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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.
Dysregulation of IL12 Signaling As a Novel Cause of an Autoimmune Lymphoproliferative like Syndrome
(2014)
Background: Virtual reality combined with a spherical treadmill is used across species for studying neural circuits underlying navigation and learning.
New method: We developed an optical flow-based method for tracking treadmill ball motion in real time using a single high-resolution camera.
Results: Tracking accuracy and timing were determined using calibration data. Ball tracking was performed at 500 Hz and integrated with an open source game engine for virtual reality projection. The projection was updated at 120 Hz with a latency with respect to ball motion of 30 ± 8 ms. The system was tested for behavior with fruit flies. The application and source code are available at https://github.com/ivan-vishniakou/neural-circuits-vr.
Comparison with existing method(s): Optical flow-based tracking of treadmill motion is typically achieved using optical mice. The camera-based optical flow tracking system developed here is based on off-the-shelf components and offers control over the image acquisition and processing parameters. This results in flexibility with respect to tracking conditions – such as ball surface texture, lighting conditions, or ball size – as well as camera alignment and calibration.
Conclusions: A fast system for rotational ball motion tracking suitable for virtual reality behavior with fruit flies was developed and characterized.
Walking has always been considered as the gold standard for navigation in Virtual Reality research. Though full rotation is no longer a technical challenge, physical translation is still restricted through limited tracked areas. While rotational information has been shown to be important, the benefit of the translational component is still unclear with mixed results in previous work. To address this gap, we conducted a mixed-method experiment to compare four levels of translational cues and control: none (using the trackpad of the HTC Vive controller to translate), upper-body leaning (sitting on a "NaviChair", leaning the upper-body to locomote), whole-body leaning/stepping (standing on a platform called NaviBoard, leaning the whole body or stepping one foot off the center to navigate), and full translation (physically walking). Results showed that translational cues and control had significant effects on various measures including task performance, task load, and simulator sickness. While participants performed significantly worse when they used a controller with no embodied translational cues, there was no significant difference between the NaviChair, NaviBoard, and actual walking. These results suggest that translational body-based motion cues and control from a low-cost leaning/stepping interface might provide enough sensory information for supporting spatial updating, spatial awareness, and efficient locomotion in VR, although future work will need to investigate how these results might or might not generalize to other tasks and scenarios.
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.
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.
Touchscreen interaction suffers from occlusion problems as fingers can cover small targets, which makes interacting with such targets challenging. To improve touchscreen interaction accuracy and consequently the selection of small or hidden objects we introduce a back-of-device force feedback system for smartphones. We introduce a new solution that combines force feedback on the back to enhance touch input on the front screen. The interface includes three actuated pins at the back of a smartphone. All three pins are driven by micro servos and can be actuated up to a frequency of 50Hz and a maximum amplitude of 5mm. In a first psychophysical user study, we explored the limits of the system. Thereafter, we demonstrate through a performance study that the proposed interface can enhance touchscreen interaction precision, compared to state-of-the-art methods. In particular the selection of small targets performed remarkably well with force feedback. The study additionally shows that users subjectively felt significantly more accurate with force feedback. Based on the results, we discuss back-to-front feedback design issues and demonstrate potential applications through several prototypical concepts to illustrate where the back-of-device force feedback could be beneficial.
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.
In recent years, a variety of methods have been introduced to exploit the decrease in visual acuity of peripheral vision, known as foveated rendering. As more and more computationally involved shading is requested and display resolutions increase, maintaining low latencies is challenging when rendering in a virtual reality context. Here, foveated rendering is a promising approach for reducing the number of shaded samples. However, besides the reduction of the visual acuity, the eye is an optical system, filtering radiance through lenses. The lenses create depth-of-field (DoF) effects when accommodated to objects at varying distances. The central idea of this article is to exploit these effects as a filtering method to conceal rendering artifacts. To showcase the potential of such filters, we present a foveated rendering system, tightly integrated with a gaze-contingent DoF filter. Besides presenting benchmarks of the DoF and rendering pipeline, we carried out a perceptual study, showing that rendering quality is rated almost on par with full rendering when using DoF in our foveated mode, while shaded samples are reduced by more than 69%.
In this work we present a new approach for counterfeit protection against remarked, overproduced, and out-of-spec integrated circuits (ICs). Our approach uses identification sequences that are regularly published by the original chip manufacturer and hidden in the electromagnetic (EM) leakage of authentic chips. A portion of the chip area is dedicated to a crypto engine running in stream cipher mode that is initialized with a unique key and initialization vector stored in one-time-programmable antifuse memory. IC identification is carried out in the field, by obtaining EM measurements of deployed ICs and by proving the presence of the genuine identification sequences in the measurements. We evaluate our approach using a proof-of-concept implementation on three FPGA boards by capturing EM leakage of the FPGAs under test at their decoupling capacitors. The results show that the user can carry out IC identification on-site, using standard lab equipment in short amount of time.
For many different applications, current information about the bandwidth-related metrics of the utilized connection is very useful as they directly impact the performance of throughput sensitive applications such as streaming servers, IPTV and VoIP applications. In literature, several tools have been proposed to estimate major bandwidth-related metrics such as capacity, available bandwidth and achievable throughput. The vast majority of these tools fall into one of Packet Pair (PP), Variable Packet Size (VPS), Self-Loading of Periodic Streams (SLoPS) or Throughput approaches. In this study, seven popular bandwidth estimation tools including nettimer, pathrate, pathchar, pchar, clink, pathload and iperf belonging to these four well-known estimation techniques are presented and experimentally evaluated in a controlled testbed environment. Differently from the rest of studies in literature, all tools have been uniformly classified and evaluated according to an objective and sophisticated classification and evaluation scheme. The performance comparison of the tools incorporates not only the estimation accuracy but also the probing time and overhead caused.
In Augmented Reality (AR), search performance for outdoor tasks is an important metric for evaluating the success of a large number of AR applications. Users must be able to find content quickly, labels and indicators must not be invasive but still clearly noticeable, and the user interface should maximize search performance in a variety of conditions. To address these issues, we have set up a series of experiments to test the influence of virtual characteristics such as color, size, and leader lines on the performance of search tasks and noticeability in both real and simulated environments. The first experiment showed that limited FOV will severe-ly limit search performance, but that appropriate placement of labels and leaders within the periphery can alleviate this problem without interfering with walking or decreasing user comfort. In the second experiment, we found that different types of motion are more no-ticeable in optical versus video see-through displays, but that blue coloration is most noticeable in both. Results can aid in designing more effective view management techniques, especially for wider field of view display.
Design optimization techniques are often used at the beginning of the design process to explore the space of possible designs. In these domains illumination algorithms, such as MAP-Elites, are promising alternatives to classic optimization algorithms because they produce diverse, high-quality solutions in a single run, instead of only a single near-optimal solution. Unfortunately, these algorithms currently require a large number of function evaluations, limiting their applicability. In this article we introduce a new illumination algorithm, Surrogate-Assisted Illumination (SAIL), that leverages surrogate modeling techniques to create a map of the design space according to user-defined features while minimizing the number of fitness evaluations. On a two-dimensional airfoil optimization problem SAIL produces hundreds of diverse but high-performing designs with several orders of magnitude fewer evaluations than MAP-Elites or CMA-ES. We demonstrate that SAIL is also capable of producing maps of high-performing designs in realistic three-dimensional aerodynamic tasks with an accurate flow simulation. Data-efficient design exploration with SAIL can help designers understand what is possible, beyond what is optimal, by considering more than pure objective-based optimization.
Studenten an Hochschulen und Universitäten haben bei der Gestaltung ihrer Studienverläufe meistens viele Freiheitsgrade. Begrenzt werden diese Freiheiten durch das Curriculum, das bestimmte Rahmenbedingungen für den Studienverlauf einer Fachrichtung festlegt und Empfehlungen bzw. Vorgaben macht, welche Veranstaltungen in welchem Semester besucht werden sollen.
In der Praxis weichen viele Studenten von den Empfehlungen des Curriculums ab. Dies führt zu einer Vielzahl individueller Studienverläufe, von denen jeder einzelne mehr oder weniger erfolgreich sein kann (z. B. in Hinblick auf das Erreichen des angestrebten Abschlusses, auf die erzielte Abschlussnote oder auf die benötigte Studiendauer).
Für eine an erfolgreichen Studienverläufen orientierte Weiterentwicklung von Curricula und zugehörigen Studienberatungen fehlen den Verantwortlichen an Hochschulen und Universitäten nicht selten detaillierte Erkenntnisse über das konkrete Studienverhalten und über erfolgreiche bzw. weniger erfolgreiche Studienverlaufsmuster. Durch Process-Mining-Techniken wie Bubble-Chart-Analysen, Fuzzy Mining und Inductive Visual Mining können die Verantwortlichen Transparenz bei der Auswertung von Studienverläufen gewinnen und darauf aufbauend gezielte Maßnahmen einleiten.
Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch towards increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.
