Biological vulnerability to depression: Linked structural and functional brain network findings

Background: Patients in recovery following episodes of major depressive disorder (MDD) remain highly vulnerable to future recurrence. Although psychological determinants of this risk are well established, little is known about associated biological mechanisms. Recent work has implicated the default mode network (DMN) in this vulnerability but specific hypotheses remain untested within the high risk, recovered state of MDD. Aims: To test the hypothesis that there is excessive DMN functional connectivity during task performance within recovered-state MDD and to test for connected DMN cortical gyrification abnormalities. Method: A multimodal structural and functional magnetic resonance imaging (fMRI) study, including task-based functional connectivity and cortical folding analysis, comparing 20 recoveredstate patients with MDD with 20 matched healthy controls. Results: The MDD group showed significant task-based DMN hyperconnectivity, associated with hypogyrification of key DMN regions (bilateral precuneus). Conclusions: This is the first evidence of connected structural and functional DMN abnormalities in recovered-state MDD, supporting recent hypotheses on biological-level vulnerability

Molecular Evolutionary Analysis of the Thiamine-Diphosphate-Dependent Enzyme, Transketolase

Members of the transketolase group of thiamine- diphosphate-dependent enzymes from 17 different organisms including mammals, yeast, bacteria, and plants have been used for phylogenetic reconstruction. Alignment of the amino acid and DNA sequences for 21 transketolase enzymes and one putative transketolase reveals a number of highly conserved regions and invariant residues that are of predicted importance for enzyme activity, based on the crystal structure of yeast transketolase. One particular sequence of 36 residues has some similarities to the nucleotide-binding motif and we designate it as the transketolase motif. We report further evidence that the recP protein from Streptococcus pneumoniae might be a transketolase and we list a number of invariant residues which might be involved in substrate binding. Phylogenies derived from the nucleotide and the amino acid sequences by various methods show a conventional clustering for mammalian, plant, and gramnegative bacterial transketolases. The branching order of the gram-positive bacteria could not be inferred reliably. The formaldehyde transketolase (sometimes known as dihydroxyacetone synthase) of the yeast Hansenula polymorpha appears to be orthologous to the mammalian enzymes but paralogous to the other yeast transketolases. The occurrence of more than one transketolase gene in some organisms is consistent with several gene duplications. The high degree of similarity in functionally important residues and the fact that the same kinetic mechanism is applicable to all characterized transketolase enzymes is consistent with the proposition that they are all derived from one common ancestral gene. Transketolase appears to be an ancient enzyme that has evolved slowly and might serve as a model for a molecular clock, at least within the mammalian clade

Molecular Evolutionary Analysis of the Thiamine-Diphosphate-Dependent Enzyme, Transketolase

Members of the transketolase group of thiamine- diphosphate-dependent enzymes from 17 different organisms including mammals, yeast, bacteria, and plants have been used for phylogenetic reconstruction. Alignment of the amino acid and DNA sequences for 21 transketolase enzymes and one putative transketolase reveals a number of highly conserved regions and invariant residues that are of predicted importance for enzyme activity, based on the crystal structure of yeast transketolase. One particular sequence of 36 residues has some similarities to the nucleotide-binding motif and we designate it as the transketolase motif. We report further evidence that the recP protein from Streptococcus pneumoniae might be a transketolase and we list a number of invariant residues which might be involved in substrate binding. Phylogenies derived from the nucleotide and the amino acid sequences by various methods show a conventional clustering for mammalian, plant, and gramnegative bacterial transketolases. The branching order of the gram-positive bacteria could not be inferred reliably. The formaldehyde transketolase (sometimes known as dihydroxyacetone synthase) of the yeast Hansenula polymorpha appears to be orthologous to the mammalian enzymes but paralogous to the other yeast transketolases. The occurrence of more than one transketolase gene in some organisms is consistent with several gene duplications. The high degree of similarity in functionally important residues and the fact that the same kinetic mechanism is applicable to all characterized transketolase enzymes is consistent with the proposition that they are all derived from one common ancestral gene. Transketolase appears to be an ancient enzyme that has evolved slowly and might serve as a model for a molecular clock, at least within the mammalian clade

Temporal Variations of Titan's Middle-Atmospheric Temperatures From 2004-2009 Observed by Cassini/CIRS

We use five and one-half years of limb- and nadir-viewing temperature mapping observations by the Composite Infrared Radiometer-Spectrometer (CIRS) on the Cassini Saturn orbiter, taken between July 2004 and December 2009 (Ls from 293deg to 4deg; northern mid-winter to just after northern spring equinox), to monitor temperature changes in the upper stratosphere and lower mesosphere of Titan. The largest changes are in the northern (winter) polar stratopause, which has declined in temperature by over 20 K between 2005 and 2009. Throughout the rest of the mid to upper stratosphere and lower mesosphere, temperature changes are less than 5 K. In the southern hemisphere, temperatures in the middle stratosphere near 1 mbar increased by 1 to 2K from 2004 through early 2007, then declined by 2 to 4K throughout 2008 and 2009, with the changes, being larger at more, polar latitudes. Middle stratospheric temperatures at mid-northern latitudes show a small 1 to 2K increase, from 2005 through 2009. At north polar latitudes within the polar vortex, temperatures in the middle stratosphe=re show a approx. 4 K increase during 2007, followed by a comparable decrease in temperatures in 2008 and into early 2009. The observed temperature. changes in the north polar region are consistent with a weakening of the subsidence within the descending branch of the middle atmosphere meridional circulation

Effects of Deletions at the Carboxyl Terminus of Zymomonas mobilis Pyruvate Decarboxylase on the Kinetic Properties and Substrate Specificity †

ABSTRACT: The three-dimensional structure of Zymomonas mobilis pyruvate decarboxylase shows that the carboxyl-terminal region of the protein occludes the active site. This observation is consistent with earlier suggestions that the active site is inaccessible to solvent during catalysis. However, the carboxylterminal region must move aside to allow entry of the substrate, and again to permit the products to leave. Here we have examined the role of the carboxyl terminus by making 15 variants of the enzyme with serial deletions. The activity is largely unaffected by removal of up to seven residues but deletion of the next two, R561 and S560, results in a drastic loss of activity. Five of these deletion mutants were purified and fully characterized and showed progressive decreases in activity, in the ability to discriminate between pyruvate and larger substrates, and in cofactor affinity. Several substitution mutants at residues R561 and S560 were prepared, purified, and fully characterized. The results indicate important roles for the side-chain of R561 and the backbone atoms of S560. It is suggested that the carboxyl-terminal region of pyruvate decarboxylase is needed to lock in the cofactors and for the proper closure of the active site that is required for discrimination between substrates and for decarboxylation to occur

The turnover of folate coenzymes in murine lymphoma cells

To estimate the turnover of 5-CH3-H4-folate in murine lymphoma cells L1210, L1210R (a methotrexate-resistant subline), and L5178Y, suspensions of whole cells were allowed to concentrate 5-[14C]CH3-[9,3',5'-3H]H4-folate; analysis of cell extracts showed that, for each cell line, 81 to 85% of the total cell [14C]CH3 groups were transferred to nonfolate compounds within 5 min and 82 to 91% at time intervals up to 60 min. The initial transfer of 14C appeared to be into [14C]methionine, but insoluble cell materials were also progressively 14C labeled. Of the total cell 3H, more than 87% remained identified as 5-CH3-[3H3]H4-folate at 60 min, showing that within this period most of the [3H2]H4-folate derived from 5-CH3-[3H3]H4-folate returned to maintain the labeling of the pool of 5-CH3-[3H3]H4-folate. To estimate the flux of folates through the pathway of thymidylate biosynthesis, L1210 and L1210R cells were allowed to concentrate either 5-CH3-[9,3',5'-3H]H4-folate in the presence of methotrexate or 5-HCO-[6-3H]H4-folate. Of total 3H taken up as 5-HCO-[6-3H]H4-folate, 28% appeared to be transferred to thymidylate in 60 min by L1210 cells and 52% by L1210R cells. In methotrexate-treated L1210 cells, 23% of the total 3H taken up as 5-CH3-[3H3]H4-folate was accumulated in 60 min as [3H3]H2-folate, a product of thymidylate biosynthesis. However, in cells of the methotrexate-resistant L1210R line, no [3H3]H2-folate was accumulated by the use of 2 mM methotrexate despite the demonstrated high flux of folates through the pathway of thymidylate biosynthesis. These data show the significance, for methotrexate resistance, of the 11-fold increase of dihydrofolate reductase in L1210R cells

Effects of a mindfulness-based weight loss intervention in adults with obesity: A randomized clinical trial.

OBJECTIVE: To determine whether adding mindfulness-based eating and stress management practices to a diet-exercise program improves weight loss and metabolic syndrome components. METHODS: In this study 194 adults with obesity were randomized to a 5.5-month program with or without mindfulness training and identical diet-exercise guidelines. Intention-to-treat analyses with multiple imputation were used for missing data. The primary outcome was 18-month weight change. RESULTS: Estimated effects comparing the mindfulness to control arm favored the mindfulness arm in (a) weight loss at 12 months, -1.9 kg (95% CI: -4.5, 0.8; P = 0.17), and 18 months, -1.7 kg (95% CI: -4.7, 1.2; P = 0.24), though not statistically significant; (b) changes in fasting glucose at 12 months, -3.1 mg/dl (95% CI: -6.3, 0.1; P = 0.06), and 18 months, -4.1 mg/dl (95% CI: -7.3, -0.9; P = 0.01); and (c) changes in triglyceride/HDL ratio at 12 months, -0.57 (95% CI: -0.95, -0.18; P = 0.004), and 18 months, -0.36 (95% CI: -0.74, 0.03; P = 0.07). Estimates for other metabolic risk factors were not statistically significant, including waist circumference, blood pressure, and C-reactive protein. CONCLUSIONS: Mindfulness enhancements to a diet-exercise program did not show substantial weight loss benefit but may promote long-term improvement in some aspects of metabolic health in obesity that requires further study