Investigation of the generalization capability of a generative adversarial network for large eddy simulation of turbulent premixed reacting flows

In the past decades, Deep Learning (DL) frameworks have demonstrated excellent performance in modeling nonlinear interactions and are a promising technique to move beyond physics-based models. In this context, super-resolution techniques may present an accurate approach as subfilter-scale (SFS) closure model for Large Eddy Simulations (LES) in premixed combustion. However, DL models need to perform accurately in a variety of physical regimes and generalize well beyond their training conditions. In this work, a super-resolution Generative Adversarial Network (GAN) is proposed as closure model for the unresolved subfilter-stress and scalar-flux tensors of the filtered reactive Navier-Stokes equations solved in LES. The model trained on a premixed methane/air jet flame is evaluated a-priori on similar configurations at different Reynolds and Karlovitz numbers. The GAN generalizes well at both lower and higher Reynolds numbers and outperforms existing algebraic models when the ratio between the filter size and the Kolmogorov scale is preserved. Moreover, extrapolation at a higher Karlovitz number is investigated indicating that the ratio between the filter size and the thermal flame thickness may not need to be conserved in order to achieve high correlation in terms of SFS field. Generalization studies obtained on substantially different flame conditions indicate that successful predictive abilities are demonstrated if the generalization criterion is matched. Finally, the reconstruction of a scalar quantity, different from that used during the training, is evaluated, revealing that the model is able to reconstruct scalar fields with large gradients that have not been explicitly used in the training. The a-priori investigations carried out assess whether out-of-sample predictions are even feasible in the first place, providing insights into the quantities that need to be conserved for the model to perform well between different regimes, and represent a crucial step toward future embedding into LES numerical solvers

Space-time adaptive reduction of unsteady flamalets

The Wavelet Adaptive Multiresolution Representation (WAMR) code and the G-Scheme framework are used for the numerical time integration of the flamelet model. The steep gradients are efficiently captured by the WAMR algorithm with an a-priori defined accuracy and an associated large reduction of the number of degrees of freedom (DOFs). A further opportunity to reduce the complexity of the problem is represented by the G-Scheme, to achieve multi-scale adaptive model reduction along-with the time integration of the differential equations

Numerical generation of multidimensional flamelet databases using an adaptive wavelet method

The Wavelet Adaptive Multiresolution Representation (WAMR) code is used for the numerical time integration of the one-dimensional laminar diffusion flames equations in trans-critical and supercritical conditions, where the thermodynamic and transport properties exhibit large changes. These steep gradients are efficiently captured by the WAMR algorithm with an a-priori defined accuracy and an associated large reduction of the number of degrees of freedom, allowing a highly efficient flamelet database generation critical conditions

Adaptive remodeling of the bacterial proteome by specific ribosomal modification regulates Pseudomonas infection and niche colonisation

Post-transcriptional control of protein abundance is a highly important, underexplored regulatory process by which organisms respond to their environments. Here we describe an important and previously unidentified regulatory pathway involving the ribosomal modification protein RimK, its regulator proteins RimA and RimB, and the widespread bacterial second messenger cyclic-di-GMP (cdG). Disruption of rimK affects motility and surface attachment in pathogenic and commensal Pseudomonas species, with rimK deletion significantly compromising rhizosphere colonisation by the commensal soil bacterium P. fluorescens, and plant infection by the pathogens P. syringae and P. aeruginosa. RimK functions as an ATP-dependent glutamyl ligase, adding glutamate residues to the C-terminus of ribosomal protein RpsF and inducing specific effects on both ribosome protein complement and function. Deletion of rimK in P. fluorescens leads to markedly reduced levels of multiple ribosomal proteins, and also of the key translational regulator Hfq. In turn, reduced Hfq levels induce specific downstream proteomic changes, with significant increases in multiple ABC transporters, stress response proteins and non-ribosomal peptide synthetases seen for both ΔrimK and Δhfq mutants. The activity of RimK is itself controlled by interactions with RimA, RimB and cdG. We propose that control of RimK activity represents a novel regulatory mechanism that dynamically influences interactions between bacteria and their hosts; translating environmental pressures into dynamic ribosomal changes, and consequently to an adaptive remodeling of the bacterial proteome

One ligand, two regulators and three binding sites: How KDPG controls primary carbon metabolism in Pseudomonas

Effective regulation of primary carbon metabolism is critically important for bacteria to successfully adapt to different environments. We have identified an uncharacterised transcriptional regulator; RccR, that controls this process in response to carbon source availability. Disruption of rccR in the plant-associated microbe Pseudomonas fluorescens inhibits growth in defined media, and compromises its ability to colonise the wheat rhizosphere. Structurally, RccR is almost identical to the Entner-Doudoroff (ED) pathway regulator HexR, and both proteins are controlled by the same ED-intermediate; 2-keto-3-deoxy-6-phosphogluconate (KDPG). Despite these similarities, HexR and RccR control entirely different aspects of primary metabolism, with RccR regulating pyruvate metabolism (aceEF), the glyoxylate shunt (aceA, glcB, pntAA) and gluconeogenesis (pckA, gap). RccR displays complex and unusual regulatory behaviour; switching repression between the pyruvate metabolism and glyoxylate shunt/gluconeogenesis loci depending on the available carbon source. This regulatory complexity is enabled by two distinct pseudo-palindromic binding sites, differing only in the length of their linker regions, with KDPG binding increasing affinity for the 28 bp aceA binding site but decreasing affinity for the 15 bp aceE site. Thus, RccR is able to simultaneously suppress and activate gene expression in response to carbon source availability. Together, the RccR and HexR regulators enable the rapid coordination of multiple aspects of primary carbon metabolism, in response to levels of a single key intermediate

Asymmetry of Chromosome Replichores Renders the DNA Translocase Activity of FtsK Essential for Cell Division and Cell Shape Maintenance in Escherichia coli

Bacterial chromosomes are organised as two replichores of opposite polarity that coincide with the replication arms from the ori to the ter region. Here, we investigated the effects of asymmetry in replichore organisation in Escherichia coli. We show that large chromosome inversions from the terminal junction of the replichores disturb the ongoing post-replicative events, resulting in inhibition of both cell division and cell elongation. This is accompanied by alterations of the segregation pattern of loci located at the inversion endpoints, particularly of the new replichore junction. None of these defects is suppressed by restoration of termination of replication opposite oriC, indicating that they are more likely due to the asymmetry of replichore polarity than to asymmetric replication. Strikingly, DNA translocation by FtsK, which processes the terminal junction of the replichores during cell division, becomes essential in inversion-carrying strains. Inactivation of the FtsK translocation activity leads to aberrant cell morphology, strongly suggesting that it controls membrane synthesis at the division septum. Our results reveal that FtsK mediates a reciprocal control between processing of the replichore polarity junction and cell division

A Defined Terminal Region of the E. coli Chromosome Shows Late Segregation and High FtsK Activity

Background: The FtsK DNA-translocase controls the last steps of chromosome segregation in E. coli. It translocates sister chromosomes using the KOPS DNA motifs to orient its activity, and controls the resolution of dimeric forms of sister chromosomes by XerCD-mediated recombination at the dif site and their decatenation by TopoIV. Methodology: We have used XerCD/dif recombination as a genetic trap to probe the interaction of FtsK with loci located in different regions of the chromosome. This assay revealed that the activity of FtsK is restricted to a,400 kb terminal region of the chromosome around the natural position of the dif site. Preferential interaction with this region required the tethering of FtsK to the division septum via its N-terminal domain as well as its translocation activity. However, the KOPSrecognition activity of FtsK was not required. Displacement of replication termination outside the FtsK high activity region had no effect on FtsK activity and deletion of a part of this region was not compensated by its extension to neighbouring regions. By observing the fate of fluorescent-tagged loci of the ter region, we found that segregation of the FtsK high activity region is delayed compared to that of its adjacent regions. Significance: Our results show that a restricted terminal region of the chromosome is specifically dedicated to the last step

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

G-scheme-based simplification and analysis methodology for hydrocarbon ignition

For the simulation of reactive flows, the use of a simplified model is a common simplification to reduce the computational cost, although the reduced model may introduce significant errors in the simulation. Using the G-Scheme, the local structure of the local tangent space is characterized through the subspaces associated with the slow, active, and fast reactive scales. This specific feature can be of great significance in the analysis of the dynamics with the aim of achieving a low-dimensional description and allowing a time-scale-aware sensitivity analysis of the problem. Such analysis can be exploited to simplify/reduce/understand the reaction dynamics of interest. We have developed specific procedures to generate simplified mechanisms with an a priori known error for chemical kinetics processes, to analyze them in order to understand the role of the most important reactions, and to identify the most important reactions paths of the processes. The procedure is based on a G-Scheme Participation Index that makes use of a G-Scheme generated database. The effectiveness of the procedures to produce simplified mechanisms is demonstrated by applying them to the auto-ignition problems for homogeneous hydrogen/air and hydrocarbon/air mixtures