Effect of 2,3-butanedione on human myeloperoxidase

1. Myeloperoxidase is inhibited by various diketones that are recognized arginine reagents. 2. Although arginine residues in the enzyme were modified in both the light and the dark, enzyme inactivation occurred only in the presence of light. 3. Under conditions where diketones caused inactivation of myeloperoxidase, spectral studies indicated marked damage to the haem residues of the enzyme. 4. It was concluded that diketones serve simply as photosensitizers of visible light-induced inactivation of myeloperoxidase. 5. Studies on other haemoproteins indicated the great ease with which the presence of diketones sensitized haem residues for photodestruction.     

Heteroplasmic mitochondrial DNA variants in cardiovascular diseases

Mitochondria are implicated in the pathogenesis of cardiovascular diseases (CVDs) but the reasons for this are not well understood. Maternally-inherited population variants of mitochondrial DNA (mtDNA) which affect all mtDNA molecules (homoplasmic) are associated with cardiometabolic traits and the risk of developing cardiovascular disease. However, it is not known whether mtDNA mutations only affecting a proportion of mtDNA molecules (heteroplasmic) also play a role. To address this question, we performed a high-depth (~1000-fold) mtDNA sequencing of blood DNA in 1,399 individuals with hypertension (HTN), 1,946 with ischemic heart disease (IHD), 2,146 with ischemic stroke (IS), and 723 healthy controls. We show that the per individual burden of heteroplasmic single nucleotide variants (mtSNVs) increases with age. The age-effect was stronger for low-level heteroplasmies (heteroplasmic fraction, HF, 5–10%), likely reflecting acquired somatic events based on trinucleotide mutational signatures. After correcting for age and other confounders, intermediate heteroplasmies (HF 10–95%) were more common in hypertension, particularly involving non-synonymous variants altering the amino acid sequence of essential respiratory chain proteins. These findings raise the possibility that heteroplasmic mtSNVs play a role in the pathophysiology of hypertension.     

eQTL mapping using allele-specific count data is computationally feasible,powerful, and provides individual-specific estimates of genetic effects

Using information from allele-specific gene expression (ASE) can improve the power to map gene expression quantitative trait loci (eQTLs). However, such practice has been limited, partly due to computational challenges and lack of clarification on the size of power gain or new findings besides improved power. We have developed geoP, a computationally efficient method to estimate permutation p-values, which makes it computationally feasible to perform eQTL mapping with ASE counts for large cohorts. We have applied geoP to map eQTLs in 28 human tissues using the data from the Genotype-Tissue Expression (GTEx) project. We demonstrate that using ASE data not only substantially improve the power to detect eQTLs, but also allow us to quantify individual-specific genetic effects, which can be used to study the variation of eQTL effect sizes with respect to other covariates. We also compared two popular methods for eQTL mapping with ASE: TReCASE and RASQUAL. TReCASE is ten times or more faster than RASQUAL and it provides more robust type I error control.     

NACOB presentation CSB New Investigator Award. Balance recovery from medio-lateral perturbations of the upper body during standing. North American Congress on Biomechanics.

Postural control strategies have in the past been predominantly characterized by kinematics, surface forces, and EMG responses (e.g. Horak and Nashner, 1986, Journal of Neurophysiology 55(6), 1369-1381). The goal of this study was to provide unique and novel insights into the underlying motor mechanisms used in postural control by determining the joint moments during balance recovery from medio-lateral (M/L) perturbations. Ten adult males received medio-lateral (M/L) pushes to the trunk or pelvis. The inverted pendulum model of balance control (Winter et al., 1998, Journal of Neurophysiology 80, 1211-1221) was validated even though the body did not behave as a single pendulum, indicating that the centre of pressure (COP) is the variable used to control the centre of mass (COM). The perturbation magnitude was random, and the central nervous system (CNS) responded with an estimate of the largest anticipated perturbation. The observed joint moments served to move the COP in the appropriate direction and to control the lateral collapse of the trunk. The individual joints involved in controlling the COP contributed differing amounts to the total recovery response: the hip and spinal moments provided the majority of the recovery (approximately 85%), while the ankles contributed a small, but significant amount (15%). The differing contributions are based on the anatomical constraints and the functional requirements of the balance task. The onset of the joint moment was synchronous with the joint angle change, and occurred too early (56-116 ms) to be result of active muscle contraction. Therefore, the first line of defense was provided by muscle stiffness, not reflex-activated muscle activity.     

A null mutation in the inflammation-associated S100 protein S100A8 causes early resorption of the mouse embryo.

S100A8 (also known as CP10 or MRP8) was the first member of the S100 family of calcium-binding proteins shown to be chemotactic for myeloid cells. The gene is expressed together with its dimerization partner S100A9 during myelopoiesis in the fetal liver and in adult bone marrow as well as in mature granulocytes. In this paper we show that S100A8 mRNA is expressed without S100A9 mRNA between 6.5 and 8. 5 days postcoitum within fetal cells infiltrating the deciduum in the vicinity of the ectoplacental cone. Targeted disruption of the S100A8 gene caused rapid and synchronous embryo resorption by day 9. 5 of development in 100% of homozygous null embryos. Until this point there was no evidence of developmental delay in S100A8-/- embryos and decidualization was normal. The results of PCR genotyping around 7.5-8.5 days postcoitum suggest that the null embryos are infiltrated with maternal cells before overt signs of resorption. This work is the first evidence for nonredundant function of a member of the S100 gene family and implies a role in prevention of maternal rejection of the implanting embryo. The S100A8 null provides a new model for studying fetal-maternal interactions during implantation.     

Implications of grazing and burning of grasslands on the sustainable use of francolins (Francolinus spp.) and on overall bird conservation in the highlands of Mpumalanga province, South Africa

We investigated the densities of the Redwing Francolinus levaillantii and Greywing Francolins F. africanus and the diversity of grassland birds in general along a land-use gradient in the highlands of Mpumalanga province, South Africa. Redwing Francolins cannot tolerate intensive grazing and frequent burning and are confined largely to unburnt, ungrazed grasslands. Their density and the species richness of grassland birds in general are negatively correlated with grazing intensity. Redwing populations drop to densities that cannot be utilised by hunters on a sustainable basis in grasslands that are grazed at even moderate levels or burned annually. Nineteen bird species (including five threatened species) were confined to essentially pristine grassland and were never observed in grazed/annually burned grasslands. The Greywing Francolin is more evenly distributed (although always at sub-utilisation densities) along the grassland land-use gradient, and its density is positively correlated with grazing intensity. There are two assemblages of grassland bird species that appear to be indicative of the intensity of habitat utilisation. Populations of grassland birds in the study area are becoming increasingly dependent on isolated patches of pristine grassland and are threatened by management involving annual burning and high stocking rates on a landscape scale.     

Two Palaeozoic Hydrothermal Vent Communities from the Southern Ural Mountains, Russia

The Sibay and Yaman Kasy massive sulphide deposits contain macrofossil assemblages that represent some of the oldest known hydrothermal vent communities. The deposits are hosted respectively by Middle Devonian and Silurian arc-related volcanic rocks in the Ural Mountains of Russia, and formed under the same environmental constraints as modern vent sulphides. The Sibay palaeocommunity comprises, in order of decreasing abundance, tubes of an indeterminate ?annelid and the vestimentiferan Tevidestus serrriformis Shpanskaya, Maslennikov and Little and articulated specimens of the modiomorphid bivalve Sibaya ivanovi gen. et sp. nov. The Yaman Kasy palaeocommunity comprises, in order of decreasing abundance, tubes of the ?polychaete Eoalvinellodes annulatus gen. et sp. nov. and the vestimentiferan Yamankasia rifeia Shpanskaya, Maslennikov and Little, and specimens of the ?kirengellid tergomyan Themoconus shadlunae gen. et sp. nov., the lingulate brachiopod Pyrodiscus lorrainae gen. et sp. nov., an indeterminate vetigastropod, and the ambonychiid bivalve Mytilarca sp. Some of these taxa have affinities to endemic taxa at modern hydrothermal vent sites and some belong to taxa that are typical of Palaeozoic non-vent marine palaeocommunities. Therefore, there has been movement of taxonomic groups in and out of the vent ecosystem through the Phanerozoic.     

Identification of chicken and C. elegans fibulin-1 homologs and characterization of the C. elegans fibulin-1 gene

Fibulin-1, a member of the emerging family of fibulin proteins, is a component of elastic extracellular matrix fibers, basement membranes and blood. Homologs of fibulin-1 have been described in man, mouse and zebrafish. In this study, we describe the isolation and sequencing of chicken fibulin-1C and D cDNA variants. We also describe identification of a C. elegans cDNA encoding fibulin-1D and cosmids containing the C. elegans fibulin-1 gene. Using the cDNA, RT-PCR and computer-based analysis of genomic sequences, the exon/intron organization of the C. elegans fibulin-1 gene was determined. The C. elegans fibulin-1 gene is located on chromosome IV, is approximately 6 kb in length, contains 16 exons and encodes fibulin-1C and D variants. Comparative analysis of the deduced amino acid sequences of nematode and chicken fibulin-1 variants with other known vertebrate fibulin-1 polypeptides showed that the number and organization of structural modules are identical. The results of this study indicate that the structure of the fibulin-1 protein has remained highly conserved over a large period of evolution, suggestive of functional conservation.     

What brain signals are suitable for feedback controzl of deep brain stimulation in Parkinson's disease?

Feedback control of deep brain stimulation (DBS) in Parkinson's disease has great potential to improve efficacy, reduce side effects, and decrease the cost of treatment. In this, the timing and intensity of stimulation are titrated according to biomarkers that capture current clinical state. Stimulation may be at standard high frequency or intelligently patterned to directly modify specific pathological rhythms. The search for and validation of appropriate feedback signals are therefore crucial. Signals recorded from the DBS electrode currently appear to be the most promising source of feedback. In particular, beta-frequency band oscillations in the local field potential recorded at the stimulation target may capture variation in bradykinesia and rigidity across patients, but this remains to be confirmed within patients. Biomarkers that reliably reflect other impairments, such as tremor, also need to be established. Finally, whether brain signals are causally important needs to be established before stimulation can be specifically patterned rather than delivered at empirically defined high frequency.     

Spatial gene expression in the T-stage mouse metanephros

The E11.5 mouse metanephros is comprised of a T-stage ureteric epithelial tubule sub-divided into tip and trunk cells surrounded by metanephric mesenchyme (MM). Tip cells are induced to undergo branching morphogenesis by the MM. In contrast, signals within the mesenchyme surrounding the trunk prevent ectopic branching of this region. In order to identify novel genes involved in the molecular regulation of branching morphogenesis we compared the gene expression profiles of isolated tip, trunk and MM cells using Compugen mouse long oligo microarrays. We identified genes enriched in the tip epithelium, sim-1, Arg2, Tacstd1, Crlf-1 and BMP7; genes enriched in the trunk epithelium, Innp1, Itm2b, Mkrn1, SPARC, Emu2 and Gsta3 and genes spatially restricted to the mesenchyme surrounding the trunk, CSPG2 and CV-2, with overlapping and complimentary expression to BMP4, respectively. This study has identified genes spatially expressed in regions of the developing kidney involved in branching morphogenesis, nephrogenesis and the development of the collecting duct system, calyces, renal pelvis and ureter.