The purpose of this investigation was to examine the validity of regulating exercise intensity using ratings of perceived exertion (RPEs) during arm crank and leg cycle exercise at 50 and 70% peak oxygen consumption (VO2peak). Ten men and seven women [26 (1) years old; mean (SE)] participated in this study. Each subject completed a maximal estimation trial and two submaximal exercise bouts (production trials) on both an arm and leg ergometer. During each maximal estimation trial, subjects were asked to give a RPE for each stage of the exercise. RPEs, heart rates (HR), and power outputs (PO) equivalent to 50 and 70% VO2peak for each exercise mode were then estimated from plots of RPE versus oxygen consumption (VO2), HR versus VO2, and PO versus VO2, respectively. During the submaximal trials, subjects were instructed to select workloads on an arm and leg ergometer that produced the previously estimated RPEs. Comparisons were made for VO2, HR, and PO between the estimation and production trials for each mode at each exercise intensity. HR did not differ between the trials at either 50 or 70% VO2peak during arm and leg ergometry. In addition, VO2 and PO did not differ between the trials at either 50 or 70% VO2peak during arm ergometry and at 50% VO2peak during leg ergometry. However, these two parameters were lower (P < 0.05) during the production trial [1.88 (0.15) l x min(-1) and 89.1 (10.1) W, respectively] as compared to the estimation trial [2.08(0.14) l x min(-1) and 102.4 (6.5)W, respectively] during leg ergometry at 70% VO2peak. In conclusion, using RPEs to regulate exercise intensity is physiologically valid during arm ergometry at both 50 and 70% VO2peak and during leg ergometry at 50% VO2peak. However, this prescriptive approach remains questionable during leg cycle exercise at 70% VO2peak.

Despite many efforts to develop hormone therapy and chemotherapy, no effective strategy to suppress prostate cancer metastasis has been established because the metastasis is not well understood. We here investigate a role of CBP/p300-interacting transactivator with E/D-rich carboxy-terminal domain-2 (CITED2) in prostate cancer metastasis. CITED2 is highly expressed in metastatic prostate cancer, and its expression is correlated with poor survival. The CITED2 gene is highly activated by ETS-related gene that is overexpressed due to chromosomal translocation. CITED2 acts as a molecular chaperone to guide PRMT5 and p300 to nucleolin, thereby activating nucleolin. Informatics and experimental data suggest that the CITED2–nucleolin axis is involved in prostate cancer metastasis. This axis stimulates cell migration through the epithelial–mesenchymal transition and promotes cancer metastasis in a xenograft mouse model. Our results suggest that CITED2 plays a metastasis-promoting role in prostate cancer and thus could be a target for preventing prostate cancer metastasis.

The prolyl hydroxlyases PHD1-3 and the asparaginly hydroxlyase FIH are oxygen sensors for HIF-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygendependent epigenetic regulation more broadly is not known. Here we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxiainduced cancer metastasis.

Harmful effects of high fructose intake on health have been widely reported. Although fructose is known to promote cancer, little is known about the underlying mechanisms. Here, we found that fructose triggers breast cancer metastasis through the ketohexokinase-A signaling pathway. Molecular experiments showed that ketohexokinase-A, rather than ketohexokinase-C, is necessary and sufficient for fructose-induced cell invasion. Ketohexokinase-A-overexpressing breast cancer was found to be highly metastatic in fructose-fed mice. Mechanistically, cytoplasmic ketohexokinase-A enters into the nucleus during fructose stimulation, which is mediated by LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and the YWHAH recruits SLUG to the CDH1 promoter, which triggers cell migration. This study provides the effect of nutrition on breast cancer metastasis. High intake of fructose should be restricted in cancer patients to reduce the risk of metastasis. From a therapeutic perspective, the ketohexokinase-A signaling pathway could be a potential target to prevent cancer metastasis.

No abstract

The aim of this study was to identify brain areas related to apathy or depression in patients with Alzheimer disease (AD). Eighty-one AD patients were enrolled in this prospective study. (99m)Tc-HMPAO single photon emission computed tomography was performed to evaluate regional cerebral blood flow (rCBF). According to the Neuropsychiatric Inventory subscores of apathy and depression, 9 patients were classified as clinically significant (cs) depressed and non-cs-apathetic (D+) groups and 9 were classified as cs-apathetic and non-cs-depressed (A+) groups. In addition, 18 patients were classified as age-matched and Mini-Mental State Examination-matched disease control groups (D-, A-). The significance of rCBF differences between groups and the correlation between rCBF and subscores in 81 AD patients were estimated by SPM (uncorrected P < 0.005) analysis. D+ patients had significantly lower perfusion in the right orbitofrontal and inferior frontal gyri than D- patients, whereas A+ patients had this in the right amygdala, temporal, posterior cingulate, right superior frontal, postcentral, and left superior temporal gyri than A- patients. The negatively correlated areas with depression subscores included the left inferior frontal and the right middle frontal gyri and those with apathy subscores included the right temporal and right medial frontal gyri. We suggest that this finding may indicate that apathy and depression in AD patients involve distinct functional circuits.

Herein, we demonstrate an engineered phage mediated matrix for osteogenic differentiation with controlled stiffness by cross-linking the engineered phage displaying Arg-Gly-Asp (RGD) and His-Pro-Gln (HPQ) with various concentrations of streptavidin or polymer, poly(diallyldimethylammonium)chloride (PDDA). Osteogenic gene expressions showed that they were specifically increased when MC3T3 cells were cultured on the stiffer phage matrix than the softer one. Our phage matrixes can be easily functionalized using chemical/genetic engineering and used as a stem cell tissue matrix stiffness platform for modulating differential cell expansion and differentiation.

The N-terminal acetyltransferase A (NatA) complex, which is composed of NAA10 and NAA15, catalyzes N-terminal acetylation of many proteins in a co-translational manner. Structurally, the catalytic subunit NAA10 was believed to have no activity toward an internal lysine residue because the gate of its catalytic pocket is too narrow. However, several studies have demonstrated that the monomeric NAA10 can acetylate the internal lysine residues of several substrates including hypoxia-inducible factor 1α (HIF-1α). How NAA10 acetylates lysine residues has been an unsolved question. We here found that human FIH (factor inhibiting HIF) hydroxylates human NAA10 at W38 oxygen-dependently and this permits NAA10 to express the lysyl-acetyltransferase activity. The hydroxylated W38 forms a new hydrogen-bond with A67 and widens the gate at the catalytic pocket, which allows the entrance of a lysine residue to the site. Since the FIH-dependent hydroxylation of NAA10 occurs oxygen-dependently, NAA10 acetylates HIF-1α under normoxia but does not under hypoxia. Consequently, the acetylation promotes the pVHL binding to HIF-1α, and in turn HIF-1α is destructed via the ubiquitin-proteasome system. This study provides a novel oxygen-sensing process that determines the substrate specificity of NAA10 depending on an ambient oxygen tension.