Abstract
Electron paramagnetic resonance (EPR) spectroscopy is a powerful and widely used technique for studying structure and dynamics of biomolecules under bio-orthogonal conditions. In-cell EPR is ...an emerging area in this field; however, it is hampered by the reducing environment present in cells, which reduces most nitroxide spin labels to their corresponding diamagnetic N-hydroxyl derivatives. To determine which radicals are best suited for in-cell EPR studies, we systematically studied the effects of substitution on radical stability using five different classes of radicals, specifically piperidine-, imidazolidine-, pyrrolidine-, and isoindoline-based nitroxides as well as the Finland trityl radical. Thermodynamic parameters of nitroxide reduction were determined by cyclic voltammetry; the rate of reduction in the presence of ascorbate, cellular extracts, and after injection into oocytes was measured by continuous-wave EPR spectroscopy. Our study revealed that tetraethyl-substituted nitroxides are good candidates for in-cell EPR studies, in particular pyrrolidine derivatives, which are slightly more stable than the trityl radical.
Summary
In a population-based study, we found that computed tomography (CT)-based bone density and strength measures from the thoracic spine predicted new vertebral fracture as well as measures from ...the lumbar spine, suggesting that CT scans at either the thorax or abdominal regions are useful to assess vertebral fracture risk.
Introduction
Prior studies have shown that computed tomography (CT)-based lumbar bone density and strength measurements predict incident vertebral fracture. This study investigated whether CT-based bone density and strength measurements from the thoracic spine predict incident vertebral fracture and compared the performance of thoracic and lumbar bone measurements to predict incident vertebral fracture.
Methods
This case-control study of community-based men and women (age 74.6 ± 6.6) included 135 cases with incident vertebral fracture at any level and 266 age- and sex-matched controls. We used baseline CT scans to measure integral and trabecular volumetric bone mineral density (vBMD) and vertebral strength (via finite element analysis, FEA) at the T8 and L2 levels. Association between these measurements and vertebral fracture was determined by using conditional logistic regression. Sensitivity and specificity for predicting incident vertebral fracture were determined for lumbar spine and thoracic bone measurements.
Results
Bone measurements from T8 and L2 predicted incident vertebral fracture equally well, regardless of fracture location. Specifically, for predicting vertebral fracture at any level, the odds ratio (per 1-SD decrease) for the vBMD and strength measurements at L2 and T8 ranged from 2.0 to 2.7 (
p
< 0.0001) and 1.8 to 2.8 (
p
< 0.0001), respectively. Results were similar when predicting fracture only in the thoracic versus the thoracolumbar spine. Lumbar and thoracic spine bone measurements had similar sensitivity and specificity for predicting incident vertebral fracture.
Conclusion
These findings indicated that like those from the lumbar spine, CT-based bone density and strength measurements from the thoracic spine may be useful for identifying individuals at high risk for vertebral fracture.
Abstract Hip fracture risk is usually evaluated using dual energy X-ray absorptiometry (DXA) or quantitative computed tomography (QCT) which provide surrogate measures for proximal femoral strength. ...However, proximal femoral strength can best be estimated explicitly by combining QCT with finite element (FE) analysis. To evaluate this technique for predicting hip fracture in older men and women, we performed a nested age- and sex-matched case–control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Baseline (pre-fracture) QCT scans of 5500 subjects were obtained. During 4–7 years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as age- and sex-matched controls. FE-strength of the left hip of each subject for stance (FStance ) and posterolateral fall (FFall ) loading, and total femur areal bone mineral density (aBMD) were computed from the QCT data. FStance and FFall in incident hip fracture subjects were 13%–25% less than in control subjects (p ≤ 0.006) after controlling for demographic parameters. The difference between FE strengths of fracture and control subjects was disproportionately greater in men (stance, 22%; fall, 25%) than in women (stance, 13%; fall, 18%) (p ≤ 0.033), considering that FStance and FFall in fracture subjects were greater in men than in women (p < 0.001). For men, FStance was associated with hip fracture after accounting for aBMD (p = 0.013). These data indicate that FStance provides information about fracture risk that is beyond that provided by aBMD (p = 0.013). These findings support further exploration of possible sex differences in the predictors of hip fracture and of sex-specific strategies for using FE analysis to manage osteoporosis.
We motivate the G infrared search for extraterrestrial civilizations with large energy supplies. We discuss some philosophical difficulties of the search for extraterrestrial intelligence (SETI), and ...how communication SETI circumvents them. We review "Dysonian SETI," the search for artifacts of alien civilizations, and find that it is highly complementary to traditional communication SETI; the two together might succeed where either one alone has not. We discuss the argument of Hart that spacefaring life in the Milky Way should be either galaxy-spanning or non-existent, and examine a portion of his argument that we call the "monocultural fallacy." We discuss some rebuttals to Hart that invoke sustainability and predict long Galaxy colonization timescales. We find that the maximum Galaxy colonization timescale is actually much shorter than previous work has found (< 10 super(9) yr), and that many "sustainability" counter-arguments to Hart's thesis suffer from the monocultural fallacy. We extend Hart's argument to alien energy supplies and argue that detectably large energy supplies can plausibly be expected to exist because life has the potential for exponential growth until checked by resources or other limitations, and intelligence implies the ability to overcome such limitations. As such, if Hart's thesis is correct, then searches for large alien civilizations in other galaxies may be fruitful; if it is incorrect, then searches for civilizations within the Milky Way are more likely to succeed than Hart argued. We review some past Dysonian SETI efforts and discuss the promise of new mid-infrared surveys, such as that of WISE.
ABSTRACT Proxima Centauri is an M dwarf approximately 15,000 au from the Alpha Centauri binary, comoving and likely in a loosely bound orbit. Dynamic simulations show that this configuration can form ...from a more tightly bound triple system. As our nearest neighbors, these stars command great interest as potential planet hosts, and the dynamics of the stars govern the formation of any planets within the system. Here we present a scenario for the evolution of Alpha Centauri A and B and Proxima Centauri as a triple system. Based on N-body simulations, we determine that this pathway to formation is plausible, and we quantify the implications for planet formation in the Alpha Centauri binary. We expect that this formation scenario may have truncated the circumstellar disk slightly more than a system that formed in the current configuration, but that it most likely does not prevent terrestrial planet formation. We simulate planet formation in this system and find that, in most scenarios, two or more terrestrial planets can be expected around either Alpha Centauri A or B, orbiting in a region out to approximately 2 au, assuming that planetesimals and planetary embryos are able to form in the system first. Additionally, terrestrial planet formation and stability in Proxima Centauri's habitable zone are also plausible. However, an absence of planets around these stars may be indicative of highly disruptive stellar dynamics in the past.
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•2–6nm distance restraints on nucleic acids by pulsed EPR spectroscopy.•Determination of relative orientation of double stranded helices with new rigid spin labels.•Conformational ...dynamics of nucleic acid molecules.•Multi-frequency/multi-field Pulsed Electron–Electron Double Resonance method.•Fitting procedure to determine conformational ensemble of frozen power sample.
Nucleic acid molecules can adopt a variety of structures and exhibit a large degree of conformational flexibility to fulfill their various functions in cells. Here we describe the use of Pulsed Electron–Electron Double Resonance (PELDOR or DEER) to investigate nucleic acid molecules where two cytosine analogs have been incorporated as spin probes. Because these new types of spin labels are rigid and incorporated into double stranded DNA and RNA molecules, there is no additional flexibility of the spin label itself present. Therefore the magnetic dipole–dipole interaction between both spin labels encodes for the distance as well as for the mutual orientation between the spin labels. All of this information can be extracted by multi-frequency/multi-field PELDOR experiments, which gives very precise and valuable information about the structure and conformational flexibility of the nucleic acid molecules. We describe in detail our procedure to obtain the conformational ensembles and show the accuracy and limitations with test examples and application to double-stranded DNA.
Summary
Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older ...adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk.
Introduction
We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study.
Methods
The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4–12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type.
Results
Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk.
Conclusion
This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.
Globular star clusters that formed at the same cosmic time may have evolved rather differently from the dynamical point of view (because that evolution depends on the internal environment) through a ...variety of processes that tend progressively to segregate stars more massive than the average towards the cluster centre. Therefore clusters with the same chronological age may have reached quite different stages of their dynamical history (that is, they may have different 'dynamical ages'). Blue straggler stars have masses greater than those at the turn-off point on the main sequence and therefore must be the result of either a collision or a mass-transfer event. Because they are among the most massive and luminous objects in old clusters, they can be used as test particles with which to probe dynamical evolution. Here we report that globular clusters can be grouped into a few distinct families on the basis of the radial distribution of blue stragglers. This grouping corresponds well to an effective ranking of the dynamical stage reached by stellar systems, thereby permitting a direct measure of the cluster dynamical age purely from observed properties.
The cocaine aptamer is a DNA three-way junction that binds cocaine at its helical junction. We studied the global conformation and overall flexibility of the aptamer in the absence and presence of ...cocaine by pulsed electron-electron double resonance (PELDOR) spectroscopy, also called double electron-electron resonance (DEER). The rigid nitroxide spin label Ç was incorporated pairwise into two helices of the aptamer. Multi-frequency 2D PELDOR experiments allow the determination of the mutual orientation and the distances between two Çs. Since Ç is rigidly attached to double-stranded DNA, it directly reports on the aptamer dynamics. The cocaine-bound and the non-bound states could be differentiated by their conformational flexibility, which decreases upon binding to cocaine. We observed a small change in the width and mean value of the distance distribution between the two spin labels upon cocaine binding. Further structural insights were obtained by investigating the relative orientation between the two spin-labeled stems of the aptamer. We determined the bend angle between this two stems. By combining the orientation information with a priori knowledge about the secondary structure of the aptamer, we obtained a molecular model describing the global folding and flexibility of the cocaine aptamer.
We describe the framework and strategy of the G infrared search for extraterrestrial civilizations with large energy supplies, which will use the wide-field infrared surveys of WISE and Spitzer to ...search for these civilizations' waste heat. We develop a formalism for translating mid-infrared photometry into quantitative upper limits on extraterrestrial energy supplies. We discuss the likely sources of false positives, how dust can and will contaminate our search, and prospects for distinguishing dust from alien waste heat. We argue that galaxy-spanning civilizations may be easier to distinguish from natural sources than circumstellar civilizations (i.e., Dyson spheres), although GAIA will significantly improve our capability to identify the latter. We present a zeroth order null result of our search based on the WISE all-sky catalog: we show, for the first time, that Kardashev Type III civilizations (as Kardashev originally defined them) are very rare in the local universe. More sophisticated searches can extend our methodology to smaller waste heat luminosities, and potentially entirely rule out (or detect) both Kardashev Type III civilizations and new physics that allows for unlimited "free" energy generation.
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