Rhenium-catalysed hydroboration of aldehydes and aldimines

The first examples for the rhenium-catalysed hydroboration of aldehydes, ketones and aldimines, including heteroaromatic quinoline, are reported herein. Reactions are remarkably chemoselective and tolerant of several functional groups. A wide array of rhenium complexes were efficient pre-catalysts for these hydroborations, including new low-valent complexes of the formula [Re(N-N)(CO)(L)]X (N-N = bipy derivative, L = labile ligand/solvent, and X = [BAr ] and [B(3,5-di-tBu-cat)]), which have been characterized fully including an X-ray diffraction study for [Re(bipy)(CO)(quin)][BAr ] (2). A new silver spiroboronate ester Ag[B(3,5-di-tBu-cat)](NCCH) (3) was prepared and characterized fully, including an X-ray diffraction study, and used to make one of the new rhenium complexes.The Oviedo authors thank MINECO and FEDER (grant CTQ2015-70231-P) and Principado de Asturias (grant FC-15-GRUPIN14-103) for funding, and Ministerio de Educación for an FPU predoctoral fellowship (to RA). SAW is grateful to the Natural Sciences and Engineering Research Council, the CRC programme and Mount Allison University for funding.Peer Reviewe

Effects of Inbreeding and Heterosis in Hereford Lines on Reproduction and Maternal Performance

Two genetic mechanisms have been described as potential explanations for heterosis. The first mechanism is dominance. Dominance occurs when there are two differing forms of a gene (alleles) at a given position (locus) on a pair of chromosomes and where one of the pair of alleles masks or over powers the effect of the second. Having two different alleles at a locus is referred to as heterozygosity and the affected individual is heterozygous. Whether an individual has one or two copies of a dominant allele makes little difference in its superiority over others having two copies of the recessive allele. A higher degree of heterozygosity is expected when one population carrying the dominant allele in high frequency is crossed with a second population carrying the recessive allele in high frequency. Alternatively, heterosis may result from joint effects of genes at several loci. This alternative mechanism is called epistasis. Previous research documents reduced performance resulting from the mating of closely related individuals (inbreeding). Inbreeding generally reduces growth and reproductive rates and delays maturity. This inbreeding depression arises from increasing the frequency with which two alleles at a locus are identical (homozygous) and again coupled with dominant gene action. Thus, effects of inbreeding and heterosis are of similar size but opposite in direction, if dominance at individual loci causes both. In this study, we used inbreeding and linecrossing of Hereford cattle in an attempt to distinguish between these two explanations for heterosis influencing maternal traits. Answering this question sheds light on the amount of heterosis to be expected in composite breeding schemes

Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells

Viruses alter a multitude of host-cell processes to create a more optimal environment for viral replication. This includes altering metabolism to provide adequate substrates and energy required for replication. Typically, viral infections induce a metabolic phenotype resembling the Warburg effect, with an upregulation of glycolysis and a concurrent decrease in cellular respiration. Human adenovirus (HAdV) has been observed to induce the Warburg effect, which can be partially attributed to the adenovirus protein early region 4, open reading frame 1 (E4orf1). E4orf1 regulates a multitude of host-cell processes to benefit viral replication and can influence cellular metabolism through the transcription factor avian myelocytomatosis viral oncogene homolog (MYC). However, E4orf1 does not explain the full extent of Warburg-like HAdV metabolic reprogramming, especially the accompanying decrease in cellular respiration. The HAdV protein early region 1A (E1A) also modulates the function of the infected cell to promote viral replication. E1A can interact with a wide variety of host-cell proteins, some of which have been shown to interact with metabolic enzymes independently of an interaction with E1A. To determine if the HAdV E1A proteins are responsible for reprogramming cell metabolism, we measured the extracellular acidification rate and oxygen consumption rate of A549 human lung epithelial cells with constitutive endogenous expression of either of the two major E1A isoforms. This was followed by the characterization of transcript levels for genes involved in glycolysis and cellular respiration, and related metabolic pathways. Cells expressing the 13S encoded E1A isoform had drastically increased baseline glycolysis and lower maximal cellular respiration than cells expressing the 12S encoded E1A isoform. Cells expressing the 13S encoded E1A isoform exhibited upregulated expression of glycolysis genes and downregulated expression of cellular respiration genes. However, tricarboxylic acid cycle genes were upregulated, resembling anaplerotic metabolism employed by certain cancers. Upregulation of glycolysis and tricarboxylic acid cycle genes was also apparent in IMR-90 human primary lung fibroblast cells infected with a HAdV-5 mutant virus that expressed the 13S, but not the 12S encoded E1A isoform. In conclusion, it appears that the two major isoforms of E1A differentially influence cellular glycolysis and oxidative phosphorylation and this is at least partially due to the altered regulation of mRNA expression for the genes in these pathways

A shared mechanistic pathway for pyridoxal phosphate–dependent arginine oxidases

The mechanism by which molecular oxygen is activated by the organic cofactor pyridoxal phosphate (PLP) for oxidation reactions remains poorly understood. Recent work has identified arginine oxidases that catalyze desaturation or hydroxylation reactions. Here, we investigate a desaturase from the Pseudoalteromonas luteoviolacea indolmycin pathway. Our work, combining X-ray crystallographic, biochemical, spectroscopic, and computational studies, supports a shared mechanism with arginine hydroxylases, involving two rounds of single-electron transfer to oxygen and superoxide rebound at the 4' carbon of the PLP cofactor. The precise positioning of a water molecule in the active site is proposed to control the final reaction outcome. This proposed mechanism provides a unified framework to understand how oxygen can be activated by PLP-dependent enzymes for oxidation of arginine and elucidates a shared mechanistic pathway and intertwined evolutionary history for arginine desaturases and hydroxylases

Elevated Mitochondrial Oxidative Stress Impairs Metabolic Adaptations to Exercise in Skeletal Muscle

<div><p>Mitochondrial oxidative stress is a complex phenomenon that is inherently tied to energy provision and is implicated in many metabolic disorders. Exercise training increases mitochondrial oxidative capacity in skeletal muscle yet it remains unclear if oxidative stress plays a role in regulating these adaptations. We demonstrate that the chronic elevation in mitochondrial oxidative stress present in <i>Sod2</i>^<i>+/-</i> mice impairs the functional and biochemical mitochondrial adaptations to exercise. Following exercise training <i>Sod2</i>^<i>+/-</i> mice fail to increase maximal work capacity, mitochondrial enzyme activity and mtDNA copy number, despite a normal augmentation of mitochondrial proteins. Additionally, exercised <i>Sod2</i>^<i>+/-</i> mice cannot compensate for their higher amount of basal mitochondrial oxidative damage and exhibit poor electron transport chain complex assembly that accounts for their compromised adaptation. Overall, these results demonstrate that chronic skeletal muscle mitochondrial oxidative stress does not impact exercise induced mitochondrial biogenesis, but impairs the resulting mitochondrial protein function and can limit metabolic plasticity.</p> </div

Exercise‐stimulated interleukin‐15 is controlled by AMPK

Aging is commonly associated with a structural deterioration of skin that compromises its barrier function, healing, and susceptibility to disease. Several lines of evidence show that these changes are driven largely by impaired tissue mitochondrial metabolism. While exercise is associated with numerous health benefits, there is no evidence that it affects skin tissue or that endocrine muscle-to-skin signaling occurs. We demonstrate that endurance exercise attenuates age-associated changes to skin in humans and mice and identify exercise-induced IL-15 as a novel regulator of mitochondrial function in aging skin. We show that exercise controls IL-15 expression in part through skeletal muscle AMP-activated protein kinase (AMPK), a central regulator of metabolism, and that the elimination of muscle AMPK causes a deterioration of skin structure. Finally, we establish that daily IL-15 therapy mimics some of the anti-aging effects of exercise on muscle and skin in mice. Thus, we elucidate a mechanism by which exercise confers health benefits to skin and suggest that low-dose IL-15 therapy may prove to be a beneficial strategy to attenuate skin aging

Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging

Aging is commonly associated with a structural deterioration of skin that compromises its barrier function, healing, and susceptibility to disease. Several lines of evidence show that these changes are driven largely by impaired tissue mitochondrial metabolism. While exercise is associated with numerous health benefits, there is no evidence that it affects skin tissue or that endocrine muscle-to-skin signaling occurs. We demonstrate that endurance exercise attenuates age-associated changes to skin in humans and mice and identify exercise-induced IL-15 as a novel regulator of mitochondrial function in aging skin. We show that exercise controls IL-15 expression in part through skeletal muscle AMP-activated protein kinase ( AMPK) , a central regulator of metabolism, and that the elimination of muscle AMPK causes a deterioration of skin structure. Finally, we establish that daily IL-15 therapy mimics some of the anti-aging effects of exercise on muscle and skin in mice. Thus, we elucidate a mechanism by which exercise confers health benefits to skin and suggest that low-dose IL-15 therapy may prove to be a beneficial strategy to attenuate skin aging

Mitochondrial complex assembly worsens in <i>Sod2</i>^<i>+/-</i> mice subjected to exercise.

<p>Lauryl-maltoside solubilized mitochondria were separated using two-dimensional Blue-Native PAGE in order to visualize native migration of each of four electron transport chain complexes. A lack of intermediate species in assembling the native complex is visualized as a shorter horizontal migration, while unassembled complexes are evident as tails or very broad bands. Note the divergent response to exercise between the two genotypes. Samples were run simultaneously on the same native gel. Image frames are identically sized for each complex and were acquired from the same film exposure. This experiment was repeated twice using different samples from each of the four groups in order to confirm that this was a reproducible observation.</p

Elevated mitochondrial oxidative stress impairs the improvement in work capacity resulting from exercise training.

<p>Mice were tested for exercise capacity on a treadmill at a 10-degree angle after 4 months of exercise training or remaining sedentary as stated in the Materials and Methods. (A) Total distance run, (B) VO_2max, and (C) total work performed during an exercise test to exhaustion. (For resting data regarding body weight, VO₂, VCO₂, food intake and ambulatory activity see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081879#pone.0081879.s001" target="_blank">Figure S1</a>). Data are mean±SE. <i>n</i> = 7-8. *Indicates a significant difference (<i>p</i> < 0.05) from the indicated group as determined by ANOVA. ^{<b><i>#</i></b>}Indicates a main effect of exercise training. </p

Mitochondrial function is compromised with exercise training in <i>Sod2</i>^<i>+/-</i> mice without influencing organelle biogenesis.

<p>Total protein lysates of tibialis anterior muscle were probed by immunoblotting for individual complex subunits (I: NDUFB8, II: SDHB, III: UQCRC2, IV: COXI, V: ATP5A) or assayed for enzyme activity. (A) The protein expression of mitochondrial proteins determined by densitometry relative to LDHA, (B) representative immunoblots of mitochondrial proteins and (C) enzyme activities of citrate synthase (CS), complex I+III, and complex IV (CIV) per unit of protein (<i>n</i> = 8-10). Data are expressed relative to the Sod2^+/+ SED group. Mitochondrial respiration rates in saponin permeabilized muscle fibers from quadriceps femoris muscle using (D) glutamate and malate without adenylates to indicate a respiratory leak state, (E) glutamate, malate, succinate and ADP to measure maximal coupled oxidative phosphorylation capacity and (F) respiratory coupling ratio of ADP stimulated and non-stimulated respiration using glutamate and malate as substrates (<i>n</i> = 4-5). (G) UCP3 and (H) ANT1 protein expression in isolated mitochondrial lysates from quadriceps femoris muscle relative to VDAC and (I) representative immunoblots for each group (<i>n</i> = 8-10). All data are mean±SE. *Indicates a significant difference (<i>p</i> < 0.05) from the indicated group as determined by 2-way ANOVA. <b><i>#</i></b>Indicates a main effect of exercise training (<i>p</i> < 0.05). <b><i>^†</i></b>Indicates a main effect of genotype (<i>p</i> < 0.05). NS, non-significant.</p