The HOX-5 and surfeit gene clusters are linked in the proximal portion of mouse chromosome 2

Using an interspecies backcross, we have mapped the HOX-5 and surfeit (surf) gene clusters within the proximal portion of mouse chromosome 2. While the HOX-5 cluster of homeobox-containing genes has been localized to chromosome 2, bands C3-E1, by in situ hybridization, its more precise position relative to the genes and cloned markers of chromosome 2 was not known. Surfeit, a tight cluster of at least six highly conserved “housekeeping” genes, has not been previously mapped in mouse, but has been localized to human chromosome 9q, a region of the human genome with strong homology to proximal mouse chromosome 2. The data presented here place HOX-5 in the vicinity of the closely linked set of developmental mutations rachiterata, lethargic, and fidget and place surf close to the proto-oncogene Abl, near the centromere of chromosome 2.     

Oncosecretomics coupled to bioenergetics identifies α-amino adipic acid, isoleucine and GABA as potential biomarkers of cancer: Differential expression of c-Myc, Oct1 and KLF4 coordinates metabolic changes

Bioenergetic profiling of tumors is a new challenge of cancer research and medicine as therapies are currently being developed. Meanwhile, methodological means must be proposed to gather information on tumor metabolism in order to adapt these potential therapies to the bioenergetic specificities of tumors. Studies performed on tumors and cancer cell lines have shown that cancer cells bioenergetics is highly variable. This profile changes with microenvironmental conditions (eg. substrate availability), the oncogenes activated (and the tumor suppressors inactivated) and the interaction with the stroma (i.e. reverse Warburg effect). Here, we assessed the power of metabolic footprinting (MFP) to unravel the bioenergetics and associated anabolic changes induced by three oncogenes, c-Myc, KLF4 and Oct1. The MFP approach provides a quantitative analysis of the metabolites secreted and consumed by cancer cells. We used ultra performance liquid chromatography for quantifying the amino acid uptake and secretion. To investigate the potential oncogene-mediated alterations in mitochondrial metabolism, we measured oxygen consumption rate and ATP production as well as the glucose uptake and lactate release. Our findings show that c-Myc deficiency initiates the Warburg effect along with a reduction of mitochondrial respiration. KLF4 deficiency also stimulated glycolysis, albeit without cellular respiration impairment. In contrast, Oct1 deficiency reduced glycolysis and enhanced oxidative phosphorylation efficiency. MFP revealed that c-Myc, KLF4 and Oct1 altered amino acid metabolism with specific patterns. We identified isoleucine, α-aminoadipic acid and GABA (γ-aminoisobutyric acid) as biomarkers related. Our findings establish the impact of Oct1, KLF4 and c-Myc on cancer bioenergetics and evidence a link between oncosecretomics and cellular bioenergetics profile.     

Migrant shorebird use of Akimiski Island, Nunavut: a sub-arctic staging site

Determining the importance of stopover and staging areas to migrating shorebirds (Aves: Charadriiformes) is essential if such habitats are to be successfully protected. Migration chronology, species composition, length of stay, body condition, and estimated total abundance of shorebirds during spring and fall migratory periods of 2008 and 2009 were documented on Akimiski Island, Nunavut, Canada. Fourteen shorebird species were observed during spring point counts and 18 during fall. Semipalmated (Calidris pusilla) and White-rumped (C. fuscicollis) Sandpipers comprised about 80?% of all individuals observed. A greater number of species and individuals were observed during fall than spring in both years. Radio-transmitters attached to juvenile Semipalmated and Least (C. minutilla) Sandpipers indicated highly variable lengths of stay ranging up to 26?days in both species (Semipalmated Sandpiper averaged 6.5?±?2.67?days, n?=?12; Least Sandpipers averaged 7.25?±?3.79?days, n?=?8). In 2009, Semipalmated Sandpipers captured and weighed later in the season were significantly heavier than those captured earlier suggesting that this species is refueling while on Akimiski Island. A fall migration seasonal density of 5,267 (2,193–8,341) shorebirds/km² was estimated given a residence probability (i.e., the probability of an individual being present in consecutive counts) of 0.906?±?0.181. Assuming similar habitat value and shorebird density, an extrapolation of the seasonal plot density of 5,267 birds/km² to the total 192?km² mudflat habitat on Akimiski Island yields an estimate of 1,011,264 (421,098–1,601,429) shorebirds during fall migration, making Akimiski Island of Hemispheric importance as a staging site for migrant arctic-breeding shorebirds.     

KLOTHO allele status and the risk of early-onset occult coronary artery disease

We previously identified a functional variant of KLOTHO (termed "KL-VS"), which harbors two amino acid substitutions in complete linkage disequilibrium and is associated with reduced human longevity when in homozygosity. Klotho-deficient mice display extensive arteriosclerosis when fed a normal diet, suggesting a potent genetic predisposition. To determine whether klotho influences atherosclerotic risk in humans, we performed cross-sectional studies to assess the association between the KL-VS allele and occult coronary artery disease (CAD) in two independent samples of apparently healthy siblings of individuals with early-onset (age <60 years) CAD (SIBS-I [N=520] and SIBS-II [N=436]). Occult CAD was defined as the occurrence of a reversible perfusion defect during exercise thallium scintigraphy and/or as an abnormal result of an exercise electrocardiogram (SIBS-I, n=97; SIBS-II, n=56). In SIBS-I, the KL-VS allele conferred a relative odds of 1.90 (95% confidence interval 1.21-2.98) for occult CAD, after adjusting for familial intraclass correlations (P<.005). Logistic regression modeling, incorporating known CAD risk factors, demonstrated that the KL-VS allele is an independent risk factor (P<.019) and that the imposed risk of KL-VS allele status is influenced by modifiable risk factors. Hypertension (P<.022) and increasing high-density lipoprotein cholesterol (HDL-C) levels (P<.022) mask or reduce the risk conferred by the KL-VS allele, respectively, whereas current smoking (P<.004) increases the risk. Remarkably concordant effects of the KL-VS allele and modifying factors on the risk of occult CAD were seen in SIBS-II. These results demonstrate that the KL-VS allele is an independent risk factor for occult CAD in two independent high-risk samples. Modifiable risk factors, including hypertension, smoking status, and HDL-C level, appear to influence the risk imposed by this allele.     

Carbon isotope evidence for recent climate‐related enhancement of CO 2 assimilation and peat accumulation rates in Antarctica

Signy Island, maritime Antarctic, lies within the region of the Southern Hemisphere that is currently experiencing the most rapid rates of environmental change. In this study, peat cores up to 2 m in depth from four moss banks on Signy Island were used to reconstruct changes in moss growth and climatic characteristics over the late Holocene. Measurements included radiocarbon dating (to determine peat accumulation rates) and stable carbon isotope composition of moss cellulose (to estimate photosynthetic limitation by CO ₂ supply and model CO ₂ assimilation rate). For at least one intensively ¹⁴C‐dated Chorisodontium aciphyllum moss peat bank, the vertical accumulation rate of peat was 3.9 mm yr^?1 over the last 30 years. Before the industrial revolution, rates of peat accumulation in all cores were much lower, at around 0.6–1 mm yr^?1. Carbon‐13 discrimination (Δ), corrected for background and anthropogenic source inputs, was used to develop a predictive model for CO ₂ assimilation. Between 1680 and 1900, there had been a gradual increase in Δ, and hence assimilation rate. Since 1800, assimilation has also been stimulated by the changes in atmospheric CO ₂ concentration, but a recent decline in Δ (over the past 50–100 years) can perhaps be attributed to documented changes in temperature and/or precipitation. The overall increase in CO ₂ assimilation rate (¹³C proxy) and enhanced C accumulation (¹⁴C proxy) are consistent with warmer and wetter conditions currently generating higher growth rates than at any time in the past three millennia, with the decline in Δ perhaps compensated by a longer growing season.     

Cerebral artery reactivity changes during pregnancy and the postpartum period: a role in eclampsia?

Eclampsia is thought to be similar to hypertensive encephalopathy, whereby acute elevations in intravascular pressure cause forced dilatation (FD) of intrinsic myogenic tone of cerebral arteries and arterioles, decreased cerebrovascular resistance, and hyperperfusion. In the present study, we tested the hypothesis that pregnancy and/or the postpartum period predispose cerebral arteries to FD by diminishing pressure-induced myogenic activity. We compared the reactivity to pressure (myogenic activity) as well as factors that modulate the level of tone of third-order branches (<200 microm) of the posterior cerebral artery (PCA) that were isolated from nonpregnant (NP, n = 7), late-pregnant (LP, 19 days, n = 10), and postpartum (PP, 3 days, n = 8) Sprague-Dawley rats under pressurized conditions. PCAs from all groups of animals developed spontaneous tone within the myogenic pressure range (50-150 mmHg) and constricted arteries at 100 mmHg (NP, 30 +/- 3; LP, 39 +/- 4; and PP, 42 +/- 7%; P > 0.05). This level of myogenic activity was maintained in the NP arteries at all pressures; however, both LP and PP arteries dilated at considerably lower pressures compared with NP, which lowered the pressure at which FD occurred from >175 for NP to 146 +/- 6.5 mmHg for LP (P < 0.01 vs. NP) and 162 +/- 7.7 mmHg for PP (P < 0.01 vs. NP). The amount of myogenic tone was also significantly diminished at 175 mmHg compared with NP: percent tone for NP, LP, and PP animals were 35 +/- 2, 11 +/- 3 (P < 0.01 vs. NP), and 20 +/- 7% (P < 0.01 vs. NP), respectively. Inhibition of nitric oxide (NO) with 0.1 mM N(omega)-nitro-l-arginine (l-NNA) caused constriction of all vessel types that was significantly increased in the PP arteries, which demonstrates significant basal NO production. Reactivity to 5-hydroxytryptamine (serotonin) was assessed in the presence of l-NNA and indomethacin. There was a differential response to serotonin: PCAs from NP animals dilated, whereas LP and PP arteries constricted. These results suggest that both pregnancy and the postpartum period predispose the cerebral circulation to FD at lower pressures, a response that may lower cerebrovascular resistance and promote hyperperfusion when blood pressure is elevated, as occurs during eclampsia.     

Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with beta-amyloid deposits in Alzheimer's disease

Alzheimer's disease (AD) is characterized by the misfolding and plaque-like accumulation of a naturally occurring peptide in the brain called amyloid beta (Abeta). Recently, this process has been associated with the binding of metal ions such as iron (Fe), copper (Cu), and zinc (Zn). It is thought that metal dyshomeostasis is involved in protein misfolding and may lead to oxidative stress and neuronal damage. However, the exact role of the misfolded proteins and metal ions in the degenerative process of AD is not yet clear. In this study, we used synchrotron Fourier transform infrared micro-spectroscopy (FTIRM) to image the in situ secondary structure of the amyloid plaques in brain tissue of AD patients. These results were spatially correlated with metal ion accumulation in the same tissue sample using synchrotron X-ray fluorescence (SXRF) microprobe. For both techniques, a spatial resolution of 5-10 microm was achieved. FTIRM results showed that the amyloid plaques have elevated beta-sheet content, as demonstrated by a strong amide I absorbance at 1625cm(-1). Using SXRF microprobe, we find that AD tissue also contains "hot spots" of accumulated metal ions, specifically Cu and Zn, with a strong spatial correlation between these two ions. The "hot spots" of accumulated Zn and Cu were co-localized with beta-amyloid plaques. Thus for the first time, a strong spatial correlation has been observed between elevated beta-sheet content in Abeta plaques and accumulated Cu and Zn ions, emphasizing an association of metal ions with amyloid formation in AD.