Quantitative Characterization of the Nanoscale Local Lattice Strain Induced by Sr Dopants in La_{1.92}Sr_{0.08}CuO_{4}.

The nanometer scale lattice deformation brought about by the dopants in the high temperature superconducting cuprate La_{2-x}Sr_{x}CuO_{4} (x=0.08) was investigated by measuring the associated x-ray diffuse scattering around multiple Bragg peaks. A characteristic diffuse scattering pattern was observed, which can be well described by continuum elastic theory. With the fitted dipole force parameters, the acoustic-type lattice deformation pattern was reconstructed and found to be of similar size to lattice thermal vibration at 7 K. Our results address the long-term concern of dopant introduced local lattice inhomogeneity, and show that the associated nanometer scale lattice deformation is marginal and cannot, alone, be responsible for the patched variation in the spectral gaps observed with scanning tunneling microscopy in the cuprates.

Determinants of telomere attrition over 1 year in healthy older women: stress and health behaviors matter.

Telomere length, a reliable predictor of disease pathogenesis, can be affected by genetics, chronic stress and health behaviors. Cross-sectionally, highly stressed postmenopausal women have shorter telomeres, but only if they are inactive. However, no studies have prospectively examined telomere length change over a short period, and if rate of attrition is affected by naturalistic factors such as stress and engagement in healthy behaviors, including diet, exercise, and sleep. Here we followed healthy women over 1 year to test if major stressors that occurred over the year predicted telomere shortening, and whether engaging in healthy behaviors during this period mitigates this effect. In 239 postmenopausal, non-smoking, disease-free women, accumulation of major life stressors across a 1-year period predicted telomere attrition over the same period-for every major life stressor that occurred during the year, there was a significantly greater decline in telomere length over the year of 35 bp (P<0.05). Yet, these effects were moderated by health behaviors (interaction B=0.19, P=0.04). Women who maintained relatively higher levels of health behaviors (1 s.d. above the mean) appeared to be protected when exposed to stress. This finding has implications for understanding malleability of telomere length, as well as expectations for possible intervention effects. This is the first study to identify predictors of telomere length change over the short period of a year.

Depression, anxiety and telomere length in young adults: evidence from the National Health and Nutrition Examination Survey.

Telomere length has been hypothesized to be a marker of cumulative exposure to stress, and stress is an established cause of depression and anxiety disorders. The aim of this study was to examine the relationship between depression, anxiety and telomere length, and to assess whether this relationship is moderated by race/ethnicity, gender and/or antidepressant use. Data were from the 1999-2002 National Health and Nutrition Examination Survey. Telomere length was assessed using the quantitative PCR method of telomere length relative to standard reference DNA. Past-year major depression (MD), generalized anxiety disorder (GAD) and panic disorder (PD), as well as depressed affect and anxious affect, were assessed using the Composite International Diagnostic Inventory (N=1290). Multiple linear regression was used to assess the relationship between depression and anxiety disorders and telomere length. Among women, those with GAD or PD had shorter telomeres than those with no anxious affect (ß: -0.07, P<0.01), but there was no relationship among men (ß: 0.08, P>0.05). Among respondents currently taking an antidepressant, those with MD had shorter telomeres than those without (ß: -0.26, P<0.05), but there was no association between MD and telomere length among those not using antidepressants (ß: -0.00, P>0.05). Neither depressive nor anxiety disorders were directly associated with telomere length in young adults. There was suggestive evidence that pharmacologically treated MD is associated with shorter telomere length, likely reflecting the more severe nature of MD that has come to clinical attention.

X-ray diffraction observations of a charge-density-wave order in superconducting ortho-II YBa2Cu3O6.54 single crystals in zero magnetic field.

X-ray diffraction measurements show that the high-temperature superconductor YBa2Cu3O6.54, with ortho-II oxygen order, has charge-density-wave order in the absence of an applied magnetic field. The dominant wave vector of the charge density wave is q(CDW)=(0,0.328(2),0.5), with the in-plane component parallel to the b axis (chain direction). It has a similar incommensurability to that observed in ortho-VIII and ortho-III samples, which have different dopings and oxygen orderings. Our results for ortho-II contrast with recent high-field NMR measurements, which suggest a commensurate wave vector along the a axis. We discuss the relationship between spin and charge correlations in YBa2Cu3O(y) and recent high-field quantum oscillation, NMR, and ultrasound experiments.

Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response.

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.

A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity.

BACKGROUND: This study examined the effects of brief daily yogic meditation on mental health, cognitive functioning, and immune cell telomerase activity in family dementia caregivers with mild depressive symptoms. METHODS: Thirty-nine family dementia caregivers (mean age 60.3 years old (SD = 10.2)) were randomized to practicing Kirtan Kriya or listening to relaxation music for 12 min per day for 8 weeks. The severity of depressive symptoms, mental and cognitive functioning were assessed at baseline and follow-up. Telomerase activity in peripheral blood mononuclear cells (PMBC) was examined in peripheral PBMC pre-intervention and post-intervention. RESULTS: The meditation group showed significantly lower levels of depressive symptoms and greater improvement in mental health and cognitive functioning compared with the relaxation group. In the meditation group, 65.2% showed 50% improvement on the Hamilton Depression Rating scale and 52% of the participants showed 50% improvement on the Mental Health Composite Summary score of the Short Form-36 scale compared with 31.2% and 19%, respectively, in the relaxation group (p < 0.05). The meditation group showed 43% improvement in telomerase activity compared with 3.7% in the relaxation group (p = 0.05). CONCLUSION: This pilot study found that brief daily meditation practices by family dementia caregivers can lead to improved mental and cognitive functioning and lower levels of depressive symptoms. This improvement is accompanied by an increase in telomerase activity suggesting improvement in stress-induced cellular aging. These results need to be confirmed in a larger sample.

Shorter telomeres are associated with obesity and weight gain in the elderly.

OBJECTIVE: Obesity and shorter telomeres are commonly associated with elevated risk for age-related diseases and mortality. Whether telomere length (TL) may be associated with obesity or variations in adiposity is not well established. Therefore, we set out to test the hypothesis that TL may be a risk factor for increased adiposity using data from a large population-based cohort study. DESIGN: Levels of adiposity were assessed in six ways (obesity status, body mass index (BMI), the percentage of body fat or % body fat, leptin, visceral and subcutaneous fat mass) in 2721 elderly subjects (42% black and 58% white). Associations between TL measured in leukocytes at baseline and adiposity traits measured at baseline, and three of these traits after 7 years of follow-up were tested using regression models adjusting for important covariates. Additionally, we look at weight changes and relative changes in BMI and % body fat between baseline and follow-up. RESULTS: At baseline, TL was negatively associated with % body fat (ß=-0.35±0.09, P=0.001) and subcutaneous fat (ß=-2.66±1.07, P=0.01), and positively associated with leptin after adjusting for % body fat (ß=0.32±0.14, P=0.001), but not with obesity, BMI or visceral fat. Prospective analyses showed that longer TL was associated with positive percent change between baseline and 7-year follow-up for both BMI (ß=0.48±0.20, P=0.01) and % body fat (ß=0.42±0.23, P=0.05). CONCLUSION: Our study suggests that shorter TL may be a risk factor for increased adiposity. Coupling with previous reports on their reversed roles, the relationship between adiposity and TL may be complicated and may warrant more prospective studies.

The fluctuation-dissipation measurement instrument at the Linac Coherent Light Source.

The development of new modes at x-ray free electron lasers has inspired novel methods for studying fluctuations at different energies and timescales. For closely spaced x-ray pulses that can be varied on ultrafast time scales, we have constructed a pair of advanced instruments to conduct studies targeting quantum materials. We first describe a prototype instrument built to test the proof-of-principle of resonant magnetic scattering using ultrafast pulse pairs. This is followed by a description of a new endstation, the so-called fluctuation-dissipation measurement instrument, which was used to carry out studies with a fast area detector. In addition, we describe various types of diagnostics for single-shot contrast measurements, which can be used to normalize data on a pulse-by-pulse basis and calibrate pulse amplitude ratios, both of which are important for the study of fluctuations in materials. Furthermore, we present some new results using the instrument that demonstrates access to higher momentum resolution.

Exploring the fragile antiferromagnetic superconducting phase in CeCoIn5.

CeCoIn5 is a heavy fermion type-II superconductor showing clear signs of Pauli-limited superconductivity. A variety of measurements give evidence for a transition at high magnetic fields inside the superconducting state, when the field is applied either parallel to or perpendicular to the c axis. When the field is perpendicular to the c axis, antiferromagnetic order develops on the high-field side of the transition. This order remains as the field is rotated out of the basal plane, but the associated moment eventually disappears above 17°, indicating that anomalies seen with the field parallel to the c axis are not related to this magnetic order. We discuss the implications of this finding.

Spatially inhomogeneous competition between superconductivity and the charge density wave in YBa2Cu3O6.67.

The charge density wave in the high-temperature superconductor YBa2Cu3O7-x (YBCO) has two different ordering tendencies differentiated by their c-axis correlations. These correspond to ferro- (F-CDW) and antiferro- (AF-CDW) couplings between CDWs in neighbouring CuO2 bilayers. This discovery has prompted several fundamental questions: how does superconductivity adjust to two competing orders and are either of these orders responsible for the electronic reconstruction? Here we use x-ray diffraction to study YBa2Cu3O6.67 as a function of magnetic field and temperature. We show that regions with F-CDW correlations suppress superconductivity more strongly than those with AF-CDW correlations. This implies that an inhomogeneous superconducting state exists, in which some regions show a fragile form of superconductivity. By comparison of F-CDW and AF-CDW correlation lengths, it is concluded that F-CDW ordering is sufficiently long-range to modify the electronic structure. Our study thus suggests that F-CDW correlations impact both the superconducting and normal state properties of YBCO.

Pessimism correlates with leukocyte telomere shortness and elevated interleukin-6 in post-menopausal women.

The combination of less positive and more negative expectations for the future (i.e., lower optimism and higher pessimism) increases risk for disease and early mortality. We tested the possibility that expectancies might influence health outcomes by altering the rate of biological aging, specifically of the immune system (immunosenescence). However, no studies to date have examined associations between optimism or pessimism and indicators of immunosenescence such as leukocyte telomere length (TL) and interleukin-6 (IL-6) levels. We investigated whether dispositional tendencies towards optimism and pessimism were associated with TL and IL-6 in a sample of 36 healthy post-menopausal women. Multiple regression analyses where optimism and pessimism were entered simultaneously, and chronological age and caregiver status were controlled, indicated that pessimism was independently associated with shorter TL (beta=-.68, p=.001) and higher IL-6 concentrations (beta=.50, p=.02). In contrast, optimism was not independently associated with either measure of immunosenescence. These findings suggest that dispositional pessimism may increase IL-6 and accelerate rate of telomere shortening. Mechanistic causal relationships between these parameters need to be investigated.

Uncapping and deregulation of telomeres lead to detrimental cellular consequences in yeast.

Telomeres are the protein-nucleic acid structures at the ends of eukaryote chromosomes. Tandem repeats of telomeric DNA are templated by the RNA component (TER1) of the ribonucleoprotein telomerase. These repeats are bound by telomere binding proteins, which are thought to interact with other factors to create a higher-order cap complex that stabilizes the chromosome end. In the budding yeast Kluyveromyces lactis, the incorporation of certain mutant DNA sequences into telomeres leads to uncapping of telomeres, manifested by dramatic telomere elongation and increased length heterogeneity (telomere deregulation). Here we show that telomere deregulation leads to enlarged, misshapen "monster" cells with increased DNA content and apparent defects in cell division. However, such deregulated telomeres became stabilized at their elongated lengths upon addition of only a few functionally wild-type telomeric repeats to their ends, after which the frequency of monster cells decreased to wild-type levels. These results provide evidence for the importance of the most terminal repeats at the telomere in maintaining the cap complex essential for normal telomere function. Analysis of uncapped and capped telomeres also show that it is the deregulation resulting from telomere uncapping, rather than excessive telomere length per se, that is associated with DNA aberrations and morphological defects.

Tandemly repeated C-C-C-C-A-A hexanucleotide of Tetrahymena rDNA is present elsewhere in the genome and may be related to the alteration of the somatic genome.

The ribosomal RNA genes of the Tetrahymena macronucleus exist as extrachromosomal, linear molecules. The termini of these molecules have been shown to contain the tandemly repeated hexanucleotide (C-C-C-C-A-A)n. In this study the same or related sequences were found in other locations of the genome. Using the depurination method, we showed that macronuclear DNA contained this sequence even after rDNA had been removed. The sequence was found mainly in the repetitive fraction of the DNA. The presence of this sequence in both the macronucleus and the micronucleus was also shown by Southern hybridization using C-C-C-C-A-A repeat as a probe. Comparison between the hybridization patterns of macronuclei and micronuclei reveals interesting differences. Whereas the two nuclei share the same genetic origin, the majority of the restriction enzyme digestion sites flanking the C-C-C-C-A-A repeat appear to be different. Such a difference was found to be specific for this sequence, because it was not detected when other sequences were used for hybridization. These results suggest that some kind of alteration has occurred in the genome during the formation of the macronucleus, and that the C-C-C-C-A-A repeat may be related to this process.

Telomerase in yeast.

The ribonucleoprotein enzyme telomerase synthesizes telomeric DNA by copying an internal RNA template sequence. The telomerase activities of the yeasts Saccharomyces castellii and Saccharomyces cerevisiae--with regular and irregular telomeric sequences, respectively--have now been identified and characterized. The S. cerevisiae activity required the telomerase RNA gene TLC1 but not the EST1 gene, both of which are required for normal telomere maintenance in vivo. This activity exhibited low processivity and produced no regularly repeated products. An inherently high stalling frequency of the S. cerevisiae telomerase may account for its in vitro properties and for the irregular telomeric sequences of this yeast.

Functional evidence for an RNA template in telomerase.

The RNA moiety of the ribonucleoprotein enzyme telomerase from the ciliate Euplotes crassus was identified and its gene was sequenced. Functional analysis, in which oligonucleotides complementary to portions of the telomerase RNA were tested for their ability to prime telomerase in vitro, showed that the sequence 5' CAAAACCCCAAA 3' in this RNA is the template for synthesis of telomeric TTTTGGGG repeats by the Euplotes telomerase. The data provide a direct demonstration of a template function for a telomerase RNA and demarcate the outer boundaries of the telomeric template. Telomerase can now be defined as a specialized reverse transcriptase.

Template boundary in a yeast telomerase specified by RNA structure.

The telomerase ribonucleoprotein has a phylogenetically divergent RNA subunit, which contains a short template for telomeric DNA synthesis. To understand how telomerase RNA participates in mechanistic aspects of telomere synthesis, we studied a conserved secondary structure adjacent to the template. Disruption of this structure caused DNA synthesis to proceed beyond the normal template boundary, resulting in altered telomere sequences, telomere shortening, and cellular growth defects. Compensatory mutations restored normal telomerase function. Thus, the RNA structure, rather than its sequence, specifies the template boundary. This study reveals a specific function for an RNA structure in the enzymatic action of telomerase.

Block in anaphase chromosome separation caused by a telomerase template mutation.

Telomeres are essential for chromosome stability, but their functions at specific cell-cycle stages are unknown. Telomeres are now shown to have a role in chromosome separation during mitosis. In telomeric DNA mutants of Tetrahymena thermophila, created by expression of a telomerase RNA with an altered template sequence, division of the germline nucleus was severely delayed or blocked in anaphase. The mutant chromatids failed to separate completely at the midzone, becoming stretched to up to twice their normal length. These results suggest a physical block in mutant telomere separation.

Telomeres.

Telomeres are specialized structures at the ends of eukaryotic linear chromosomes, consisting of protein-bound tandemly repeated simple DNA sequences. Telomeric DNA is unique in that it is copied from an RNA template that forms part of the enzyme, telomerase. This review discusses the synthesis and maintenance of these unusual structures.

Ligand discovery and virtual screening using the program LIDAEUS.

This paper discusses advances in docking and scoring approaches with examples from the high-throughput virtual screening program LIDAEUS. We describe the discovery of small molecule inhibitors for the immunophilin CypA, the cyclin-dependent kinase CDK2 and the cyclapolin series of potent Polo-like kinase inhibitors. These results are discussed in the context of advances in massively parallel computing and in the development of annotated databases.

Telomerase: Dr Jekyll or Mr Hyde?

The past year has seen the ectopic expression of human telomerase and the consequent increased replicative lifespan of cells, whereas mice lacking telomerase have lived and reproduced for six generations. Core telomerase activity from various organisms was reconstituted in vitro, yet how its action is regulated remains largely unknown. Telomerase activation preceded oncogenic transformation in some human cell types, yet was lacking in other transformed cells. These advances highlight the potentials of telomerase-based therapeutics and warn of their pitfalls.