Minimizing the makespan in a flexible flowshop with sequence dependent setup times, uniform machines, and limited buffers

This research addresses the problem of minimizing the makespan in a flexible flowshop with sequence dependent setup times, uniform machines, and limited buffers. A mathematical model was developed to solve this problem. The problem is NP-Hard in the strong sense and only very small problems could be solved optimally. For exact methods, the computation times are long and not practical even when the problems are relatively small. Two construction heuristics were developed that could find solutions quickly. Also a simulated annealing heuristic was constructed that improved the solutions obtained from the construction heuristics. The combined heuristics could compute a good solution in a short amount of time. The heuristics were tested in three different environments: 3 stages, 4 stages, and 5 stages. To assess the quality of the solutions, a lower bound and two simple heuristics were generated for comparison purposes. The proposed heuristics showed steady improvement over the simple heuristics. When compared to the lower bounds, the heuristics performed well for the smaller environment, but the performance quality decreased as the number of stages increased. The combination of these heuristics defiantly shows promise for solving the problem

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

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

Objective: Adult polyglucosan body disease (APBD) is an adult-onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. Methods: We characterized the effects of knocking out two pro-glycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. Results: APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro- and micro-gliosis in the brains of GYS1- and PPP1R3C-deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. Interpretation: GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients

Disentangling Fine- and Broad- scale Effects of Habitat on Predator–prey Interactions Author Links Open Overlay Panel

Predator–prey interactions can be influenced by habitat at different spatial scales. In seagrass systems, blade density can provide refugia for prey at fine scales, which are further embedded within broad-scale features such as variation in biotic (e.g., predator assemblages) and abiotic attributes (e.g., turbidity, salinity). Fine-scale effects of seagrass habitats on predator–prey interactions involving invertebrates have been well studied while less is known about their effects on fish as prey. A field experiment was conducted in Tampa Bay, Florida, USA to examine and separate the effects of habitat across fine and broad scales on the relative predation rates of tethered pinfish (Lagodon rhomboides). Artificial seagrass units (ASUs) were used at three levels of blade density and deployed in different locations within the seascape. Predation rates on pinfish decreased with increasing seagrass blade density. The effects of blade density were consistent across locations, but overall mortality was higher in the lower Bay, where the water was less turbid, higher in salinity, and characterized by a different suite of predators compared to the mid Bay. Using controlled-laboratory experiments, it was found that pinfish reduced their activity levels in more turbid water as well as in response to the presence of a common predator in both clear and more turbid waters. Thus, predation rates were influenced by the combined effects of refugia (fine scale), variation in prey behavior (broad scale), and detection by predators (both scales). This study demonstrates the strong influence habitat can have at different spatial scales in mediating predator–prey interactions of mobile species in estuarine environments

Plant size, latitude, and phylogeny explain within-population variability in herbivory

Interactions between plants and herbivores are central in most ecosystems, but their strength is highly variable. The amount of variability within a system is thought to influence most aspects of plant-herbivore biology, from ecological stability to plant defense evolution. Our understanding of what influences variability, however, is limited by sparse data. We collected standardized surveys of herbivory for 503 plant species at 790 sites across 116° of latitude. With these data, we show that within-population variability in herbivory increases with latitude, decreases with plant size, and is phylogenetically structured. Differences in the magnitude of variability are thus central to how plant-herbivore biology varies across macroscale gradients. We argue that increased focus on interaction variability will advance understanding of patterns of life on Earth