Different prostate cancer bone metastasis models respond differently to treadmill exercise (Abstract only)

Background: Prostate cancer (PCa) is a leading cause of death in men with a predilection to metastasize into bone, when the disease is considered to be uncurable. Exercise has been suggested to improve the health of patients with PCa but no current studies on its effects on PCa bone metastasis. Hypothesis: Treadmill exercise can prevent the progression of PCa bone metastasis. Methods: Human xenograft PCa cell line PC3 and murine syngeneic RM1-BM cells were intracardiacally injected (~1x10 cells/injection) into BALB/c nude (n=8) and C57BL/6J mice (n=12), respectively. The following day, the mice were subjected to treadmill exercise (12 meters/minute, 5° inclination, 30 minutes/day, 5 days/week) for 3 weeks. Bioluminescence assay was used to track skeletal tumour growth weekly and micro-CT was used to analyse bone morphometrics ex vivo. Naïve mice (n>6) were subject to the same treadmill protocol and used to assess the osteogenic response. Animal procedures were ethically approved by The University of Sheffield, UK. Results: In the xenograft model, the treadmill exercised mice developed significantly higher tumour burden (p< 0.05, Mann-Whitney test) in their hindlimbs compared to sedentary controls. The bone structure was not improved by treadmill exercise according to micro-CT analysis. In contrast, the syngeneic model showed significantly lower tumour burden in exercised mice compared to controls (p< 0.05, Mann-Whitney test) and a tendency to significantly improved survival curve (p=0.07, Gehan-Breslow-Wilcoxon test). The trabecular thickness (Tb.Th) was found significantly higher compared to controls (p< 0.001, unpaired t-test). In the naïve baseline study, the trabecular BV/TV had a 7.5% increase in C57BL/6J but 8.5% reduction in BALB/c nude mice, compared between exercised to sedentary controls. Conclusion: Treadmill exercise alleviates PCa growth in bones of syngeneic RM1-BM/C57BL/6J but not the xenograft PC3/BALB/c nude model, a possible consequence of different osteogenic response to treadmill by the two mouse strains

Ingestion of Small-Bodied Zooplankton by Zebra Mussels (Dreissena polymorpha): Can Cannibalism on Larvae Influence Population Dynamics?

The zebra mussel Dreissena polymorpha established populations in western Lake Erie in 1986 and achieved densities exceeding 3.4 × 105 individuals∙m−2 during 1990. We assessed apparently incidental predation on Lake Erie and Erindale Pond zooplankton by adult mussels. Dreissena larvae and small rotifers (Polyarthra spp., Keratella spp., Trichocerca) sustained moderate to high predatory mortality whereas larger taxa (Bosmina, Scapholeberis) were invulnerable to predation. Larval Dreissena almost always sustain \u3e 99% mortality in European lakes. While mortality has been ascribed primarily to lack of suitable settling substrate and unfavourable environmental conditions, it may be confounded by larval predation by adults. We demonstrate using STELLA™-modelling that with a larval mortality rate of 99%, settled mussel densities observed in western Lake Erie during 1990 would not be achieved until at least 1994. A model that combines a lower rate (70%) of abiotic mortality with larval predation by adult mussels c..., Les populations de dreissena polymorphe (Dreissena polymorpha) déjà établies dans la partie ouest du lac Érié en 1986 atteignaient des densités supérieures à 3,4 × 105 individus par mètre carré au cours de 1990. Nous avons évalué Ta prédation du zooplancton du lac Érié et de l\u27étang Erindale par les dreissenas adultes. Les larves des dreissenas et les petits rotifères (Polyarthra spp., Keratella spp., Trichocerca) présentaient une mortalité par prédation variant de moyenne à élevée tandis que les plus gros taxons (Bosmima, Scapholeberis) résistaient à toute prédation. Les larves de Dreissena des lacs européeens présentent presque toujours un taux de mortalité supérieur à 99%. La mortalité a surtout été attribuée à l\u27absence d\u27un substrat de fixation adéquat et à des conditions environnementales défavorables, mais elle peut être confondue avec celle découlant de la prédation des larves par les adultes. Nous avons montré, à l\u27aide d\u27un modèle STELLAmd, que les densités de dreissenas fixées notées en 1990 n\u27..

Food storage facilitates professional religious specialization in hunter–gatherer societies

Professional religious specialists centralised religious authority in early human societies and represented some of the earliest instances of formalised social leadership. These individuals played a central role in the emergence of organised religion and transitions to more stratified human societies. Evolutionary theories highlight a range of environmental, economic and social factors that are potentially causally related to the emergence of professional religious specialists in human history. There remains little consensus over the relative importance of these factors and whether professional religious specialists were the outcome or driver of increased socio-cultural complexity. We built a global dataset of hunter–gatherer societies and developed a novel method of exploratory phylogenetic path analysis. This enabled us to systematically identify the factors associated with the emergence of professional religious specialists and infer the directionality of causal dependencies. We find that environmental predictability, environmental richness, pathogen load, social leadership and food storage systems are all correlated with professional religious specialists. However, only food storage is directly related to the emergence of professional religious specialists. Our findings are most consistent with the claim that the early stages of organised religion were the outcome rather than driver of increased socio-economic complexity.Introduction Methods and results Conclusio

Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair

Microcephaly with early-onset, intractable seizures and developmental delay (MCSZ) is a hereditary disease caused by mutations in polynucleotide kinase/phosphatase (PNKP), a DNA strand break repair protein with DNA 5'-kinase and DNA 3'-phosphatase activity. To investigate the molecular basis of this disease, we examined the impact of MCSZ mutations on PNKP activity in vitro and in cells. Three of the four mutations currently associated with MCSZ greatly reduce or ablate DNA kinase activity of recombinant PNKP at 30°C (L176F, T424Gfs48X and exon15Δfs4X), but only one of these mutations reduces DNA phosphatase activity under the same conditions (L176F). The fourth mutation (E326K) has little impact on either DNA kinase or DNA phosphatase activity at 30°C, but is less stable than the wild-type enzyme at physiological temperature. Critically, all of the MCSZ mutations identified to date result in ∼10-fold reduced cellular levels of PNKP protein, and reduced rates of chromosomal DNA strand break repair. Together, these data suggest that all four known MCSZ mutations reduce the cellular stability and level of PNKP protein, with three mutations likely ablating cellular DNA 5'-kinase activity and all of the mutations greatly reducing cellular DNA 3'-phosphatase activity

Steeper size spectra with decreasing phytoplankton biomass indicate strong trophic amplification and future fish declines

Under climate change, model ensembles suggest that declines in phyto�plankton biomass amplify into greater reductions at higher trophic levels, with serious implications for fisheries and carbon storage. However, the extent and mechanisms of this trophic amplification vary greatly among models, and validation is problematic. In situ size spectra offer a novel alternative, com�paring biomass of small and larger organisms to quantify the net efficiency of energy transfer through natural food webs that are already challenged with multiple climate change stressors. Our global compilation of pelagic size spectrum slopes supports trophic amplification empirically, independently from model simulations. Thus, even a modest (16%) decline in phytoplankton this century would magnify into a 38% decline in supportable biomass of fish within the intensively-fished mid-latitude ocean. We also show that this amplification stems not from thermal controls on consumers, but mainly from temperature or nutrient controls that structure the phytoplankton baseline of the food web. The lack of evidence for direct thermal effects on size structure contrasts with most current thinking, based often on more acute stress experiments or shorter-timescale responses. Our synthesis of size spectra integrates these short-term dynamics, revealing the net efficiency of food webs acclimating and adapting to climatic stressor

A novel reagentless glutamate microband biosensor for real-time cell toxicity monitoring

A reagentless glutamate biosensor was applied to the determination of glutamate released from liver hepatocellular carcinoma cells (HepG2) in response to toxic challenge from various concentrations of paracetamol. A screen printed carbon electrode (SPCE) containing the electrocatalyst Meldola's Blue (MB-SPCE) served as the electron mediator for the oxidation of NADH.A mixture of the enzyme glutamate dehydrogenase (GLDH), cofactor nicotinamide adenine dinucleotide (NAD+) and the biopolymer chitosan (CHIT) were drop-coated onto the surface of the transducer (MB-SPCE) in a simple one step fabrication process.The reagentless biosensor was used with amperometry in stirred solution at an applied potential of +0.1 V (vs. Ag/AgCl). All experiments were carried out at the following conditions: pH 7, temperature 37 °C, atmosphere 5% CO2.The linear range of the device was found to be 25–125 μM in phosphate buffer (75 mM, containing 0.05 M NaCl) and 25–150 μM in cell culture medium. The limits of detection (LOD) were found to be 1.2 μM and 4.2 μM based on three times signal to noise, using PBS and culture medium respectively. The sensitivity was calculated to be 106 nA μM−1 cm−2 and 210 nA μM−1 cm−2 in PBS and cell medium respectively. The response time was ∼60 s in an agitated solution.HepG2 cells were exposed to various concentrations of paracetamol (1 mM, 5 mM and 10 mM) in order to investigate the drug-induced release of glutamate into the culture medium in real time. Two toxicity studies were investigated using different methods of exposure and analysis.The first method consisted of a single measurement of the glutamate concentration, using the method of standard addition, after 24 h incubation. The concentrations of glutamate were found to be 52 μM, 93 μM and 177 μM, released on exposure to 1 mM, 5 mM and 10 mM paracetamol respectively.The second method involved the continuous monitoring of glutamate released from HepG2 cells upon exposure to paracetamol over 8 h. The concentrations of glutamate released in the presence of 1 mM, 5 mM and 10 mM paracetamol, increased in proportion to the drug concentration, ie: 16 μM, 28 μM and 62 μM respectively. This result demonstrates the feasibility of using this approach to monitor early metabolic changes after exposure to a model toxic compound

Steeper size spectra with decreasing phytoplankton biomass indicate strong trophic amplification and future fish declines

Under climate change, model ensembles suggest that declines in phytoplankton biomass amplify into greater reductions at higher trophic levels, with serious implications for fisheries and carbon storage. However, the extent and mechanisms of this trophic amplification vary greatly among models, and validation is problematic. In situ size spectra offer a novel alternative, comparing biomass of small and larger organisms to quantify the net efficiency of energy transfer through natural food webs that are already challenged with multiple climate change stressors. Our global compilation of pelagic size spectrum slopes supports trophic amplification empirically, independently from model simulations. Thus, even a modest (16%) decline in phytoplankton this century would magnify into a 38% decline in supportable biomass of fish within the intensively-fished mid-latitude ocean. We also show that this amplification stems not from thermal controls on consumers, but mainly from temperature or nutrient controls that structure the phytoplankton baseline of the food web. The lack of evidence for direct thermal effects on size structure contrasts with most current thinking, based often on more acute stress experiments or shorter-timescale responses. Our synthesis of size spectra integrates these short-term dynamics, revealing the net efficiency of food webs acclimating and adapting to climatic stressors

Right-handed 14-Helix in β3-Peptides from L-Aspartic Acid Monomers

β-Peptides made from L-aspartic acid monomers form a new class of β3-peptides. Here we report the first three-dimensional NMR solution structure of a β3-hexapeptide (1) from L-aspartic acid monomers in 2,2,2-trifluoroethanol (TFE). We show that 1 forms a right-handed 14-helical structure in TFE. α-peptides from naturally occurring L-amino acids adopt a right-handed α-helix whereas β3-peptides formed from β3-amino acids derived from naturally occurring L-amino acids form left-handed 14-helices. The right-handed 14-helical conformation of 1 is a better mimic of α-peptide conformations. Using the NMR structure of 1 in TFE, we further study the conformation of 1 in water, as well as two similar β3-peptides (2 and 3) in water and TFE by molecular dynamics (MD) simulations. NMR and MD results suggest loss of secondary structure of 1 in water and show that it forms a fully extended structure. 2 and 3 contain residues with oppositely charged side chains that engage in salt-bridge interactions and dramatically stabilize the 14-helical conformation in aqueous media

Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures