On the geometry of elementary flux modes

Elementary flux modes (EFMs) play a prominent role in the constraint-based analysis of metabolic networks. They correspond to minimal functional units of the metabolic network at steady-state and as such have been studied for almost 30 years. The set of all EFMs in a metabolic network tends to be very large and may have exponential size in the number of reactions. Hence, there is a need to elucidate the structure of this set. Here we focus on geometric properties of EFMs. We analyze the distribution of EFMs in the face lattice of the steady-state flux cone of the metabolic network and show that EFMs in the relative interior of the cone occur only in very special cases. We introduce the concept of degree of an EFM as a measure how elementary it is and study the decomposition of flux vectors and EFMs depending on their degree. Geometric analysis can help to better understand the structure of the set of EFMs, which is important from both the mathematical and the biological viewpoint

Blocking analysis of spin locks under partitioned fixed-priority scheduling

Partitioned fixed-priority scheduling is widely used in embedded multicore real-time systems. In multicore systems, spin locks are one well-known technique used to synchronize conflicting accesses from different processor cores to shared resources (e.g., data structures). The use of spin locks can cause blocking. Accounting for blocking is a crucial part of static analysis techniques to establish correct temporal behavior. In this thesis, we consider two aspects inherent to the partitioned fixed-priority scheduling of tasks sharing resources protected by spin locks: (1) the assignment of tasks to processor cores to ensure correct timing, and (2) the blocking analysis required to derive bounds on the blocking. Heuristics commonly used for task assignment fail to produce assignments that ensure correct timing when shared resources protected by spin locks are used. We present an optimal approach that is guaranteed to find such an assignment if it exists (under the original MSRP analysis). Further, we present a well-performing and inexpensive heuristic. For most spin lock types, no blocking analysis is available in prior work, which renders them unusable in real-time systems. We present a blocking analysis approach that supports eight different types and is less pessimistic than prior analyses, where available. Further, we show that allowing nested requests for FIFO- and priority-ordered locks renders the blocking analysis problem NP-hard.Partitioned Fixed-Priority Scheduling ist in eingebetteten Multicore-Echtzeitsystemen weit verbreitet. In Multicore-Systemen sind Spinlocks ein bekannter Mechanismus um konkurrierende Zugriffe von unterschiedlichen Prozessorkernen auf geteilte Resourcen (z.B. Datenstrukturen) zu koordinieren. Bei der Nutzung von Spinlocks können Blockierungen auftreten, die in statischen Analysetechniken zum Nachweis des korrekten zeitlichen Verhaltens eines Systems zu berücksichtigen sind. Wir betrachten zwei Aspekte von Partitioned Fixed-Priority Scheduling in Verbindung mit Spinlocks zum Schutz geteilter Resourcen: (1) die Zuweisung von Tasks zu Prozessorkernen unter Einhaltung zeitlicher Vorgaben und (2) die Analyse zur Entwicklung oberer Schranken für die Blockierungsdauer. Übliche Heuristiken finden bei der Nutzung von Spinlocks oft keine Taskzuweisung, bei der die Einhaltung zeitlicher Vorgaben garantiert ist. Wir stellen einen optimalen Ansatz vor, der dies (mit der ursprünglichen MSRP Analyse) garantiert, falls eine solche Zuweisung existiert. Zudem präsentieren wir eine leistungsfähige Heuristik. Die meisten Arten von Spinlocks können mangels Analyse der Blockierungsdauer nicht für Echtzeitsysteme verwendet werden. Wir stellen einen Analyseansatz vor, der acht Spinlockarten unterstützt und weniger pessimistische Schranken liefert als vorherige Analysen, soweit vorhanden. Weiterhin zeigen wir, dass die Analyse bei verschachtelten Zugriffen mit FIFO- und prioritäts-geordneten Locks ein NP-hartes Problem ist

Topology-Preserving Simplification of OpenStreetMap Network Data for Large-scale Simulation in SUMO

Converting OpenStreetMap (OSM) data to a road network suitable for microscopic traffic simulation keeps being a challenging task: both missing information and excessive details, as well as wrong typologies present in the dataset frequently confuses automatic converters. In this paper, we present a method along with a reference implementation, Traffic Simulation Map Maker (TSMM), which aims at substantially increasing the automation level of road network prototyping by simplifying the OSM data while preserving important topology information. The main objective of this work is to enable the study of traffic simulation dynamics at scale using real-world road networks, while minimizing the need for solving the long tail of problems related to the road network generation. Our proposed approach yields what we believe is a good trade-off between precision and automation, making bold yet acceptable decisions that solve most of the errors at the source, i.e., the map. While there is definitely a loss in fidelity with respect to the real world, many properties of the road network are preserved. We argue that TSMM greatly improves the availability of arbitrarily large and usable road networks on top of available OSM maps by reducing the complexity for conversion tools and traffic simulation researchers alike. A proof-of-concept study using OSM data from Binjiang, China, demonstrates that TSMM is able to generate a road network with well-preserved topological information which avoids the many errors and deadlocks that occur when building the network using the original input sources

PR1-Specific T Cells Are Associated with Unmaintained Cytogenetic Remission of Chronic Myelogenous Leukemia After Interferon Withdrawal

Interferon-alpha (IFN) induces complete cytogenetic remission (CCR) in 20-25% CML patients and in a small minority of patients; CCR persists after IFN is stopped. IFN induces CCR in part by increasing cytotoxic T lymphocytes (CTL) specific for PR1, the HLA-A2-restricted 9-mer peptide from proteinase 3 and neutrophil elastase, but it is unknown how CCR persists after IFN is stopped.We reasoned that PR1-CTL persist and mediate CML-specific immunity in patients that maintain CCR after IFN withdrawal. We found that PR1-CTL were increased in peripheral blood of 7/7 HLA-A2+ patients during unmaintained CCR from 3 to 88 months after IFN withdrawal, as compared to no detectable PR1-CTL in 2/2 IFN-treated CML patients not in CCR. Unprimed PR1-CTL secreted IFNgamma and were predominantly CD45RA+/-CD28+CCR7+CD57-, consistent with functional naïve and central memory (CM) T cells. Similarly, following stimulation, proliferation occurred predominantly in CM PR1-CTL, consistent with long-term immunity sustained by self-renewing CM T cells. PR1-CTL were functionally anergic in one patient 6 months prior to cytogenetic relapse at 26 months after IFN withdrawal, and in three relapsed patients PR1-CTL were undetectable but re-emerged 3-6 months after starting imatinib.These data support the hypothesis that IFN elicits CML-specific CM CTL that may contribute to continuous CCR after IFN withdrawal and suggest a role for T cell immune therapy with or without tyrosine kinase inhibitors as a strategy to prolong CR in CML

Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Morphologische und biologische Bildgebung zur Therapiekontrolle von Malignomen des Gastrointestinaltraktes

Mit der [18F]-FDG-PET konnte beim Ösophaguskarzinom bereits 14 Tage nach Beginn einer (Radio-)Chemotherapie zwischen histopathologischen Respondern und Nonrespondern differenziert werden. Zudem war die Veränderung der Stoffwechselaktivität unter Therapie von prognostischer Bedeutung. Patienten, welche ein metabolisches Ansprechen auf die Therapie gezeigt hatten, wiesen ein signifikant besseres Überleben auf als Patienten ohne Ansprechen auf die Therapie in der [18F]-FDG-PET. Änderungen des Glukosemetabolismus in der Untersuchung nach Abschluss der neoadjuvanten Therapie (vor OP) zeigten keine höhere diagnostische Genauigkeit als die Änderungen nach 14 Tagen. Mit der [18F]-FDG-PET können bereits zu einem frühen Zeitpunkt während einer neoadjuvanten Therapie Patienten erfasst werden, deren Tumoren nicht auf die Therapie ansprechen. Bei diesen Patienten besteht dann die Möglichkeit, das therapeutische Procedere zu ändern. Durch einen individualisierten therapeutischen Ansatz können Nebenwirkungen und Kosten der Therapie bei metabolischen Non-Respondern reduziert werden