Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats

Folate is essential for the synthesis, repair and methylation of DNA. Folate depletion causes nuclear genetic and epigenetic aberrations in cell culture, rodents and humans. We hypothesized that folate depletion may also damage mitochondrial (Mt) DNA and induce large-scale deletions due to DNA breakage. MtDNA deletions and mutations accumulate during aging and tumorogenesis and may play causative roles in these processes. Weanling and adult (12 months) Sprague Dawley rats consumed folate deplete, replete and supplemented diets (0, 2 and 8 mg/kg folate, respectively) for 20 weeks. The presence of random and common (4.8 kb) MtDNA deletions was measured in colonic mucosa and liver. Six Mt genomes (<16 kb) harboring random deletions were detected in the liver (3.5-7.0 kb) and three in the colon (3.8-8 kb). Older rats had significantly more random hepatic MtDNA deletions than young rats (64 and 3.2% of samples, respectively, P < 0.0001), while age had no effect on these deletions in the colon (3.1 and 7.7% in young and old, respectively). Folate intake had no effect on the frequency of random deletions in either tissue. There was no discrete effect of aging on the common 4.8 kb deletion in the liver or colon. However, in the liver of old rats, increasing amounts of dietary folate reduced the deletion frequency, with replete and supplemented rats having 2.2- and 3.2-fold less deletions than the depleted rats. Our results confirm that random MtDNA deletions accumulate with age in a tissue-specific fashion. Furthermore, in contrast to previous work, we report that the common 4.8 kb deletion was not modulated by age, but is reduced by folate supplementation in the liver of rats.     

Disturbance frequency and community structure in a twenty-five year intervention study

Models of community regulation commonly incorporate gradients of disturbance inversely related to the role of biotic interactions in regulating intermediate trophic levels. Higher trophic-level organisms are predicted to be more strongly limited by intermediate levels of disturbance than are the organisms they consume. We used a manipulation of the frequency of hydrological disturbance in an intervention analysis to examine its effects on small-fish communities in the Everglades, USA. From 1978 to 2002, we monitored fishes at one long-hydroperiod (average 350 days) and at one short-hydroperiod (average 259 days; monitoring started here in 1985) site. At a third site, managers intervened in 1985 to diminish the frequency and duration of marsh drying. By the late 1990s, the successional dynamics of density and relative abundance at the intervention site converged on those of the long-hydroperiod site. Community change was manifested over 3 to 5 years following a dry-down if a site remained inundated; the number of days since the most recent drying event and length of the preceding dry period were useful for predicting population dynamics. Community dissimilarity was positively correlated with the time since last dry. Community dynamics resulted from change in the relative abundance of three groups of species linked by life-history responses to drought. Drought frequency and intensity covaried in response to hydrological manipulation at the landscape scale; community-level successional dynamics converged on a relatively small range of species compositions when drought return-time extended beyond 4 years. The density of small fishes increased with diminution of drought frequency, consistent with disturbance-limited community structure; less-frequent drying than experienced in this study (i.e., longer return times) yields predator-dominated regulation of small-fish communities in some parts of the Everglades. Electronic Supplementary Material Supplementary material is available for this article at     

Intersex inflorescences of Rumex acetosa demonstrate that sex determination is unique to each flower

* A triploid intersex individual of the normally dioecious species Rumex acetosa showed extreme variability in gynoecium development. Analysis of the development and distribution of these flowers on inflorescences enabled insight to be gained into the mechanism of sex determination. * Floral phenotypes on intersex inflorescences were classified according to gynoecium development. Flower morphology was investigated by scanning electron and light microscopy. Organ identity gene expression in intersex floral primordia was assessed using in situ hybridization. * The distribution of the different floral phenotypes shows that each individual flower is determined separately, and that the phenotype of each flower is not influenced by its position on the inflorescence, or by the phenotype of neighbouring flowers. C-function gene expression persisted in gynoecia that had ceased development. * Gynoecium development in mutant flowers resembled the phenotype of the Arabidopsis mutant ettin and suggests that a hormone gradient may be involved. C-function expression does not appear to control the extent of female development, and indicates that genes which are downstream of the organ-identity genes must control organ suppression.     

Prediction of cystine connectivity using SVM

One of the major contributors to protein structures is the formation of disulphide bonds between selected pairs of cysteines at oxidized state. Prediction of such disulphide bridges from sequence is challenging given that the possible combination of cysteine pairs as the number of cysteines increases in a protein. Here, we describe a SVM (support vector machine) model for the prediction of cystine connectivity in a protein sequence with and without a priori knowledge on their bonding state. We make use of a new encoding scheme based on physico-chemical properties and statistical features (probability of occurrence of each amino acid residue in different secondary structure states along with PSI-blast profiles). We evaluate our method in SPX (an extended dataset of SP39 (swiss-prot 39) and SP41 (swiss-prot 41) with known disulphide information from PDB) dataset and compare our results with the recursive neural network model described for the same dataset.     

United Nations system efforts to support the response to AIDS in China

In the last two years, we have seen a remarkable intensification in the response to AIDS in China. A number of organizations have joined and contributed to the efforts of the Chinese government in responding the AIDS epidemic in China. This article specifically describes the role of the United Nations (UN) in supporting and strengthening those responses. Achievements of the United Nations highlighted in the article include: strengthened leadership and political commitment to respond to AIDS; improved HIV/AIDS surveillance and information; expanded prevention efforts; improved treatment, care and support to people living with HIV and increased resources for AIDS programs. Additional roles of the United Nations system in the near future include strengthening national leadership by supporting the 'three ones', i.e., one national plan on AIDS; one national coordinating authority for AIDS; and one monitoring and evaluation system for AIDS. In addition, the UN system is expected to strengthen alignment and harmonization of activities of all international organizations and improved accountability and oversight. Remaining challenges identified include increasing awareness of AIDS and reducing stigma and discrimination; reducing vulnerability and risk behaviour among specific groups; providing improved treatment, care and support for people living with HIV; promoting stronger engagement by civil society, and; addressing the gender dimensions of AIDS.     

rhVEGF treatment preserves pulmonary vascular reactivity and structure in an experimental model of pulmonary hypertension in fetal sheep

We have previously shown that lung VEGF expression is decreased in a fetal lamb model of PPHN and that VEGF165 inhibition causes severe pulmonary hypertension in fetal lambs. Therefore, we hypothesized that treatment with rhVEGF165 would preserve endothelium-dependent vasodilation and reduce the severity of pulmonary vascular remodeling in an experimental model of PPHN. We studied the effects of daily intrapulmonary infusions of rhVEGF after partial ligation of the ductus arteriosus (DA). We performed surgery in 24 late-gestation fetal lambs and placed catheters in the main pulmonary artery, left atrium, and aorta for pressure measurements and in the left pulmonary artery for drug infusions. A pressure transducer was placed around the LPA to measure blood flow to the left lung (Qp), and the DA was surgically constricted to induce pulmonary hypertension. rhVEGF165 or vehicle was infused for 7 or 14 days. ACh or 8-BrcGMP was infused on days 2 and 13 to assess endothelium-dependent and -independent vasodilation, respectively. ACh-induced vasodilation was reduced in PPHN lambs after 14 days (change in Qp from baseline, 106% vs. 11%). In contrast, the response to ACh was preserved in lambs treated with rhVEGF (change in Qp, 94% vs. 90%). Pulmonary vasodilation to 8-BrcGMP was not altered in PPHN lambs or enhanced by VEGF treatment. rhVEGF treatment increased expression of lung eNOS protein and decreased pulmonary artery wall thickness by 34% vs. PPHN lambs. We conclude that VEGF165 preserves endothelium-dependent vasodilation, upregulates eNOS expression, and reduces the severity of pulmonary vascular remodeling in experimental PPHN.     

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation

Mechanisms that maintain high pulmonary vascular resistance (PVR) and oppose vasodilation in the fetal lung are poorly understood. In fetal lambs, increased pulmonary artery pressure evokes a potent vasoconstriction, suggesting that a myogenic response contributes to high PVR in the fetus. In adult systemic circulations, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been shown to modulate the myogenic response, but its role in the fetal lung is unknown. We hypothesized that acute increases in pulmonary artery pressure release 20-HETE, which causes vasoconstriction, or a myogenic response, in the fetal lung. To address this hypothesis, we studied the hemodynamic effects of N-methylsufonyl-12,12-dibromododec-11-enamide (DDMS), a specific inhibitor of 20-HETE production, on the pulmonary vasoconstriction caused by acute compression of the ductus arteriosus (DA) in chronically prepared fetal sheep. An inflatable vascular occluder around the DA was used to increase pulmonary artery pressure under three study conditions: control, after pretreatment with nitro-L-arginine (L-NA; to inhibit shear-stress vasodilation), and after combined treatment with both L-NA and a specific 20-HETE inhibitor, DDMS. We found that DA compression after L-NA treatment increased PVR by 44 +/- 12%. Although intrapulmonary DDMS infusion did not affect basal PVR, DDMS completely abolished the vasoconstrictor response to DA compression in the presence of L-NA (44 +/- 12% vs. 2 +/- 4% change in PVR, L-NA vs. L-NA + DDMS, P < 0.05). We conclude that 20-HETE mediates the myogenic response in the fetal pulmonary circulation and speculate that pharmacological inhibition of 20-HETE might have a therapeutic role in neonatal conditions characterized by pulmonary hypertension.     

The benefits of a functional exercise circuit for older adults

The physical benefits of a functional exercise circuit are not well known in an elderly population. The purpose of this study was to evaluate the effect of a functional exercise circuit on mobility and perceived health in the elderly. Subjects were 119 men and women (aged 74 [+/-4.2] years) who received pre- and posttests of mobility (e.g., sit to stand, get up and go, timed walk), flexibility (sit and reach), and balance (standing reach) and who completed the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). A supervised functional exercise circuit that included 10 different upper- and lower-body exercises performed under time constraints was performed 3 times per week for 12 consecutive weeks. Paired t-tests showed significant differences at posttest for the get up and go (p < 0.001), standing reach (p < 0.001), sit and reach (p < 0.001), and selected items from the SF-36, including physical functioning (p < 0.001), pain (p = 0.001), vitality (p = 0.001), and number of doctor visits (p < 0.001). A functional exercise circuit such as the one employed in this study may offer promise as an effective means of promoting mobility and perceived health in older adults.     

The role of suppressors of cytokine signalling in thymopoiesis and T cell activation

Cytokines play an essential role in mediating interactions between cells of the immune system. Suppressors of cytokine signalling proteins act to negatively regulate these cytokine signals, thereby exerting control over the expression of cytokine responsive genes. Various lines of experimental evidence suggest that two closely related members of the this family, suppressor of cytokine signalling 1 and 3, are important in the processes of T cell development, activation and homeostasis. This review outlines the principles underlying these processes and relates these to the potentially important roles played by suppressor of cytokine signalling 1 and 3.