative dihedral force constants. Prior to this work, ACPYPE only converted AMBER topologies that used uniform, default 1–4 scaling factors and positive dihedral force constants. We demonstrate that the updated ACPYPE accurately transfers the GLYCAM06 force field from AMBER to GROMACS topology files, which employs non-uniform 1–4 scaling factors as well as negative dihedral force constants. Validation was performed using β-d-GlcNAc through gas-phase analysis of dihedral energy curves and probability density functions. The updated ACPYPE retains all of its original functionality, but now allows the simulation of complex glycomolecular systems in GROMACS using AMBER-originated force fields. ACPYPE is available for download at https://github.com/alanwilter/acpype.
Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.
Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post–allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post–allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients’ first relapses, which disappeared in the post–allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children’s post–allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post–allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.
This work addresses the issue of finding an optimal flight zone for a side-by-side tracking and following Unmanned Aerial Vehicle(UAV) adhering to space-restricting factors brought upon by a dynamic Vector Field Extraction (VFE) algorithm. The VFE algorithm demands a relatively perpendicular field of view of the UAV to the tracked vehicle, thereby enforcing the space-restricting factors which are distance, angle and altitude. The objective of the UAV is to perform side-by-side tracking and following of a lightweight ground vehicle while acquiring high quality video of tufts attached to the side of the tracked vehicle. The recorded video is supplied to the VFE algorithm that produces the positions and deformations of the tufts over time as they interact with the surrounding air, resulting in an airflow model of the tracked vehicle. The present limitations of wind tunnel tests and computational fluid dynamics simulation suggest the use of a UAV for real world evaluation of the aerodynamic properties of the vehicle’s exterior. The novelty of the proposed approach is alluded to defining the specific flight zone restricting factors while adhering to the VFE algorithm, where as a result we were capable of formalizing a locally-static and a globally-dynamic geofence attached to the tracked vehicle and enclosing the UAV.