The Apolipoprotein E Antagonistic Pleiotropy Hypothesis: Review and Recommendations

Research on apolipoprotein E (APOE) has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD). However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area

Antibiotics increase gut metabolism and antioxidant proteins and decrease acute phase response and necrotizing enterocolitis in preterm neonates

BACKGROUND: The appropriate use of antibiotics for preterm infants, which are highly susceptible to develop necrotizing enterocolitis (NEC), is not clear. While antibiotic therapy is commonly used in neonates with NEC symptoms and sepsis, it remains unknown how antibiotics may affect the intestine and NEC sensitivity. We hypothesized that broad-spectrum antibiotics, given immediately after preterm birth, would reduce NEC sensitivity and support intestinal protective mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Preterm pigs were treated with antibiotics for 5 d (oral and systemic doses of gentamycin, ampicillin and metrodinazole; AB group) and compared with untreated pigs. Only the untreated pigs showed evidence of NEC lesions and reduced digestive function, as indicated by lowered villus height and activity of brush border enzymes. In addition, 53 intestinal and 22 plasma proteins differed in expression between AB and untreated pigs. AB treatment increased the abundance of intestinal proteins related to carbohydrate and protein metabolism, actin filaments, iron homeostasis and antioxidants. Further, heat shock proteins and the complement system were affected suggesting that all these proteins were involved in the colonization-dependent early onset of NEC. In plasma, acute phase proteins (haptoglobin, complement proteins) decreased, while albumin, cleaved C3, ficolin and transferrin increased. CONCLUSIONS/SIGNIFICANCE: Depressed bacterial colonization following AB treatment increases mucosal integrity and reduces bacteria-associated inflammatory responses in preterm neonates. The plasma proteins C3, ficolin, and transferrin are potential biomarkers of the colonization-dependent NEC progression in preterm neonates

Experimental evaluation of the pseudotime principle for nonisothermal polymer flows

We have applied a series of start-up of uniaxial extensions to very high strain followed by stress relaxation. A potential temperature change was applied during the stress relaxation. We used two thermorheological simple polymers; a linear polystyrene and a branched low density polyethylene. Experiments performed with temperature changes during the stress relaxation were shown to be identical with isothermal ones in the “pseudotime”, within the accuracy of the experiments. This verifies that the pseudotime approach seems to be the general basis for nonisothermal microstructural modeling for flow of polymers. The pseudotime is given as ξ(t) = ∫to 1/aT(T(t1))dT1, where aT are the well established time-temperature superposition shift factors, calculated from the past temperatures (at time t0) in a particle path

The pharmacokinetics of the interstitial space in humans

BACKGROUND: The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. METHODS: The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphine-6-glucuronide, morphine-3-glucuronide, inulin and β-lactam antibiotics with a range of protein binding (amoxicillin, piperacillin, cefatrizine, ceforanide, flucloxacillin, dicloxacillin). A PBPK data set was developed for extracellular solutes based on the literature for interstitial organ volumes. The program PKQuest was used to generate the PBPK model predictions. The pharmacokinetics of the protein (albumin) bound β-lactam antibiotics were characterized by two parameters: 1) the free fraction of the solute in plasma; 2) the interstitial albumin concentration. A new approach to estimating the capillary permeability is described, based on the pharmacokinetics of the highly protein bound antibiotics. RESULTS: About 42% of the total body water is extracellular. There is a large variation in the organ distribution of this water – varying from about 13% of total tissue water for skeletal muscle, up to 70% for skin and connective tissue. The weakly bound antibiotics have flow limited capillary-tissue exchange kinetics. The highly protein bound antibiotics have a significant capillary permeability limitation. The experimental pharmacokinetics of the 11 solutes is well described using the new PBPK data set and PKQuest. CONCLUSIONS: Only one adjustable parameter (systemic clearance) is required to completely characterize the PBPK for these extracellular solutes. Knowledge of just this systemic clearance allows one to predict the complete time course of the absolute drug concentrations in the major organs. PKQuest is freely available

Impacts of land use change to short rotation forestry for bioenergy on soil greenhouse gas emissions and soil carbon

Short Rotation Forestry (SRF) for bioenergy could be used to meet biomass requirements and contribute to achieving renewable energy targets. As an important source of biomass it is important to gain an understanding of the implications of large-scale application of SRF on the soil-atmosphere greenhouse gas (GHG) exchange. This study examined the effects of land use change (LUC) from grassland to SRF on soil fluxes of methane (CH4), nitrous oxide (N2O) and carbon dioxide (CO2), and the important drivers in action. Examining soils from a range of sites across the UK, CO2 emission potentials were reduced under SRF with differences between coniferous and broadleaved transitions; these changes were found to be related to changes in soil pH and microbial biomass. However, there were limited effects of SRF tree species type on CH4 and N2O fluxes. A detailed study at an experimental SRF site over 16 months demonstrated a reduction in CH4 and net CO2 emissions from soils under SRF and revealed intriguing temporal dynamics of N2O under Sitka spruce and common alder. A significant proportion of the variation in soil N2O fluxes was attributed to differences between tree species, water table depth, spatial effects, and their interactions. The effects of microtopography (ridges, troughs, flats), and its interactions with water table depth on soil GHG fluxes under different tree species was tested using mesocosm cores collected in the field. Microtopography did not significantly affect soil GHG fluxes but trends suggested that considering this spatial factor in sampling regimes could be important. N2O fluxes from Sitka spruce soils did not respond to water table depth manipulation in the laboratory suggesting that they may also be determined by tree-driven nitrogen (N) availability, with other research showing N deposition to be higher in coniferous plantations. An N addition experiment lead to increased N2O emissions with greatest relative response in the Sitka spruce soils. Overall, LUC from rough grassland to SRF resulted in a reduction in soil CH4 emissions, increased N2O emissions and a reduction or no change in net CO2 emissions. These changes in emissions were influenced both directly and indirectly by tree species type with Sitka spruce having the greatest effect on N2O in particular, thus highlighting the importance of considering soil N2O emissions in any life cycle analysis or GHG budgets of LUC to SRF for bioenergy. This research can help inform decisions around SRF tree species selection in future large-scale bioenergy planting

Catalogue of Beluga and Narwhal Click Spectra and Spectrograms from SoundTrap Recordings

This supplementary file accompanies a journal article focused on beluga and narwhal echolocation click classification. This document provides an overview of the data included in all beluga and narwhal acoustic events (each 1 hour) from SoundTrap recordings collected at the Kong Oscar and Fisher Islands mooring sites. There are two figures for each event: (1) concatenated click spectrogram, and (2) mean power spectrum for all detections within the event. Summary statistics are provided for each event showing the number of detections and the sound pressure level (SPL) difference in decibels (dB) between selected third-octave frequency bands. Visual inspection of the enclosed figures demonstrates clear differences between beluga and narwhal click spectra