Mathematical Models of Tumor-Immune System Dynamics

"This collection of papers offers a broad synopsis of state-of-the-art mathematical methods used in modeling the interaction between tumors and the immune system. These papers were presented at the four-day workshop on Mathematical Models of Tumor-Immune System Dynamics held in Sydney, Australia from January 7th to January 10th, 2013. The workshop brought together applied mathematicians, biologists, and clinicians actively working in the field of cancer immunology to share their current research and to increase awareness of the innovative mathematical tools that are applicable to the growing field of cancer immunology. Recent progress in cancer immunology and advances in immunotherapy suggest that the immune system plays a fundamental role in host defense against tumors and could be utilized to prevent or cure cancer. Although theoretical and experimental studies of tumor-immune system dynamics have a long history, there are still many unanswered questions about the mechanisms that govern the interaction between the immune system and a growing tumor. The multidimensional nature of these complex interactions requires a cross-disciplinary approach to capture more realistic dynamics of the essential biology. The papers presented in this volume explore these issues and the results will be of interest to graduate students and researchers in a variety of fields within mathematical and biological sciences."--Publisher website

Excited-state dynamics in diketopyrrolopyrrole-based copolymer for organic photovoltaics investigated by transient optical spectroscopy

We investigate the photoexcited state dynamics in a donor-acceptor copolymer, poly{3,6-dithiophene-2-yl-2,5-di(2-octyldodecyl)-pyrrolo[3,4-c]- pyrrole-1,4-dione-alt-naphthalene} (pDPP-TNT), by picosecond fluorescence and femtosecond transient absorption spectroscopies. Timeresolved fluorescence lifetime measurements of pDPP-TNT thin films reveal that the lifetime of the singlet excited state is 185 ± 5 ps and that singlet-singlet annihilation occurs at excitation photon densities above 6 × 1017 photons/cm3. From the results of singlet-singlet annihilation analysis, we estimate that the single-singlet annihilation rate constant is (6.0 ± 0.2) × 109cm3 s-1 and the singlet diffusion length is -7 nm. From the comparison of femtosecond transient absorption measurements and picosecond fluorescence measurements, it is found that the time profile of the photobleaching signal in the charge-transfer (CT) absorption band coincides with that of the fluorescence intensity and there is no indication of long-lived species, which clearly suggests that charged species, such as polaron pairs and triplet excitons, are not effectively photogenerated in the neat pDPP-TNT polymer.

Role of the N-terminal region in G protein-coupled receptor functions : negative modulation revealed by 5-HT2B receptor polymorphisms

The putative role of the N-terminal region of rhodopsin-like 7 transmembrane biogenic amine receptors in agonist-induced signaling has not yet been clarified despite recent advances in 7 transmembrane receptor structural biology. Given the existence of N-terminal nonsynonymous polymorphisms (R6G;E42G) within the HTR2B gene in a drug-abusing population, we assessed whether these polymorphisms affect 5-hydroxytryptamine 2B (5-HT2B) receptor in vitro pharmacologic and coupling properties in transfected COS-7 cells. Modification of the 5-HT2B receptor N terminus by the R6G;E42G polymorphisms increases such agonist signaling pathways as inositol phosphate accumulation as assessed by either classic or operational models. The N-terminal R6G;E42G mutations of the 5-HT2B receptor also increase cell proliferation and slow its desensitization kinetics compared with the wild-type receptor, further supporting a role for the N terminus in transduction efficacy. Furthermore, by coexpressing a tethered wild-type 5-HT2B receptor N terminus with a 5-HT2B receptor bearing a N-terminal deletion, we were able to restore original coupling. This reversion to normal activity of a truncated 5-HT2B receptor by coexpression of the membrane-tethered wild-type 5-HT2B receptor N terminus was not observed using a membrane-tethered 5-HT2B receptor R6G;E42G N terminus. These data suggest that the N terminus exerts a negative control over basal as well as agonist-stimulated receptor activity that is lost in the R6G;E42G mutant. Our findings reveal a new and unanticipated role of the 5-HT2B receptor N terminus as a negative modulator, affecting both constitutive and agonist-stimulated activity. Moreover, our data caution against excluding the N terminus and extracellular loops in structural studies of this 7 transmembrane receptor family

Determinants of plant performance dynamics : empirical analysis of the manufacturing sector in Indonesia, 1990-2000

We identify determinants of plant dynamics and find their differences before, during, and after the Asian financial crisis. The results show that the distinction of the crisis is important and the effects of the crisis do not seem to persist after 1998. Furthermore, we reject Gibrat's law as the right functional form to describe plant growth. We are not able to support empirically the theoretical results that smaller and efficient plants tend to grow faster than larger and inefficient plants with the exception of the crisis period. The results reflect that there was a trickle down effect of economic development.

Sentencing and public confidence in Australia: The dynamics and foci of small group deliberations

This study is the first of its kind in Australia to use the deliberative small group methodology to explore participants’ deeper, nuanced thoughts on specific criminal justice issues in order to gain insight into the underlying beliefs that influence people’s opinions on sentencing. The use of small group discussions allows an analysis of the dynamics of people’s interactions and the potential of these to elicit deeper, more thoughtful deliberation. Participants’ comments around two policy areas – mandatory sentencing and the use of alternatives to imprisonment – were founded on concerns about the need for judges to tailor the sentence to fit the specific circumstances of each case. The methodology itself has shown that people may change their initial opinions on complex issues when given the opportunity to discuss and reflect on their beliefs.

Speckle-type POZ protein mutations interrupt tumor suppressor function of speckle-type POZ protein in prostate cancer by affecting androgen receptor degradation

Large scale exome sequencing studies have revealed regions of the genome, which contribute to the castrate resistant prostate cancer (CRPC) phenotype. [1],[2],[3] Such studies have identified mutations in genes, which may have diagnostic/prognostic potential, or which may be targeted therapeutically. Two of these genes include the androgen receptor (AR) and speckle-type POZ protein (SPOP) genes. However, the findings from these exome sequencing studies can only be translated therapeutically once the functional consequences of these mutations have been determined. Here, we highlight the recent study by An et al. [4] which investigated the functional effects of mutations in the SPOP gene that were identified in the aforementioned exome sequencing studies, particularly in the context of SPOP-mediated degradation of the AR.

The dynamics of expertise acquisition in sport : the role of affective learning design

Objectives The aim of this position paper is to discuss the role of affect in designing learning experiences to enhance expertise acquisition in sport. The design of learning environments and athlete development programmes are predicated on the successful sampling and simulation of competitive performance conditions during practice. This premise is captured by the concept of representative learning design, founded on an ecological dynamics approach to developing skill in sport, and based on the individual-environment relationship. In this paper we discuss how the effective development of expertise in sport could be enhanced by the consideration of affective constraints in the representative design of learning experiences. Conclusions Based on previous theoretical modelling and practical examples we delineate two key principles of Affective Learning Design: (i) the design of emotion-laden learning experiences that effectively simulate the constraints of performance environments in sport; (ii) recognising individualised emotional and coordination tendencies that are associated with different periods of learning. Considering the role of affect in learning environments has clear implications for how sport psychologists, athletes and coaches might collaborate to enhance the acquisition of expertise in sport.

Protein ingestion increases myofibrillar protein synthesis after concurrent exercise

PURPOSE: We determined the effect of protein supplementation on anabolic signaling and rates of myofibrillar and mitochondrial protein synthesis after a single bout of concurrent training. METHODS: Using a randomized cross-over design, 8 healthy males were assigned to experimental trials consisting of resistance exercise (8 × 5 leg extension, 80% 1-RM) followed by cycling (30 min at ~70% VO2peak) with either post-exercise protein (PRO: 25 g whey protein) or placebo (PLA) ingestion. Muscle biopsies were obtained at rest, 1 and 4 h post-exercise. RESULTS: Akt and mTOR phosphorylation increased 1 h after exercise with PRO (175-400%, P<0.01) and was different from PLA (150-300%, P<0.001). MuRF1 and Atrogin-1 mRNA were elevated post-exercise but were higher with PLA compared to PRO at 1 h (50-315%, P<0.05), while PGC-1α mRNA increased 4 h post-exercise (620-730%, P<0.001) with no difference between treatments. Post-exercise rates of myofibrillar protein synthesis increased above rest in both trials (75-145%, P <0.05) but were higher with PRO (67%, P<0.05) while mitochondrial protein synthesis did not change from baseline. CONCLUSION: Our results show that a concurrent training session promotes anabolic adaptive responses and increases metabolic/oxidative mRNA expression in skeletal muscle. Protein ingestion after combined resistance and endurance exercise enhances myofibrillar protein synthesis and attenuates markers of muscle catabolism and thus is likely an important nutritional strategy to enhance adaptation responses with concurrent training.

Reduced resting skeletal muscle protein synthesis is rescued by resistance exercise and protein ingestion following short-term energy deficit

The myofibrillar protein synthesis (MPS) response to resistance exercise (REX) and protein ingestion during energy deficit (ED) is unknown. We determined, in young men (n=8) and women (n=7), protein signaling, resting post-absorptive MPS during energy balance [EB: 45 kcal∙(kg FFM∙d)-1] and after 5d of ED [30 kcal∙(kg FFM∙d)-1] as well as MPS while in ED after acute REX in the fasted state and with the ingestion of whey protein (15 and 30 g). Post-absorptive rates of MPS were 27% lower in ED than EB (P<0.001), but REX stimulated MPS to rates equal to EB. Ingestion of 15 and 30 g of protein after REX in ED increased MPS ~16 and ~34% above resting EB, (P<0.02). p70 S6Kthr389 phosphorylation increased above EB only with combined exercise and protein intake (~2-7 fold; P<0.05). In conclusion, short-term ED reduces post-absorptive MPS, however, a bout of REX in ED restores MPS to values observed at rest in EB. The ingestion of protein after REX further increases MPS above resting EB in a dose-dependent manner. We conclude that combining REX with increased protein availability after exercise enhances rates of skeletal muscle protein synthesis during short term ED and could, in the long term, preserve muscle mass.

The dynamics of cellular automata on 2-manifolds is affected by topology

In this paper, we demonstrate that the distribution of Wolfram classes within a cellular automata rule space in the triangular tessellation is not consistent across different topological general. Using a statistical mechanics approach, cellular automata dynamical classes were approximated for cellular automata defined on genus-0, genus-1 and genus-2 2-manifolds. A distribution-free equality test for empirical distributions was applied to identify cases in which Wolfram classes were distributed differently across topologies. This result implies that global structure and local dynamics contribute to the long term evolution of cellular automata.

Interpreting scratch assays using pair density dynamics and approximate Bayesian computation

Quantifying the impact of biochemical compounds on collective cell spreading is an essential element of drug design, with various applications including developing treatments for chronic wounds and cancer. Scratch assays are a technically simple and inexpensive method used to study collective cell spreading; however, most previous interpretations of scratch assays are qualitative and do not provide estimates of the cell diffusivity, D, or the cell proliferation rate,l. Estimating D and l is important for investigating the efficacy of a potential treatment and provides insight into the mechanism through which the potential treatment acts. While a few methods for estimating D and l have been proposed, these previous methods lead to point estimates of D and l, and provide no insight into the uncertainty in these estimates. Here, we compare various types of information that can be extracted from images of a scratch assay, and quantify D and l using discrete computational simulations and approximate Bayesian computation. We show that it is possible to robustly recover estimates of D and l from synthetic data, as well as a new set of experimental data. For the first time, our approach also provides a method to estimate the uncertainty in our estimates of D and l. We anticipate that our approach can be generalized to deal with more realistic experimental scenarios in which we are interested in estimating D and l, as well as additional relevant parameters such as the strength of cell-to-cell adhesion or the strength of cell-to-substrate adhesion.

An observational analysis of the impact of board dynamics and directors’ participation on perceived board effectiveness

This study addresses calls for closer examination of board dynamics by offering an inside view of director interactions. Video-observations of three board meetings at each of two Australian corporations matched with director interviews and secondary data reveal distinct patterns of director interactions, their sources of variation and impact on perceived board effectiveness. Our data reveal that director interactions are multi-dimensional and dynamic: while group interactions across agenda items are similar, with a few directors leading the discussion, the contributing directors change across items. Moreover, directors’ inclusiveness and evenness of participation are associated with higher perceptions of board effectiveness. Last, we find that director interactions change with the nature of the items, board climate and board meeting arrangements. The study contributes to the literature by moving beyond the individual-level analysis of directors’ skills or independence, and offering a detailed view of how the joint group and individual dimensions of board dynamics affect board functioning.