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Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with <nCR after first ASCT were assigned tandem ASCT in both trials. In patients with <nCR and tandem ASCT (LEN: n = 54 vs. BTZ: n = 84), LEN MT significantly improved PFS (HR = 0.61, p = 0.04) but not OS (HR = 0.46, p = 0.09). In conclusion, the significant PFS benefit after eliminating the impact of different tandem ASCT rates supports the current standard of LEN MT after ASCT.
Background Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Methodology/Principal Findings Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Conclusion Thus, aging Pink1 -/- mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.
We present data on charged kaons (K±) and ϕ mesons in Au(1.23A GeV)+Au collisions. It is the first simultaneous measurement of K− and ϕ mesons in central heavy-ion collisions below a kinetic beam energy of 10A GeV. The ϕ/K− multiplicity ratio is found to be surprisingly high with a value of 0.52±0.16 and shows no dependence on the centrality of the collision. Consequently, the different slopes of the K+ and K− transverse-mass spectra can be explained solely by feed-down, which substantially softens the spectra of K− mesons. Hence, in contrast to the commonly adapted argumentation in literature, the different slopes do not necessarily imply diverging freeze-out temperatures of K+ and K− mesons caused by different couplings to baryons.
Partial wave analysis of the reaction p(3.5 GeV) + p → pK +Λ to search for the "ppK−" bound state
(2015)
Employing the Bonn–Gatchina partial wave analysis framework (PWA), we have analyzed HADES data of the reaction p(3.5 GeV) + p → pK +Λ. This reaction might contain information about the kaonic cluster “ppK −” (with quantum numbers J P = 0− and total isospin I = 1/2) via its decay into pΛ. Due to interference effects in our coherent description of the data, a hypothetical KNN (or, specifically “ppK −”) cluster signal need not necessarily show up as a pronounced feature (e.g. a peak) in an invariant mass spectrum like pΛ. Our PWA analysis includes a variety of resonant and non-resonant intermediate states and delivers a good description of our data (various angular distributions and two-hadron invariant mass spectra) without a contribution of a KNN cluster. At a confidence level of CLs = 95% such a cluster cannot contribute more than 2–12% to the total cross section with a pK +Λ final state, which translates into a production cross-section between 0.7 μb and 4.2 μb, respectively. The range of the upper limit depends on the assumed cluster mass, width and production process.
In this letter we report the first multi-differential measurement of correlated pion-proton pairs from 2 billion Au+Au collisions at sNN=2.42 GeV collected with HADES. In this energy regime the population of Δ(1232) resonances plays an important role in the way energy is distributed between intrinsic excitation energy and kinetic energy of the hadrons in the fireball. The triple differential d3N/dMπ±pdpTdy distributions of correlated π±p pairs have been determined by subtracting the πp combinatorial background using an iterative method. The invariant-mass distributions in the Δ(1232) mass region show strong deviations from a Breit-Wigner function with vacuum width and mass. The yield of correlated pion-proton pairs exhibits a complex isospin, rapidity and transverse-momentum dependence. In the invariant mass range 1.1<Minv(GeV/c2)<1.4, the yield is found to be similar for π+p and π−p pairs, and to follow a power law 〈Apart〉α, where 〈Apart〉 is the mean number of participating nucleons. The exponent α depends strongly on the pair transverse momentum (pT) while its pT-integrated and charge-averaged value is α=1.5±0.08st±0.2sy.
We present the results of two-pion production in tagged quasi-free np collisions at a deutron incident beam energy of 1.25 GeV/c measured with the High-Acceptance Di-Electron Spectrometer (HADES) installed at GSI. The specific acceptance of HADES allowed for the first time to obtain high-precision data on π+π− and π−π0 production in np collisions in a region corresponding to large transverse momenta of the secondary particles. The obtained differential cross section data provide strong constraints on the production mechanisms and on the various baryon resonance contributions (∆∆, N(1440), N(1520), ∆(1600)). The invariant mass and angular distributions from the np → npπ+π −and np → ppπ−π0 reactions are compared with different theoretical model predictions.
We present first data on sub-threshold production of Ks0 mesons and Λ hyperons in Au+Au collisions at sNN=2.4 GeV. We observe an universal 〈Apart〉 scaling of hadrons containing strangeness, independent of their corresponding production thresholds. Comparing the yields, their 〈Apart〉 scaling, and the shapes of the rapidity and the pt spectra to state-of-the-art transport model (UrQMD, HSD, IQMD) predictions, we find that none of them can simultaneously describe these observables with reasonable χ2 values.
We investigate identical pion HBT intensity interferometry in central Au+Au collisions at 1.23A GeV. High-statistics π−π− and π+π+ data are measured with HADES at SIS18/GSI. The radius parameters, derived from the correlation function depending on relative momenta in the longitudinally comoving system and parametrized as three-dimensional Gaussian distribution, are studied as function of transverse momentum. A substantial charge-sign difference of the source radii is found, particularly pronounced at low transverse momentum. The extracted source parameters agree well with a smooth extrapolation of the center-of-mass energy dependence established at higher energies, extending the corresponding excitation functions down towards a very low energy.
We present new concepts to integrate logic synthesis and physical design. Our methodology uses general Boolean transformations as known from technology-independent synthesis, and a recursive bi-partitioning placement algorithm. In each partitioning step, the precision of the layout data increases. This allows effective guidance of the logic synthesis operations for cycle time optimization. An additional advantage of our approach is that no complicated layout corrections are needed when the netlist is changed.
Retiming is a widely investigated technique for performance optimization. It performs powerful modifications on a circuit netlist. However, often it is not clear, whether the predicted performance improvement will still be valid after placement has been performed. This paper presents a new retiming algorithm using a highly accurate timing model taking into account the effect of retiming on capacitive loads of single wires as well as fanout systems. We propose the integration of retiming into a timing-driven standard cell placement environment based on simulated annealing. Retiming is used as an optimization technique throughout the whole placement process. The experimental results show the benefit of the proposed approach. In comparison with the conventional design flow based on standard FEAS our approach achieved an improvement in cycle time of up to 34% and 17% on the average.
A new approach to optimize multilevel logic circuits is introduced. Given a multilevel circuit, the synthesis method optimizes its area while simultaneously enhancing its random pattern testability. The method is based on structural transformations at the gate level. New transformations involving EX-OR gates as well as Reed–Muller expansions have been introduced in the synthesis of multilevel circuits. This method is augmented with transformations that specifically enhance random-pattern testability while reducing the area. Testability enhancement is an integral part of our synthesis methodology. Experimental results show that the proposed methodology not only can achieve lower area than other similar tools, but that it achieves better testability compared to available testability enhancement tools such as tstfx. Specifically for ISCAS-85 benchmark circuits, it was observed that EX-OR gate-based transformations successfully contributed toward generating smaller circuits compared to other state-of-the-art logic optimization tools.
We present the FPGA implementation of an algorithm [4] that computes implications between signal values in a boolean network. The research was performed as a masterrsquos thesis [5] at the University of Frankfurt. The recursive algorithm is rather complex for a hardware realization and therefore the FPGA implementation is an interesting example for the potential of reconfigurable computing beyond systolic algorithms. A circuit generator was written that transforms a boolean network into a network of small processing elements and a global control logic which together implement the algorithm. The resulting circuit performs the computation two orders of magnitudes faster than a software implementation run by a conventional workstation.
We present a theoretical analysis of structural FSM traversal, which is the basis for the sequential equivalence checking algorithm Record & Play presented earlier. We compare the convergence behaviour of exact and approximative structural FSM traversal with that of standard BDD-based FSM traversal. We show that for most circuits encountered in practice exact structural FSM traversal reaches the fixed point as fast as symbolic FSM traversal, while approximation can significantly reduce in the number of iterations needed. Our experiments confirm these results.
Channel routing is an NP-complete problem. Therefore, it is likely that there is no efficient algorithm solving this problem exactly.In this paper, we show that channel routing is a fixed-parameter tractable problem and that we can find a solution in linear time for a fixed channel width.We implemented our approach for the restricted layer model. The algorithm finds an optimal route for channels with up to 13 tracks within minutes or up to 11 tracks within seconds.Such narrow channels occur for example as a leaf problem of hierarchical routers or within standard cell generators.
Retiming is a widely investigated technique for performance optimization. In general, it performs extensive modifications on a circuit netlist, leaving it unclear, whether the achieved performance improvement will still be valid after placement has been performed. This paper presents an approach for integrating retiming into a timing-driven placement environment. The experimental results show the benefit of the proposed approach on circuit performance in comparison with design flows using retiming only as a pre- or postplacement optimization method.
One of the most severe short-comings of currently available equivalence checkers is their inability to verify integer multipliers. In this paper, we present a bit level reverse-engineering technique that can be integrated into standard equivalence checking flows. We propose a Boolean mapping algorithm that extracts a network of half adders from the gate netlist of an addition circuit. Once the arithmetic bit level representation of the circuit is obtained, equivalence checking can be performed using simple arithmetic operations. Experimental results show the promise of our approach.
This paper presents a new timing driven approach for cell replication tailored to the practical needs of standard cell layout design. Cell replication methods have been studied extensively in the context of generic partitioning problems. However, until now it has remained unclear what practical benefit can be obtained from this concept in a realistic environment for timing driven layout synthesis. Therefore, this paper presents a timing driven cell replication procedure, demonstrates its incorporation into a standard cell placement and routing tool and examines its benefit on the final circuit performance in comparison with conventional gate or transistor sizing techniques. Furthermore, we demonstrate that cell replication can deteriorate the stuck-at fault testability of circuits and show that stuck-at redundancy elimination must be integrated into the placement procedure. Experimental results demonstrate the usefulness of the proposed methodology and suggest that cell replication should be an integral part of the physical design flow complementing traditional gate sizing techniques.
n this paper we report on the investigation of baryonic resonance production in proton-proton collisions at the kinetic energies of 1.25 GeV and 3.5 GeV, based on data measured with HADES. Exclusive channels npπ+ and ppπ0 as well as ppe+e− were studied simultaneously in the framework of a one-boson exchange model. The resonance cross sections were determined from the one-pion channels for Δ(1232) and N(1440) (1.25 GeV) as well as further Δ and N* resonances up to 2 GeV/c2 for the 3.5 GeV data. The data at 1.25 GeV energy were also analysed within the framework of the partial wave analysis together with the set of several other measurements at lower energies. The obtained solutions provided the evolution of resonance production with the beam energy, showing a sizeable non-resonant contribution but with still dominating contribution of Δ(1232)P33. In the case of 3.5 GeV data, the study of the ppe+e− channel gave the insight on the Dalitz decays of the baryon resonances and, in particular, on the electromagnetic transition form-factors in the time-like region. We show that the assumption of a constant electromagnetic transition form-factors leads to underestimation of the yield in the dielectron invariant mass spectrum below the vector mesons pole. On the other hand, a comparison with various transport models shows the important role of intermediate ρ production, though with a large model dependency. The exclusive channels analysis done by the HADES collaboration provides new stringent restrictions on the parameterizations used in the models.
his contribution aims to give a basic overview of the latest results regarding the production of resonances in different collision systems. The results were extracted from experimental data collected with HADES that is a multipurpose detector located at the GSI Helmholtzzentrum, Darmstadt. The main points discussed here are: the properties of the strange resonances Λ(1405) and Σ(1385), the role of Δ’s as a source of pions in the final state, the production dynamics reflected in form of differential cross sections, and the role of the ϕ meson as a source for K− particles.
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.