Parallels between embryo and cancer cell metabolism

A key characteristic of cancer cells is the ability to switch from a predominantly oxidative metabolism to glycolysis and the production of lactate even when oxygen is plentiful. This metabolic switch, known as the Warburg effect, was first described in the 1920s, and has fascinated and puzzled researchers ever since. However, a dramatic increase in glycolysis in the presence of oxygen is one of the hallmarks of the development of the early mammalian embryo; a metabolic switch with many parallels to the Warburg effect of cancers. The present review provides a brief overview of this and other similarities between the metabolism in tumours and early embryos and proposes whether knowledge of early embryo metabolism can help us to understand metabolic regulation in cancer cells

Aminoglycosides Rapidly Inhibit NAD(P)H Metabolism Increasing Reactive Oxygen Species and Cochlear Cell Demise

Despite causing permanent hearing loss by damaging inner ear sensory cells, aminoglycosides (AGs) remain one of the most widely used classes of antibiotics in the world. Although the mechanisms of cochlear sensory cell damage are not fully known, reactive oxygen species (ROS) are clearly implicated. Mitochondrial-specific ROS formation was evaluated in acutely cultured murine cochlear explants exposed to gentamicin (GM), a representative ototoxic AG antibiotic. Superoxide (O2·-) and hydrogen peroxide (H2O2) were measured using MitoSOX Red and Dihydrorhodamine 123, respectively, in sensory and supporting cells. A 1-h GM exposure significantly increased O2·- formation in IHCs and increased H2O2 formation in all cell types. At the same time point, GM significantly increased manganese superoxide dismutase (MnSOD) levels while significantly decreasing copper/zinc superoxide dismutase (CuZnSOD) in cochlear sensory cells. This suggests (1) a rapid conversion of highly reactive O2·- to H2O2 during the acute stage of ototoxic antibiotic exposure and (2) that the endogenous antioxidant system is significantly altered by AGs. Fluorescence intensity-based measurements of reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] and mitochondrial membrane potential were measured to determine if increases in GM-induced ROS production were correlated with changes in mitochondrial metabolism. This project provides a basis for understanding the mechanisms of mitochondrial ROS production in cochlear cells exposed to ototoxic antibiotics. Understanding the nature of ototoxic antibiotic-induced changes in mitochondrial metabolism is critical for developing hearing loss treatment and prevention strategies

The Outcome of Neutrophil-T Cell Contact Differs Depending on Activation Status of Both Cell Types

Neutrophils and T cells exist in close proximity in lymph nodes and inflamed tissues duringhealth and disease. They are able to form stable interactions, with profound effects on thephenotype and function of the T cells. However, the outcome of these effects arefrequently contradictory; in some systems neutrophils suppress T cell proliferation, inothers they are activatory or present antigen directly. Published protocols modelling theseinteractions in vitro do not reflect the full range of interactions found in vivo; they do notexamine how activated and naïve T cells differentially respond to neutrophils, or whetherde-granulating or resting neutrophils induce different outcomes. Here, we established aculture protocol to ask these questions with human T cells and autologous neutrophils.We find that resting neutrophils suppress T cell proliferation, activation and cytokineproduction but that de-granulating neutrophils do not, and neutrophil-releasedintracellular contents enhance proliferation. Strikingly, we also demonstrate that T cellsearly in the activation process are susceptible to suppression by neutrophils, while laterstage T cells are not, and naïve T cells do not respond at all. Our protocol therefore allowsnuanced analysis of the outcome of interaction of these cells and may explain thecontradictory results observed previously

A Randomized Cross-Over Trial Comparing the Effect of Intramuscular Versus Intranasal Naloxone Reversal of Intravenous Fentanyl on Odor Detection in Working Dogs

Fentanyl is a potent opioid used clinically as a pain medication and anesthetic but has recently seen a sharp rise as an illicit street drug. The potency of fentanyl means mucous membrane exposure to a small amount of the drug can expose first responders, including working canines, to accidental overdose. Naloxone, a fast-acting opioid antagonist administered intranasally (IN) or intramuscularly (IM) is currently carried by emergency personnel in the case of accidental exposure in both humans and canines. Despite the fact that law enforcement relies heavily on the olfactory abilities of canine officers, the effects of fentanyl exposure and subsequent reversal by naloxone on the olfactory performance of canines are unknown. In a block-randomized, crossover trial, we tested the effects of IN and IM naloxone on the abilities of working dogs to recognize the odor of Universal Detection Calibrant (UDC) prior to, and two, 24, and 48 h after intravenous fentanyl sedation and naloxone reversal. No detectable influence of fentanyl sedation and naloxone reversal on the dogs’ olfactory abilities was detected. We also found no difference in olfactory abilities when dogs received IN or IM naloxone. Together, results suggest no evidence that exposure to intravenous fentanyl followed by naloxone reversal impairs canine olfactory ability under these conditions

Eruption plumes extended more than 30 km in altitude in both phases of the Millennium eruption of Paektu (Changbaishan) volcano

The Millennium Eruption of Paektu volcano, on the border of China and North Korea, generated tephra deposits that extend >1000 km from the vent, making it one of the largest eruptions in historical times. Based on observed thicknesses and compositions of the deposits, the widespread tephra dispersal is attributed to two eruption phases fuelled by chemically distinct magmas that produced both pyroclastic flows and fallout deposits. We used an ensemble-based method with a dual step inversion, in combination with the FALL3D atmospheric tephra transport model, to constrain these two different phases. The volume of the two distinct phases has been calculated. The results indicate that about 3-16 km3 (with a best estimate of 7.2 km3) and 4-20 km3 (with a best estimate of 9.3 km3) of magma were erupted during the comendite and trachyte phases of the eruption, respectively. Eruption rates of up to 4 × 108 kg/s generated plumes that extended 30-40 km up into the stratosphere during each phase

Multiplex ligation-dependent probe amplification (MLPA) analysis is an effective tool for the detection of novel intragenic PLA2G6 mutations: Implications for molecular diagnosis

Phospholipase associated neurodegeneration (PLAN) comprises a heterogeneous group of autosomal recessive neurological disorders caused by mutations in the PLA2G6 gene. Direct gene sequencing detects 85% mutations in infantile neuroaxonal dystrophy. We report the novel use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect novel PLA2G6 duplications and deletions. The identification of such copy number variants (CNVs) expands the PLAN mutation spectrum and may account for up to 12.5% of PLA2G6 mutations. MLPA should thus be employed to detect CNVs of PLA2G6 in patients who show clinical features of PLAN but in whom both disease-causing mutations cannot be identified on routine sequencin

Formation of Highly Oxidized Molecules from NO3 Radical Initiated Oxidation of Delta-3-Carene : A Mechanistic Study

NO3 radical oxidation of most monoterpenes is a significant source of secondary organic aerosol (SOA) in many regions influenced by both biogenic and anthropogenic emissions, but there are very few published mechanistic studies of NO3 chemistry beyond simple first generation products. Here, we present a computationally derived mechanism detailing the unimolecular pathways available to the second generation of peroxy radicals following NO3 oxidation of Delta-3-carene, defining generations based on the sequence of peroxy radicals formed rather than number of oxidant attacks. We assess five different types of unimolecular reactions, including peroxy and alkoxy radical (RO2 and RO) hydrogen shifts, RO2 and RO ring closing (e.g., endoperoxide formation), and RO decomposition. Rate constants calculated using quantum chemical methods indicate that this chemical system has significant contribution from both bimolecular and unimolecular pathways. The dominant unimolecular reactions are endoperoxide formation, RO H-shifts, and RO decomposition. However, the complexity of the overall reaction is tempered as only 1 or 2 radical propagation pathways dominate the fate of each radical intermediate. Chemical ionization mass spectrometry (CIMS) measurements using the NO3- reagent ion during Delta-3-carene + NO3 chamber experiments show products consistent with each of the three types of unimolecular reactions predicted to be important from the computational mechanism. Moreover, the SIMPOL group contribution method for predicting vapor pressures suggests that a majority of the closed-shell products inferred from these unimolecular reactions are likely to have low enough vapor pressure to be able to contribute to SOA formation.Peer reviewe

Does habitat stability structure intraspecific genetic diversity? It’s complicated...

Regional phylogeographic studies have long been conducted in the southeastern United States for a variety of species. With some exceptions, many of these studies focus on single species or single clades of organisms, and those considering multiple species tend to focus on deep historical breaks causing differentiation. However, in many species more recent factors may be influencing genetic diversity. To understand the roles of historic and contemporary processes in structuring genetic diversity, we reanalyzed existing genetic data from Southeast of North America using approaches gleaned from phylogeographic and landscape genetic literature that were implemented across species including AMOVAs, PCoAs, Species Distribution Modelling, and tests of isolation by distance, environment, and habitat instability. Genetic variance was significantly partitioned by ecoregions, watersheds, and across phylogeographic breaks in the majority of species. Similarly, genetic variation was significantly associated with some combination of geographic or environmental distance or habitat instability in most species. Patterns of genetic variation were largely idiosyncratic across species. While habitat instability over time is significantly correlated with genetic diversity in some species, it appears generally less important than isolation by geographic or environmental distance. Our results suggest that many factors, both historical and contemporary, impact genetic diversity within a species, and more so, that these patterns aren’t always similar in closely related species. This supports the importance of species- specific factors and cautions against assumptions that closely related species will respond to historical and contemporary forces in similar ways