Goal-based h-adaptivity of the 1-D diamond difference discrete ordinate method.

The quantity of interest (QoI) associated with a solution of a partial differential equation (PDE) is not, in general, the solution itself, but a functional of the solution. Dual weighted residual (DWR) error estimators are one way of providing an estimate of the error in the QoI resulting from the discretisation of the PDE. This paper aims to provide an estimate of the error in the QoI due to the spatial discretisation, where the discretisation scheme being used is the diamond difference (DD) method in space and discrete ordinate (SNSN) method in angle. The QoI are reaction rates in detectors and the value of the eigenvalue (Keff)(Keff) for 1-D fixed source and eigenvalue (KeffKeff criticality) neutron transport problems respectively. Local values of the DWR over individual cells are used as error indicators for goal-based mesh refinement, which aims to give an optimal mesh for a given QoI

Funktionelle Charakterisierung von BCKDK im Hinblick auf seine Funktion im Pankreaskarzinom

Das duktale Adenokarzinom des Pankreas (PDAC) zeichnet sich durch eine hohe Mortalität aus: die Fünf-Jahres-Überlebensrate liegt bei nur 8%. Ursächlich hierfür ist zum einen die späte Diagnose aufgrund fehlender Frühsymptome, sodass der Tumor bei Erstdiagnose oftmals schon metastasiert und eine operative Entfernung nicht möglich ist. Zum anderen zeigen sich Pankreaskarzinome äußerst resistent gegen eine chemotherapeutische Behandlung. Nach dem derzeitigen Stand der Forschung entsteht das PDAC aus Vorläuferläsionen durch eine Akkumulation charakteristischer Genmutationen. Die genauen molekularpathologischen Mechanismen sind jedoch noch nicht verstanden. Dementsprechend wurde in den letzten Jahren intensiv nach Proteinen gesucht, die eine wichtige Rolle in der Pathogenese des Pankreaskarzinoms spielen und somit Angriffspunkte für neue Therapien darstellen. Eines dieser Proteine ist die Branched-Chain α-Ketoacid Dehydrogenase-Kinase (BCKDK). In einem Kinom-Screening zeigte sich nach Repression von BCKDK in Pankreaskarzinomzellen eine erhöhte Apoptoserate. Zudem konnte eine vermehrte Expression des BCKDK-Gens in primären humanen Pankreaskarzinomgeweben nachgewiesen werden. Die BCKDK reguliert die Branched-Chain α-Ketoacid Dehydrogenase und ist somit ein Schlüsselenzym im Abbau verzweigtkettiger Aminosäuren. Eine weitere Funktion der Kinase ist bisher nicht beschrieben. Im Rahmen dieser Arbeit wurde die möglicherweise pro-onkogene Wirkung der BCKDK im PDAC näher untersucht. Hierzu wurde die Expression der Kinase mithilfe dreier siRNAs (siRNA 1, 3 und 5) in zwei Pankreaskarzinomzelllinien supprimiert und jeweils die Auswirkungen auf Apoptose, Proliferation und Expression von Zielproteinen untersucht. Die Versuchsreihen lieferten unterschiedliche Ergebnisse. Die Verwendung der siRNA 1 führte in beiden Zelllinien zu einer Abnahme der Zellviabilität. Als Ursache hierfür konnte eine Apoptoseinduktion nachgewiesen werden. Zusätzlich sank die Proliferationsrate und es kam zu einem Zellzyklusarrest der Zellen in der G2-Phase. Die Repression des Zielgens mit der siRNA 3 führte ebenfalls zu einer Abnahme der Zellviabilität durch Apoptoseinduktion, es kam jedoch nur in einer der verwendeten Zelllinien zu einer signifikanten Abnahme der Proliferationsrate. Die Zellen, die mit der siRNA 5 transfiziert worden waren, blieben hingegen sowohl in der Zellviabilität als auch in der Proliferation im Vergleich zur Kontrolle unverändert. Diese sehr unterschiedlichen Versuchsergebnisse sind möglicherweise durch Off-Target-Effekte der siRNAs zu erklären. Die zugrundeliegenden molekularpathologischen Mechanismen konnten in der vorliegenden Arbeit jedoch nicht vollständig aufgedeckt werden und bedürfen weiterer Analysen

Microbiome Diversity and Community-Level Change Points within Manure-based small Biogas Plants

Theuerl S, Klang J, Hülsemann B, Mächtig T, Hassa J. Microbiome Diversity and Community-Level Change Points within Manure-based small Biogas Plants. Microorganisms. 2020;8(8).Efforts to integrate biogas plants into bioeconomy concepts will lead to an expansion of manure-based (small) biogas plants, while their operation is challenging due to critical characteristics of some types of livestock manure. For a better process understanding, in this study, three manure-based small biogas plants were investigated with emphasis on microbiome diversity. Due to varying digester types, feedstocks, and process conditions, 16S rRNA gene amplicon sequencing showed differences in the taxonomic composition. Dynamic variations of each investigated biogas plant microbiome over time were analyzed by terminal restriction fragment length polymorphism (TRFLP), whereby nonmetric multidimensional scaling (NMDS) revealed two well-running systems, one of them with a high share of chicken manure, and one unstable system. By using Threshold Indicator Taxa Analysis (TITAN), community-level change points at ammonium and ammonia concentrations of 2.25 g L-1 and 193 mg L-1 or volatile fatty acid concentrations of 0.75 g L-1were reliably identified which are lower than the commonly reported thresholds for critical process stages based on chemical parameters. Although a change in the microbiome structure does not necessarily indicate an upcoming critical process stage, the recorded community-level change points might be a first indication to carefully observe the process

Effect of age, diet and tissue type on PCr response to creatine supplementation

Creatine/phosphorylcreatine (PCr) responses to creatine supplementation may be modulated by age, diet, and tissue, but studies assessing this possibility are lacking. Therefore we aimed to determine whether PCr responses vary as a function of age, diet, and tissue. Fifteen children, 17 omnivorous and 14 vegetarian adults, and 18 elderly individuals (“elderly”) participated in this study. Participants were given placebo and subsequently creatine (0.3 g·kg−1·day−1) for 7 days in a single-blind fashion. PCr was measured through phosphorus magnetic resonance spectroscopy (31P-MRS) in muscle and brain. Creatine supplementation increased muscle PCr in children (P < 0.0003) and elderly (P < 0.001), whereas the increase in omnivores did not reach statistically significant difference (P = 0.3348). Elderly had greater PCr increases than children and omnivores (P < 0.0001 for both), whereas children experienced greater PCr increases than omnivores (P = 0.0022). In relation to diet, vegetarians (P < 0.0001), but not omnivores, had significant increases in muscle PCr content. Brain PCr content was not affected by creatine supplementation in any group, and delta changes in brain PCr (−0.7 to +3.9%) were inferior to those in muscle PCr content (+10.3 to +27.6%; P < 0.0001 for all comparisons). PCr responses to a standardized creatine protocol (0.3 g·kg−1·day−1 for 7 days) may be affected by age, diet, and tissue. Whereas creatine supplementation was able to increase muscle PCr in all groups, although to different extents, brain PCr was shown to be unresponsive overall. These findings demonstrate the need to tailor creatine protocols to optimize creatine/PCr accumulation both in muscle and in brain, enabling a better appreciation of the pleiotropic properties of creatine

array CGH screening of 134 unrelated families

Background A growing number of non-coding regulatory mutations are being identified in congenital disease. Very recently also some exons of protein coding genes have been identified to act as tissue specific enhancer elements and were therefore termed exonic enhancers or “eExons”. Methods We screened a cohort of 134 unrelated families with split-hand/split-foot malformation (SHFM) with high resolution array CGH for CNVs with regulatory potential. Results In three families with an autosomal dominant non-syndromic SHFM phenotype we detected microdeletions encompassing the exonic enhancer (eExons) 15 and 17 of DYNC1I1. In a fourth family, who had hearing loss in addition to SHFM, we found a larger deletion of 510 kb including the eExons of DYNC1I1 and, in addition, the human brain enhancer hs1642. Exons 15 and 17 of DYNC1I1 are known to act as tissue specific limb enhancers of DLX5/6, two genes that have been shown to be associated with SHFM in mice. In our cohort of 134 unrelated families with SHFM, deletions of the eExons of DYNC1I1 account for approximately 3% of the cases, while 17p13.3 duplications were identified in 13% of the families, 10q24 duplications in 12%, and TP63 mutations were detected in 4%. Conclusions We reduce the minimal critical region for SHFM1 to 78 kb. Hearing loss, however, appears to be associated with deletions of a more telomeric region encompassing the brain enhancer element hs1642. Thus, SHFM1 as well as hearing loss at the same locus are caused by deletion of regulatory elements. Deletions of the exons with regulatory potential of DYNC1I1 are an example of the emerging role of exonic enhancer elements and their implications in congenital malformation syndromes

A quasi‐cache‐aware model for optimal domain partitioning in parallel geometric multigrid

Stencil computations form the heart of numerical simulations to solve Partial Differential Equations using Finite Difference, Finite Element, and Finite Volume methods. Geometric Multigrid is an optimal O(N), hierarchical tool employing stencil computations in its chief constituents, namely, smoothing, restriction, and interpolation. When Multigrid is parallelized over distributed‐shared memory architectures, traditionally, the domain partitioning creates cubic partitions of the mesh to minimize overall communication. Thus, the orthodox approach considers only load‐balancing and communication minimization for completely determining the domain partitioning. In this article, we show that these two factors are not sufficient to obtain optimal partitions for Parallel Geometric Multigrid. To this effect, we develop and validate a high level analytical model to show that “close to 2‐D” partitions for Geometric Multigrid can give higher performance than the partitions returned by the MPI_Dims_create() function which minimizes the communication volume by default. We quantify sub‐domain level cache‐misses in Parallel Geometric Multigrid and obtain families of optimal domain partitions. We conclude that the sub‐domain level cache‐misses for the application‐specific stencil computational kernel and communicated planes should be taken into account in addition to communication minimization/load‐balance to obtain optimal partitions for Parallel Geometric Multigrid

Integrating clinical decision support systems for pharmacogenomic testing into clinical routine - a scoping review of designs of user-system interactions in recent system development

Background: Pharmacogenomic clinical decision support systems (CDSS) have the potential to help overcome some of the barriers for translating pharmacogenomic knowledge into clinical routine. Before developing a prototype it is crucial for developers to know which pharmacogenomic CDSS features and user-system interactions have yet been developed, implemented and tested in previous pharmacogenomic CDSS efforts and if they have been successfully applied. We address this issue by providing an overview of the designs of user-system interactions of recently developed pharmacogenomic CDSS. Methods: We searched PubMed for pharmacogenomic CDSS published between January 1, 2012 and November 15, 2016. Thirty-two out of 118 identified articles were summarized and included in the final analysis. We then compared the designs of user-system interactions of the 20 pharmacogenomic CDSS we had identified. Results: Alerts are the most widespread tools for physician-system interactions, but need to be implemented carefully to prevent alert fatigue and avoid liabilities. Pharmacogenomic test results and override reasons stored in the local EHR might help communicate pharmacogenomic information to other internal care providers. Integrating patients into user-system interactions through patient letters and online portals might be crucial for transferring pharmacogenomic data to external health care providers. Inbox messages inform physicians about new pharmacogenomic test results and enable them to request pharmacogenomic consultations. Search engines enable physicians to compare medical treatment options based on a patient’s genotype. Conclusions: Within the last 5 years, several pharmacogenomic CDSS have been developed. However, most of the included articles are solely describing prototypes of pharmacogenomic CDSS rather than evaluating them. To support the development of prototypes further evaluation efforts will be necessary. In the future, pharmacogenomic CDSS will likely include prediction models to identify patients who are suitable for preemptive genotyping

Optogenetic regulation of endogenous proteins

Techniques of protein regulation, such as conditional gene expression, RNA interference, knock-in and knock-out, lack sufficient spatiotemporal accuracy, while optogenetic tools suffer from non-physiological response due to overexpression artifacts. Here we present a near-infrared light-activatable optogenetic system, which combines the specificity and orthogonality of intrabodies with the spatiotemporal precision of optogenetics. We engineer optically-controlled intrabodies to regulate genomically expressed protein targets and validate the possibility to further multiplex protein regulation via dual-wavelength optogenetic control. We apply this system to regulate cytoskeletal and enzymatic functions of two non-tagged endogenous proteins, actin and RAS GTPase, involved in complex functional networks sensitive to perturbations. The optogenetically-enhanced intrabodies allow fast and reversible regulation of both proteins, as well as simultaneous monitoring of RAS signaling with visible-light biosensors, enabling all-optical approach. Growing number of intrabodies should make their incorporation into optogenetic tools the versatile technology to regulate endogenous targets. Optogenetic approaches to control protein-protein interactions usually require overexpression of the target proteins. Here the authors integrate intrabodies into near-infrared- and blue-light activatable optogenetic tools to control endogenous proteins in mammalian cells.Peer reviewe

Goal-based error estimation for the multi-dimensional diamond difference and box discrete ordinate (SN) methods

Goal-based error estimation due to spatial discretization and adaptive mesh refinement (AMR) has previously been investigated for the one dimensional, diamond difference, discrete ordinate (1-D DD-SN) method for discretizing the Neutron Transport Equation (NTE). This paper investigates the challenges of extending goal-based error estimation to multi-dimensions with supporting evidence provided on 2-D fixed (extraneous) source and Keff eigenvalue (criticality) verification test cases. It was found that extending Hennart’s weighted residual view of the lowest order 1-D DD equations to multi-dimensions gave what has previously been called the box method. This paper shows how the box method can be extended to higher orders. The paper also shows an equivalence between the higher order box methods and the higher order DD methods derived by Hébert et al. Though, less information is retained in the final solution in the latter case. These extensions allow for the definition of dual weighted residual (DWR) error estimators in multi-dimensions for the DD and box methods. However, they are not applied to drive AMR in the multi-dimensional case due to the various challenges explained in this paper