A genomewide admixture mapping panel for Hispanic/Latino populations

Admixture mapping (AM) is a promising method for the identification of genetic risk factors for complex traits and diseases showing prevalence differences among populations. Efficient application of this method requires the use of a genomewide panel of ancestry-informative markers (AIMs) to infer the population of origin of chromosomal regions in admixed individuals. Genomewide AM panels with markers showing high frequency differences between West African and European populations are already available for disease-gene discovery in African Americans. However, no such a map is yet available for Hispanic/Latino populations, which are the result of two-way admixture between Native American and European populations or of three-way admixture of Native American, European, and West African populations. Here, we report a genomewide AM panel with 2,120 AIMs showing high frequency differences between Native American and European populations. The average intermarker genetic distance is ~1.7 cM. The panel was identified by genotyping, with the Affymetrix GeneChip Human Mapping 500K array, a population sample with European ancestry, a Mesoamerican sample comprising Maya and Nahua from Mexico, and a South American sample comprising Aymara/Quechua from Bolivia and Quechua from Peru. The main criteria for marker selection were both high information content for Native American/European ancestry (measured as the standardized variance of the allele frequencies, also known as "f value") and small frequency differences between the Mesoamerican and South American samples. This genomewide AM panel will make it possible to apply AM approaches in many admixed populations throughout the Americas.     

Identification of a mitochondrial alcohol dehydrogenase in Schizosaccharomyces pombe: new insights into energy metabolism

In the present study we have shown that mitochondria isolated from Schizosaccharomyces pombe exhibit antimycin A-sensitive oxygen uptake activity that is exclusively dependent on ethanol and is inhibited by trifluoroethanol, a potent inhibitor of ADH (alcohol dehydrogenase). Ethanol-dependent respiratory activity has, to our knowledge, not been reported in S. pombe mitochondria to date, which is surprising as it has been concluded previously that only one ADH gene, encoding a cytosolic enzyme, occurs in this yeast. Spectrophotometric enzyme assays reveal that ADH activity in isolated mitochondria is increased approximately 16-fold by Triton X-100, which demonstrates that the enzyme is located in the matrix. Using genetic knockouts, we show conclusively that the novel mitochondrial ADH is encoded by adh4 and, as such, is unrelated to ADH isoenzymes found in mitochondria of other yeasts. By performing a modular-kinetic analysis of mitochondrial electron transfer, we furthermore show how ethanol-dependent respiratory activity (which involves oxidation of matrix-located NADH) compares with that observed when succinate or externally added NADH are used as substrates. This analysis reveals distinct kinetic differences between substrates which fully explain the lack of respiratory control generally observed during ethanol oxidation in yeast mitochondria.     

Identification of a novel targeting sequence for regulated secretion in the serine protease inhibitor neuroserpin

Ns (neuroserpin) is a member of the serpin (serine protease inhibitor) gene family that is primarily expressed within the central nervous system. Its principal target protease is tPA (tissue plasminogen activator), which is thought to contribute to synaptic plasticity and to be secreted in a stimulus-dependent manner. In the present study, we demonstrate in primary neuronal cultures that Ns co-localizes in LDCVs (large dense core vesicles) with the regulated secretory protein chromogranin B. We also show that Ns secretion is regulated and can be specifically induced 4-fold by secretagogue treatment. A novel 13-amino-acid sorting signal located at the C-terminus of Ns is identified that is both necessary and sufficient to target Ns to the regulated secretion pathway. Its deletion renders Ns no longer responsive to secretagogue stimulation, whereas PAI-Ns [Ns (neuroserpin)-PAI-1 (plasminogen activator inhibitor-1) chimaera appending the last 13 residues of Ns sequence to the C-terminus of PAI-1] shifts PAI-1 secretion into a regulated secretory pathway.     

Trisomy 17 in a baboon (Papio hamadryas) with polydactyly, patent foramen ovale and pyelectasis

Trisomy 13 in humans is the third most common autosomal abnormality at birth, after trisomy 21 and trisomy 18. It has a reported incidence of between 1:5,000 and 1:30,000 live births. It is associated with multiple abnormalities, many of which shorten lifespan. We describe here the first reported case of a baboon (Papio hamadryas) with trisomy of chromosome 17, which is homologous to human chromosome 13. The trisomic infant was born to a consanguineous pair of baboons and had morphological characteristics similar to those observed in human trisomy 13, including bilateral polydactyly in the upper limbs, a patent foramen ovale, and pyelectasis. Molecular DNA analysis using human chromosome 13 markers was consistent with the affected infant inheriting two copies of chromosome 17 derived from the same parental chromosome. This trisomy was, therefore, due to either an error in meiosis II or the result of postzygotic nondisjunction. The parental origin, however, could not be determined.     

Blastomycosis in indoor cats: Suburban Chicago, Illinois, USA

Blastomyces dermatitidis, the etiologic agent of blastomycosis, a potentially life-threatening systemic mycosis of humans and animals, is acquired from a yet incompletely defined environmental niche. There is controversy regarding the potential for contact with the fungus in or near one’s home, particularly in urban areas. We investigated an outbreak of blastomycosis among five urban, indoor cats diagnosed at three veterinary clinics March 3–July 13, 2005, in suburban Chicago, Illinois, by owner interviews, site visits, environmental cultures for B. dermatitidis, GIS analysis, and analysis of local weather data. There were no environmental exposures common to the five cats that lived a median of 300 m from nearest body of water, in homes on a loam soil. Closest and farthest case home sites were 3.4 and 26.1 km, respectively. All cats were confined indoors except one cat that averaged 15 min/week in his backyard and was exposed to excavation. B. dermatitidis was not isolated from any of 60 environmental samples. The annualized incidence rate March through July 2005 among 6,761 cats in these practices was 178/100,000, compared to none in the previous 4 years, and 0.14/100,000 cat visits from a nationwide animal hospital registry. Precipitation January through June 2005 was 9.30 versus period mean of 14.05 ± 1.69 inches the previous 4 years (P = 0.01). Circumstantial evidence suggests acquisition of B. dermatitidis from the home site environment in five cats. Relative drought may have contributed to an apparent outbreak of blastomycosis in this urban locale.     

Germ-line DNA copy number variation frequencies in a large North American population

Genomic copy number variation (CNV) is a recently identified form of global genetic variation in the human genome. The Affymetrix GeneChip 100 and 500 K SNP genotyping platforms were used to perform a large-scale population-based study of CNV frequency. We constructed a genomic map of 578 CNV regions, covering approximately 220 Mb (7.3%) of the human genome, identifying 183 previously unknown intervals. Copy number changes were observed to occur infrequently (<1%) in the majority (>93%) of these genomic regions, but encompass hundreds of genes and disease loci. This North American population-based map will be a useful resource for future genetic studies. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis

Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum -induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.     

Chronic sodium hydrosulfide treatment decreases medial thickening of intramyocardial coronary arterioles, interstitial fibrosis, and ROS production in spontaneously hypertensive rats

Hydrogen sulfide (H(2)S) is a gasotransmitter that regulates cardiovascular functions. The present study aimed to examine the hypothesis that chronic treatment with sodium hydrosulfide (NaHS, an H(2)S donor) is able to prevent left-ventricular remodeling in spontaneously hypertensive rats (SHR). Four-week-old SHR were treated with NaHS (10, 30, and 90 micromol x kg(-1) x day(-1)), a combination of NaHS (30 micromol x kg(-1) x day(-1)) and glibenclamide (5 mg x kg(-1) x day(-1)), glibenclamide alone (5 mg x kg(-1) x day(-1)), hydralazine alone (10 mg x kg(-1) x day(-1)), and placebo for 3 mo. At the end of the treatment period, variables such as cardiac geometry and function, intramyocardial arterioles ranging in diameter from 25 to 100 microm, perivascular and interstitial collagen content, reactive oxygen species (ROS), thiol groups, conjugated dienes, and DNA base modification were examined. The novel finding of the present study is that chronic NaHS treatment prevented the hypertrophy of intramyocardial arterioles and ventricular fibrosis, as well as decreased myocardial ROS and conjugated diene levels. The cardioprotective effects were blunted by coadministration of glibenclamide, suggesting a role of ATP-sensitive potassium channels in mediating the action of NaHS. Hydralazine caused a comparable reduction of blood pressure compared with NaHS treatment; however, it exerted no effect on the remodeling process or on ROS and conjugated diene levels. Moreover, NaHS treatment caused an increase in myocardial thiol group levels, whereas DNA base modification was not altered by NaHS treatment. In conclusion, the superior cardioprotective effects of NaHS treatment are worthy to be further explored to develop novel therapeutic approaches for the treatment of cardiac remodeling in hypertension.     

Determinants of blood oxygenation during pregnancy in Andean and European residents of high altitude

High altitude decreases birth weight, but this effect is diminished in long vs. short-resident, high-altitude populations. We asked whether women from long vs. short-resident, high-altitude populations had higher arterial oxygenation levels by comparing 42 Andean and 26 European residents of La Paz, Bolivia (3,600 m), serially during pregnancy (weeks 20, 30, and 36) and again 4 mo postpartum. Pregnancy raised hypoxic ventilatory sensitivity threefold, resting ventilation (.Ve), and arterial O(2) saturation (Sa(O2)) in both groups. Ancestry, as identified using 81 genetic markers, correlated with respiratory pattern, such that greater Andean ancestry was associated with higher respiratory frequency and lower tidal volume. Pregnancy increased total blood and plasma volume approximately 40% in both groups without changing red blood cell mass relative to body weight; hence, hemoglobin fell. The hemoglobin decline was compensated for by the rise in .Ve and Sa(O2) with the result that arterial O2 content (Ca(O2)) was maintained near nonpregnant levels in both groups. Birth weights were similar for all Andean and European babies, but after adjusting for variation in gestational age, maternal height and parity, Andeans weighed 209 g more than Europeans. Babies with heavier birth weights and greater ponderal indices were born to Andean women with higher Ve during pregnancy. We concluded that while maternal .Ve and arterial oxygenation were important, some factor other than higher Ca(O2) was responsible for protecting Andeans from altitude-associated reductions in fetal growth.