Prostate cancer is one of the most common cancers in men. Although it has a relatively high 5-year survival rate, development of resistance to standard androgen-deprivation therapy is a significant clinical problem. Therefore, novel therapeutic strategies are urgently needed. The protein kinase C (PKC) family is a putative prostate cancer drug target, but so far no PKC-targeting drugs are available for clinical use. By contrast to the standard approach of developing PKC inhibitors, we have developed isophthalate derivatives as PKC agonists. In this study, we have characterized the effects of the most potent isophthalate, 5-(hydroxymethyl) isophthalate 1a3 (HMI-1a3), on three prostate cancer cell lines (LNCaP, DU145, and PC3) using both 2D and 3D cell culture models. In 2D cell culture, HMI-1a3 reduced cell viability or proliferation in all cell lines as determined by the metabolic activity of the cells (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay) and thymidine incorporation. However, the mechanism of action in LNCaP cells was different to that in DU145 or PC3 cells. In LNCaP cells, HMI-1a3 induced a PKC-dependent activation of caspase 3/7, indicating an apoptotic response, whereas in DU145 and PC3 cells, it induced senescence, which was independent of PKC. This was observed as typical senescent morphology, increased beta-galactosidase activity, and upregulation of the senescence marker p21 and downregulation of E2F transcription factor 1. Using a multicellular spheroid model, we further showed that HMI-1a3 affects the growth of LNCaP and DU145 cells in a 3D culture, emphasizing its potential as a lead compound for cancer drug development.

The effects of two alternative formulations of sapwood senescence on the behavior of model LIGNUM (with parameter values adjusted for Scots pine growing southern Finland) were studied. The two alternatives were: autonomous sapwood senescence assuming a maximum age for the tree ring and sapwood senescence that is controlled by the mortality of foliage. For the latter alternative two hypothetical further mechanisms were stipulated. All the formulations were implemented in LIGNUM. Simulations were made with all model variants for fertile and poor soil conditions using high, normal and low rates of foliage mortality. The simulation results were compared against of a data set consisting of 11 open grown Scots pine trees from southern Finland. Observations of heartwood proportion were used in this study. They show that heartwood starts to increase in trees from age of approximately 20 years onwards. The simulation results showed no differences between fertile and poor soil conditions as regards heartwood formation. Of the variants of foliage controlled sapwood senescence the one where death of sapwood in a tree segment induces sapwood senescence in the tree parts below only slightly was the best. This and the autonomous sapwood senescence corresponded equally well to the observations. In order to make more refined conclusions additional data and simulations are necessary.

Individuals of long-lived animal species can improve their reproductive success through experience. While individual’s resources available for survival and reproduction decrease toward the end of its lifespan through senescence, terminal investment hypothesis predicts the less likely old individuals reproduce again the more they invest in their current offspring. Experience gained through a long lifespan might have an important role in changing behavior to optimize the use of resources and compensate the effects of senescence. In addition, behavioral plasticity allows animals to respond changes in their habitat within much shorter timespan than on an evolutionary timescale. Svalbard reindeer (Rangifer tarandus platyrhynchus) is a wild subspecies of reindeer. It is only found in Svalbard, a remote archipelago in the Arctic with extreme weather conditions rapidly changing due to climate change. It has been isolated at least 5000 years and adapted to a barren habitat with nearly no hunting, predation or harassment of flying insects. The objective of this study is to investigate the effect of age and a calf at heel in Svalbard reindeer females’ maternal, vigilant, and social behavior and time budget in the light of life history theory and its senescence and terminal investment hypotheses. I carried out the field work for the study in two periods in summer in Semmeldalen valley and the south-western part of Reindalen valley on the island of Spitsbergen, Svalbard. I collected behavioral data on marked individuals by instant scan sampling and focal watch methods, wrote observations down manually and later fed them into computer. In addition, I have used birth year data collected by the long-term monitoring program by the Norwegian Polar Institute. I used generalized linear mixed models to analyze the effects of age and calf at heel to the behavior of females. The main results include that young dams maintained shorter distance to their calf in July than in August, and old females were less vigilant. Younger dams and older females without calves were in smaller groups than older dams and younger females without calves. In addition, females with calves spend proportionately less time lying down than females without calves. Dams maintained a longer distance to the nearest neighbor than females without calves. Older dams spend proportionately more time feeding and in groups in August than younger dams. These results show that the age and calf at heel do play a role in the behavior of Svalbard reindeer females and the effect varies over the course of the short Arctic summer. Experience may make older females more effective mothers by optimize the use of resources for example from vigilance to feeding in a predator-free environment. On the other hand, senescence may affect the amount of energy females can spend on their calves, potentially influencing their survival.

Rcd1 (radical-induced cell death1) is an Arabidopsis thaliana mutant, which exhibits high tolerance to paraquat [methyl viologen (MV)], herbicide that interrupts photosynthetic electron transport chain causing the formation of superoxide and inhibiting NADPH production in the chloroplast. To understand the biochemical mechanisms of MV resistance and the role of RCD1 in oxidative stress responses, we performed metabolite profiling of wild type (Col-0) and rcd1 plants in light, after MV exposure and after prolonged darkness. The function of RCD1 has been extensively studied at transcriptomic and biochemical level, but comprehensive metabolite profiling of rcd1 mutant has not been conducted until now. The mutant plants exhibited very different metabolic features from the wild type under light conditions implying enhanced glycolytic activity, altered nitrogen and nucleotide metabolism. In light conditions, superoxide production was elevated in rcd1, but no metabolic markers of oxidative stress were detected. Elevated senescence-associated metabolite marker levels in rcd1 at early developmental stage were in line with its early-senescing phenotype and possible mitochondrial dysfunction. After MV exposure, a marked decline in the levels of glycolytic and TCA cycle intermediates in Col-0 suggested severe plastidic oxidative stress and inhibition of photosynthesis and respiration, whereas in rcd1 the results indicated sustained photosynthesis and respiration and induction of energy salvaging pathways. The accumulation of oxidative stress markers in both plant lines indicated that MV-resistance in rcd1 derived from the altered regulation of cellular metabolism and not from the restricted delivery of MV into the cells or chloroplasts. Considering the evidence from metabolomic, transcriptomic and biochemical studies, we propose that RCD1 has a negative effect on reductive metabolism and rerouting of the energy production pathways. Thus, the altered, highly active reductive metabolism, energy salvaging pathways and redox transfer between cellular compartments in rcd1 could be sufficient to avoid the negative effects of MV-induced toxicity.