Homocysteine, grey matter and cognitive function in adults with cardiovascular disease

Background

Elevated total plasma homocysteine (tHcy) has been associated with cognitive impairment, vascular disease and brain atrophy.

Methods

We investigated 150 volunteers to determine if the association between high tHcy and cerebral grey matter volume and cognitive function is independent of cardiovascular disease.

Results

Participants with high tHcy (≥15 µmol/L) showed a widespread relative loss of grey matter compared with people with normal tHcy, although differences between the groups were minimal once the analyses were adjusted for age, gender, diabetes, hypertension, smoking and prevalent cardiovascular disease. Individuals with high tHcy had worse cognitive scores across a range of domains and less total grey matter volume, although these differences were not significant in the adjusted models.

Conclusions

Our results suggest that the association between high tHcy and loss of cerebral grey matter volume and decline in cognitive function is largely explained by increasing age and cardiovascular diseases and indicate that the relationship is not causal.     

Atrophic cardiac remodeling induced by taurine deficiency in wistar rats

Introduction

Micronutrient deficiency is observed in heart failure patients. Taurine, for example, represents 50% of total free amino acids in the heart, and in vivo studies have linked taurine deficiency with cardiomyopathy.

Methods

Thirty-four male Wistar rats (body weight = 100 g) were weighed and randomly assigned to one of two groups: Control (C) or taurine-deficient (T (-)). Beta-alanine at a concentration of 3% was added to the animals’ water to induce taurine deficiency in the T (-) group. On day 30, the rats were individually submitted to echocardiography; morphometrical and histopathological evaluation and metalloproteinase activity, oxidative stress and inflammation evaluation were performed. Tissue samples were collected to determine the taurine concentration in the heart.

Results

Taurine deficiency led to decreases in: ventricular wall thickness, left ventricle dry weight, myocyte sectional area, left ventricle posterior wall thickness and ventricular geometry. With regard to heart function, the velocity of the A wave, the ratio between the E and A wave, the ejection fraction, fractional shortening and cardiac output values were decreased in T (-) rats, suggesting abnormal diastolic and systolic function. Increased fibrosis, inflammation and increased activation of metalloproteinases were not observed. Oxidative stress was increased in deficient animals.

Conclusions

These data suggest that taurine deficiency promotes structural and functional cardiac alterations with unique characteristics.     

Cultivation of a highly enriched ammonia-oxidizing archaeon of thaumarchaeotal group I.1b from an agricultural soil

Nitrification of excess ammonia in soil causes eutrophication of water resources and emission of atmospheric N₂O gas. The first step of nitrification, ammonia oxidation, is mediated by Archaea as well as Bacteria. The physiological reactions mediated by ammonia‐oxidizing archaea (AOA) and their contribution to soil nitrification are still unclear. Results of non‐culture‐based studies have shown the thaumarchaeotal group I.1b lineage of AOA to be dominant over both AOA of group I.1a and ammonia‐oxidizing bacteria in various soils. We obtained from an agricultural soil a highly enriched ammonia‐oxidizing culture dominated by a single archaeal population [c. 90% of total cells, as determined microscopically (by fluorescence in situ hybridization) and by quantitative PCR of its 16S rRNA gene]. The archaeon (termed ‘strain JG1’) fell within thaumarchaeotal group I.1b and was related to the moderately thermophilic archaeon, Candidatus Nitrososphaera gargensis, and the mesophilic archaeon, Ca. Nitrososphaera viennensis with 97.0% and 99.1% 16S rRNA gene sequence similarity respectively. Strain JG1 was neutrophilic (growth range pH 6.0–8.0) and mesophilic (growth range temperature 25–40°C). The optimum temperature of strain JG1 (35–40°C) is > 10°C higher than that of ammonia‐oxidizing bacteria (AOB). Membrane analysis showed that strain JG1 contained a glycerol dialkyl glycerol tetraether, GDGT‐4, and its regioisomer as major core lipids; this crenarchaeol regioisomer was previously detected in similar abundance in the thermophile, Ca. N. gargensis and has been frequently observed in tropical soils. Substrate uptake assays showed that the affinity of strain JG1 for ammonia and oxygen was much higher than those of AOB. These traits may give a competitive advantage to AOA related to strain JG1 in oligotrophic environments. ¹³C‐bicarbonate incorporation into archaeal lipids of strain JG1 established its ability to grow autotrophically. Strain JG1 produced a significant amount of N₂O gas – implicating AOA as a possible source of N₂O emission from soils. Sequences of archaeal amoA and 16S rRNA genes closely related to those of strain JG1 have been retrieved from various terrestrial environments in which lineage of strain JG1 is likely engaged in autotrophic nitrification.     

Drosophila Src regulates anisotropic apical surface growth to control epithelial tube size

Networks of epithelial and endothelial tubes are essential for the function of organs such as the lung, kidney and vascular system. The sizes and shapes of these tubes are highly regulated to match their individual functions. Defects in tube size can cause debilitating diseases such as polycystic kidney disease and ischaemia. It is therefore critical to understand how tube dimensions are regulated. Here we identify the tyrosine kinase Src as an instructive regulator of epithelial-tube length in the Drosophila tracheal system. Loss-of-function Src42 mutations shorten tracheal tubes, whereas Src42 overexpression elongates them. Surprisingly, Src42 acts distinctly from known tube-size pathways and regulates both the amount of apical surface growth and, with the conserved formin dDaam, the direction of growth. Quantitative three-dimensional image analysis reveals that Src42- and dDaam-mutant tracheal cells expand more in the circumferential than the axial dimension, resulting in tubes that are shorter in length-but larger in diameter-than wild-type tubes. Thus, Src42 and dDaam control tube dimensions by regulating the direction of anisotropic growth, a mechanism that has not previously been described.     

Inhibition of Akt potentiates 2-DG-induced apoptosis via downregulation of UPR in acute lymphoblastic leukemia

The ability to pair the regulation of metabolism and cellular energetics with oncogenes and tumor suppressor genes provides cancer cells with a growth and survival advantage over normal cells. We investigated the mechanism of cell death induced by 2-deoxy-D-glucose (2-DG), a sugar analog with dual activity of inhibiting glycolysis and N-linked glycosylation, in acute lymphoblastic leukemia (ALL). We found that, unlike most other cancer phenotypes in which 2-DG only inhibits cell proliferation under normoxic conditions, ALL lymphoblasts undergo apoptosis. Bp-ALL cell lines and primary cells exhibited sensitivity to 2-DG, whereas T-ALL cells were relatively resistant, revealing phenotypic differences within ALL subtypes. Cotreatment with D-mannose, a sugar essential for N-linked glycosylation, rescues 2-DG-treated ALL cells, indicating that inhibition of N-linked glycosylation and induction of ER stress and the unfolded protein response (UPR) is the predominant mechanism of 2-DG's cytotoxicity in ALL. 2-DG-treated ALL cells exhibit upregulation of P-AMPK, P-Akt, and induction of ER stress/UPR markers (IRE1α, GRP78, P-eIF2α, and CHOP), which correlate with PARP cleavage and apoptosis. In addition, we find that pharmacologic and genetic Akt inhibition upregulates P-AMPK, downregulates UPR, and sensitizes ALL cells to remarkably low doses of 2-DG (0.5 mmol/L), inducing 85% cell death and overcoming the relative resistance of T-ALL. In contrast, AMPK knockdown rescues ALL cells by upregulating the prosurvival UPR signaling. Therefore, 2-DG induces ALL cell death under normoxia by inducing ER stress, and AKT and AMPK, traditionally thought to operate predominantly on the glycolytic pathway, differentially regulate UPR activity to determine cell death or survival.     

Clade age and species richness are decoupled across the eukaryotic tree of life

Explaining the dramatic variation in species richness across the tree of life remains a key challenge in evolutionary biology. At the largest phylogenetic scales, the extreme heterogeneity in species richness observed among different groups of organisms is almost certainly a function of many complex and interdependent factors. However, the most fundamental expectation in macroevolutionary studies is simply that species richness in extant clades should be correlated with clade age: all things being equal, older clades will have had more time for diversity to accumulate than younger clades. Here, we test the relationship between stem clade age and species richness across 1,397 major clades of multicellular eukaryotes that collectively account for more than 1.2 million described species. We find no evidence that clade age predicts species richness at this scale. We demonstrate that this decoupling of age and richness is unlikely to result from variation in net diversification rates among clades. At the largest phylogenetic scales, contemporary patterns of species richness are inconsistent with unbounded diversity increase through time. These results imply that a fundamentally different interpretative paradigm may be needed in the study of phylogenetic diversity patterns in many groups of organisms.     

The identification of cutin synthase: formation of the plant polyester cutin

A hydrophobic cuticle consisting of waxes and the polyester cutin covers the aerial epidermis of all land plants, providing essential protection from desiccation and other stresses. We have determined the enzymatic basis of cutin polymerization through characterization of a tomato extracellular acyltransferase, CD1, and its substrate, 2-mono(10,16-dihydroxyhexadecanoyl)glycerol. CD1 has in vitro polyester synthesis activity and is required for cutin accumulation in vivo, indicating that it is a cutin synthase.     

Lymphoid tissue damage in HIV-1 infection depletes naïve T cells and limits T cell reconstitution after antiretroviral therapy

Highly active antiretroviral therapy (HAART) can suppress HIV-1 replication and normalize the chronic immune activation associated with infection, but restoration of na?ve CD4+ T cell populations is slow and usually incomplete for reasons that have yet to be determined. We tested the hypothesis that damage to the lymphoid tissue (LT) fibroblastic reticular cell (FRC) network contributes to na?ve T cell loss in HIV-1 infection by restricting access to critical factors required for T cell survival. We show that collagen deposition and progressive loss of the FRC network in LTs prior to treatment restrict both access to and a major source of the survival factor interleukin-7 (IL-7). As a consequence, apoptosis within na?ve T cell populations increases significantly, resulting in progressive depletion of both na?ve CD4+ and CD8+ T cell populations. We further show that the extent of loss of the FRC network and collagen deposition predict the extent of restoration of the na?ve T cell population after 6 month of HAART, and that restoration of FRC networks correlates with the stage of disease at which the therapy is initiated. Because restoration of the FRC network and reconstitution of na?ve T cell populations are only optimal when therapy is initiated in the early/acute stage of infection, our findings strongly suggest that HAART should be initiated as soon as possible. Moreover, our findings also point to the potential use of adjunctive anti-fibrotic therapies to avert or moderate the pathological consequences of LT fibrosis, thereby improving immune reconstitution.     

Outcome of the first electron microscopy validation task force meeting

This Meeting Review describes the proceedings and conclusions from the inaugural meeting of the Electron Microscopy Validation Task Force organized by the Unified Data Resource for 3DEM (http://www.emdatabank.org) and held at Rutgers University in New Brunswick, NJ on September 28 and 29, 2010. At the workshop, a group of scientists involved in collecting electron microscopy data, using the data to determine three-dimensional electron microscopy (3DEM) density maps, and building molecular models into the maps explored how to assess maps, models, and other data that are deposited into the Electron Microscopy Data Bank and Protein Data Bank public data archives. The specific recommendations resulting from the workshop aim to increase the impact of 3DEM in biology and medicine.