On immunotherapies and cancer vaccination protocols: A mathematical modelling approach

In this paper we develop a new mathematical model of immunotherapy and cancer vaccination, focusing on the role of antigen presentation and co-stimulatory signaling pathways in cancer immunology. We investigate the effect of different cancer vaccination protocols on the well-documented phenomena of cancer dormancy and recurrence, and we provide a possible explanation of why adoptive (i.e. passive) immunotherapy protocols can sometimes actually promote tumour growth instead of inhibiting it (a phenomenon called immunostimulation), as opposed to active vaccination protocols based on tumour-antigen pulsed dendritic cells. Significantly, the results of our computational simulations suggest that elevated numbers of professional antigen presenting cells correlate well with prolonged time periods of cancer dormancy.     

Role of cyclic adenosine 3'',5''-monophosphate on cessation of respiration in ultraviolet-irradiated Escherichia coli.

The addition of cyclic adenosine 3',5'-monophosphate (cAMP) to ultraviolet-irradiated Escherichia coli B/r cultures causes additional cells to cease respiring and to die. These effects of cAMP are greater on glucose-grown cells, where the effects of ultraviolet radiations alone are smaller and where the intracellular concentrations of cAMP are known to be lower.     

MSH-MLH complexes formed at a DNA mismatch are disrupted by the PCNA sliding clamp

In the yeast Saccharomyces cerevisiae, mismatch repair (MMR) is initiated by the binding of heterodimeric MutS homolog (MSH) complexes to mismatches that include single nucleotide and loop insertion/deletion mispairs. In in vitro experiments, the mismatch binding specificity of the MSH2-MSH6 heterodimer is eliminated if ATP is present. However, addition of the MutL homolog complex MLH1-PMS1 to binding reactions containing MSH2-MSH6, ATP, and mismatched substrate results in the formation of a stable ternary complex. The stability of this complex suggests that it represents an intermediate in MMR that is subsequently acted upon by other MMR factors. In support of this idea, we found that the replication processivity factor proliferating cell nuclear antigen (PCNA), which plays a critical role in MMR at step(s) prior to DNA resynthesis, disrupted preformed ternary complexes. These observations, in conjunction with experiments performed with streptavidin end-blocked mismatch substrates, suggested that PCNA interacts with an MSH-MLH complex formed on DNA mispairs.     

Inheritance of grain filling duration in spring wheat (<Emphasis Type="Italic">Triticum aestivum</Emphasis> L. em thell)

To understand the genetic control of grain filling duration (GFD), i.e., the number of days from anthesis to physiological maturity, we studied the F₁, F₂, BC1 and BC₂ generations of six spring wheat crosses from nine varieties/genotypes. Generation mean analysis for gene effects indicated that one or more types of epistasis were significant in all crosses. In each pairing, the F₁ and F₂ means were either intermediate or closer to the mean of the parent having the longer GFD. Our narrow-sense heritability estimate was reasonably high, at 47.67 (based on diallel analysis). This demonstrated that progress could be made from the selection in these crosses for either long or short GFD. The two early varieties that had identical maturity durations differed in their GFD values, indicating that maturity dates are not good criteria when choosing parents for modifying GFD. To utilize favorable additive × additive effects during this selection, we suggest that a single seed descent (SSD) or bulk popula-tion approach be adopted. In comparison, dominance effects would prove quite useful in hybrid wheat breeding programs.     

Metabolic dynamics in the human red cell. Part IV--Data prediction and some model computations

The biochemical information on the basic cellular determinants of the human red cell has been compiled into a comprehensive model of the red cell metabolic machinery. This model gives a consistent interpretation--both qualitative and quantitative--of the experimental findings. The predicted steady states and the dynamic states of the model are compared with the experimental findings, and the utility of this model is demonstrated.     

Conditions for the trivers-willard hypothesis to be valid: A minimal population-genetic model

The very insightful Trivers-Willard hypothesis, proposed in the early 1970s, states that females in good physiological condition are more likely to produce male offspring when the variance of reproductive success among males is high. The hypothesis has inspired a number of studies over the last three decades aimed at its experimental verification, and many of them have found adequate supportive evidence in its favour. Theoretical investigations, on the other hand, have been few, perhaps because formulating a population-genetic model for describing the Trivers-Willard hypothesis turns out to be surprisingly complex. The present study is aimed at using a minimal population-genetic model to explore one specific scenario, namely how is the preference for a male offspring by females in good condition altered wheng, the proportion of such females in the population, changes from a low to a high value. As expected, when the proportion of such females in good condition is low in the population, i.e. for low values ofg, the Trivers-Willard (TW) strategy goes to fixation against the equal investment strategy. This holds true up to g_max, a critical value ofg, above which the two strategies coexist, but the proportion of the TW strategy steadily decreases asg increases to unity. Similarly, when the effect of well-endowed males attaining disproportionately high number of matings is more pronounced, the TW strategy is more likely to go to fixation. Interestingly, the success of the TW strategy has a complex dependence on the variance of the physiological condition of females. If the difference in the two types of conditions is not large, TW strategy is favoured, and its success is more likely as the difference increases. However, beyond a critical value of the difference, the TW strategy is found to be less and less likely to succeed as the difference becomes larger. Possible reasons for these effects are discussed. This paper is dedicated to the memory of W. D. Hamilton.     

Seasonal histological changes in the ovaries of a mountain stream teleost, Schizothorax richardsonii (Gray and Hard).

In S. richardsonii, unlike its testis, the whole of the ovary is fertile. The oogonia pass through seven maturation stages to form the ripe ova. The residual oogonia are responsible for the development of the new crop of oogonia. The zonation of the ooplasm reveals that a majority of the oocytes have a darkly stained inner and a lightly stained outer zone. The yolk nucleus probably has some relationship with the process of vitellogenesis. The nucleoli are produced by the division and fragmentation of the nucleolus. Extrusion of nucleoli appears to be associated with the formation of yolk. The formation of yolk globules in the oocyte begins in the periphery of the ooplasm and moves inward till the whole of the ooplasm in impregnated with yolk. As the yolk vesicles are PAS-positive in this fish, they contain mucopolysaccharides. The ovarian cycle can be divided into five stages. The ovary becomes much enlarged and distended in the month of October and delicate and thin in March. The spawning season extends from late October to December and the ovary exhibits asynchronism.     

E.s.r. study of the post-radiolysis growth of spin-trapped radicals in gamma-irradiated aqueous solutions of thymine.

The post-irradiation growth of the spin-adduct nitroxide radical produced by the addition of the thymine--OD radical to t-nitrosobutane (tNB) in gamma-irradiated, de-aerated D2O solutions was investigated by e.s.r. The thymine--OD radical was formed by the addition of an OD radical to the C(5) position of thymine. Growth reached a greater maximum value and was more rapid with increasing dose. At a fixed dose, growth was also greater and more rapid if oxygen was present after gamma-radiolysis. The addition of a second radical to the spin-adduct nitroxide during radiolysis to give a diamagnetic intermediate, which can regenerate the spin-adduct radical during storage in air-free and in air-saturated solutions at room temperature, was inferred to be responsible for post-irradiation growth. U.V. photolysis at 260-280 nm of a solution containing the diamagnetic intermediate rapidly regenerates the spin-adduct nitroxide. The longer lifetime of the diamagnetic intermediate in oxygen-free solutions may be relevant to an understanding of the anoxic sensitization by nitroxides in cellular systems.