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Seat effective amplitude transmissibilities (SEAT values) quantify the influence of seats on discomfort caused by vibration. This study investigated SEAT values with vertical mechanical shocks at low, medium, and high magnitudes (0.5, 1.0, and 2.0 ms-1.75) at frequencies between 1.0 and 16 Hz. With 18 subjects sitting on a rigid seat and two foam cushions, SEAT values were measured objectively (from the transmitted vibration), measured subjectively (by the responses of subjects), and predicted (using a model of the seat-passenger system). Except with high magnitude low frequency shocks, predicted SEAT values were similar to measured SEAT values. With shocks causing subjects to rise off a cushion and subsequently impact the cushion (low frequencies around 1 g), subjective SEAT values were better estimated using predicted SEAT values than objectively measured SEAT values, because accelerometers on cushions exaggerated the impact of the falling subject. However, accelerometers on rigid seats will underestimate such impacts. [ABSTRACT FROM AUTHOR]

Sleep disturbance may be the most often endorsed symptom of posttraumatic stress disorder (PTSD). Much of this research is based on subjective reports from trauma survivors; however, objective measures of sleep-related impairment have yielded findings inconsistent with self-report data. More studies investigating subjective and objective assessments concordantly are needed to understand sleep impairment in PTSD. The current study examined PTSD-related sleep disturbance in a female interpersonal violence cohort with full PTSD diagnoses ( N =51) assessing subjective (global and daily diary measures) and objective (actigraphy) sleep measures concurrently. PTSD severity was positively associated with global, subjective reports of sleep impairment and insomnia. Subjective measures of sleep (including global sleep impairment, insomnia, and daily sleep diary reports of total sleep time, sleep efficiency, and sleep onset latency) were moderately to strongly correlated. However, no significant correlations between subjective and objective reports of sleep impairment were found in this cohort. Analyses demonstrated an overall elevation in subjectively reported sleep impairment when compared to objective measurement assessed concurrently. Findings demonstrate a lack of agreement between subjective and objective measurements of sleep in a PTSD-positive female cohort, suggesting objective and subjective sleep impairments are distinct sleep parameters that do not necessarily directly co-vary. [ABSTRACT FROM AUTHOR]

Backrests influence the comfort of seated people. With 21 subjects sitting with three backrest heights (no backrest, short backrest, high backrest) discomfort caused by lateral, roll, and fully roll-compensated lateral oscillation was investigated at frequencies between 0.25 and 1.0 Hz. With lateral oscillation, the short backrest reduced discomfort at frequencies less than 0.63 Hz and the high backrest reduced discomfort at frequencies less than 1.0 Hz. With roll oscillation, the high backrest reduced discomfort at frequencies less than 0.63 Hz, but increased discomfort at 1.0 Hz. With fully roll-compensated lateral oscillation, the short backrest reduced discomfort at 0.4 Hz and the high backrest reduced discomfort at 0.5 and 0.63 Hz. As predicted by current standards, a backrest can increase discomfort caused by high frequencies of vibration. However, a backrest can reduce discomfort caused by low frequencies, with the benefit depending on the frequency and direction of oscillation and backrest height. [ABSTRACT FROM AUTHOR]

The detection of a vibration may be reduced by the presence of another vibration: a phenomenon known as ‘masking’. This study investigated how the detection of one frequency of vibration is influenced by vibration at another frequency. With nine subjects, thresholds for detecting fore-and-aft backrest vibration were determined (for 4, 8, 16, and 31.5-Hz sinusoidal vibration) in the presence of a masker vibration (4-Hz random vibration, 1/3-octave bandwidth at six intensities). The masker vibration increased thresholds for perceiving vibration at each frequency by an amount that reduced with increasing difference between the frequency of the sinusoidal vibration and the frequency of the masker vibration. The 4-Hz random vibration almost completely masked 4-Hz sinusoidal vibration, partially masked 8- and 16-Hz vibration, and only slightly masked 31.5-Hz vibration. The findings might be explained by the involvement of different sensory systems and different body locations in the detection of different frequencies of vibration. [ABSTRACT FROM AUTHOR]

The discomfort caused by lateral oscillation, roll oscillation, and fully roll-compensated lateral oscillation has been investigated at frequencies between 0.25 and 1.0 Hz when sitting on a rigid seat and when sitting on a compliant cushion, both without a backrest. Judgements of vibration discomfort and the transmission of lateral and roll oscillation through the seat cushion were obtained with 20 subjects. Relative to the rigid seat, the cushion increased lateral acceleration and roll oscillation at the lower frequencies and also increased discomfort during lateral oscillation (at frequencies less than 0.63 Hz), roll oscillation (at frequencies less than 0.4 Hz), and fully roll-compensated lateral oscillation (at frequencies between 0.315 and 0.5 Hz). The root-sums-of-squares of the frequency-weighted lateral and roll acceleration at the seat surface predicted the greater vibration discomfort when sitting on the cushion. The frequency-dependence of the predicted discomfort may be improved by adjusting the frequency weighting for roll acceleration at frequencies between 0.25 and 1.0 Hz. [ABSTRACT FROM AUTHOR]

The extent to which a seat can provide useful attenuation of vehicle vibration depends on three factors: the characteristics of the vehicle motion, the vibration transmissibility of the seat, and the sensitivity of the body to vibration. The ‘seat effective amplitude transmissibility’ (i.e., SEAT value) reflects how these three factors vary with the frequency and the direction of vibration so as to predict the vibration isolation efficiency of a seat. The SEAT value is mostly used to select seat cushions or seat suspensions based on the transmission of vertical vibration to the principal supporting surface of a seat. This study investigated the accuracy of SEAT values in predicting how seats with backrests influence the discomfort caused by multiple-input vibration. Twelve male subjects participated in a four-part experiment to determine equivalent comfort contours, the relative discomfort, the location of discomfort, and seat transmissibility with three foam seats and a rigid reference seat at 14 frequencies of vibration in the range 1–20 Hz at magnitudes of vibration from 0.2 to 1.6 ms −2 r.m.s. The ‘measured seat dynamic discomfort’ (MSDD) was calculated for each foam seat from the ratio of the vibration acceleration required to cause similar discomfort with the foam seat and with the rigid reference seat. Using the frequency weightings in current standards, the SEAT values of each seat were calculated from the ratio of overall ride values with the foam seat to the overall ride values with the rigid reference seat, and compared to the corresponding MSDD at each frequency. The SEAT values provided good predictions of how the foam seats increased vibration discomfort at frequencies around the 4-Hz resonance but reduced vibration discomfort at frequencies greater than about 6.3 Hz, with discrepancies explained by a known limitation of the frequency weightings. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The affinity constants of a ligand for active and inactive states of a receptor ultimately determine its capacity to activate downstream signaling events. In this report, we describe a reverse-engineering strategy for estimating these microscopic constants. Methods: Our approach involves analyzing responses measured downstream in the signaling pathway of a G protein-coupled receptor under conditions of allosteric modulation and reduced receptor expression or partial receptor inactivation. The analysis also yields estimates of the isomerization constant of the unoccupied receptor, the sensitivity constant of the signaling pathway, and the more empirical parameters of the receptor population including the observed affinities and efficacies of allosteric and orthosteric ligands – including inverse agonists – and the efficacy of the unoccupied receptor (i.e., constitutive activity). Results and discussion: We validate our approach with an analytical proof and by analysis of simulated data. We also use our method to analyze data from the literature. We show that the values of the microscopic constants of orthosteric and allosteric ligands are constant regardless of the allosteric interaction and the nature of the receptor-signaling pathway as long as the same active state mediates the response. Our analysis is useful for quantifying probe-dependent allosteric interactions and the selectivity of agonists for different signaling pathways. Knowing the isomerization constant and sensitivity constant of a signaling pathway in a given cell line or tissue preparation enables future investigators to estimate the affinity constants of agonists for receptor states simply through analysis of their concentration–response curves. Our approach also provides a means of validating in silico estimates of ligand affinity for crystal structures of active and inactive states of the receptor. [Copyright &y& Elsevier]

Abstract: Previous research has suggested that faces and words are processed and remembered differently as reflected by different ERP patterns for the two types of stimuli. Specifically, face stimuli produced greater late positive deflections for old items in anterior compared to posterior regions, while word stimuli produced greater late positive deflections in posterior compared to anterior regions. Given that words have existing representations in subjects׳ long-term memories (LTM) and that face stimuli used in prior experiments were of unknown individuals, we conducted an ERP study that crossed face and letter stimuli with the presence or absence of a prior (stable or existing) memory representation. During encoding, subjects judged whether stimuli were known (famous face or real word) or not known (unknown person or pseudo-word). A surprise recognition memory test required subjects to distinguish between stimuli that appeared during the encoding phase and stimuli that did not. ERP results were consistent with previous research when comparing unknown faces and words; however, the late ERP pattern for famous faces was more similar to that for words than for unknown faces. This suggests that the critical ERP difference is mediated by whether there is a prior representation in LTM, and not whether the stimulus involves letters or faces. [Copyright &y& Elsevier]

Abstract: While walking on an instrumented treadmill, 20 subjects were perturbed by lateral sinusoidal oscillations representative of those encountered in transport: frequencies in the range 0.5–2 Hz and accelerations in the range 0.1–2.0 ms−2 r.m.s., corresponding to velocities in the range 0.032–0.16 ms−1 r.m.s. Postural stability was assessed from the self-reported probability of losing balance (i.e., perceived risk of falling) and the movements of the centre of pressure beneath the feet. With the same acceleration at all frequencies, the velocities and displacements of the oscillatory perturbations were greater with the lower frequency oscillations, and these caused greater postural instability. With the same velocity at all frequencies, postural instability was almost independent of the frequency of oscillation. Movements of the centre of pressure show that subjects attempted to compensate for the perturbations by increasing their step width and increasing their step rate. [Copyright &y& Elsevier]

Abstract: The method of magnitude estimation is used in psychophysical studies to obtain numerical values for the intensity of perception of environmental stresses (e.g., noise and vibration). The exponent in a power function relating the subjective magnitude of a stimulus (e.g., the degree of discomfort) to the physical magnitude of the stimulus shows the rate of growth of sensations with increasing stimulus magnitude. When judging noise and vibration, there is no basis for deciding whether magnitude estimation should be performed with a reference stimulus (i.e., relative magnitude estimation, RME) or without a reference stimulus (i.e., absolute magnitude estimation, AME). Twenty subjects rated the discomfort caused by thirteen magnitudes of whole-body vertical vibration and 13 levels of noise, by both RME and AME on three occasions. There were high correlations between magnitude estimates of discomfort and the magnitudes of vibration and noise. Both RME and AME provided rates of growth of discomfort with high consistency over the three repetitions. When judging noise, RME was more consistent than AME, with less inter-subject variability in the exponent, n s. When judging vibration, RME was also more consistent than AME, but with greater inter-subject variability in the exponent, n v. When judging vibration, AME may be beneficial because sensations caused by the RME reference stimulus may differ (e.g., occur in a different part of the body) from the sensations caused by the stimuli being judged. [Copyright &y& Elsevier]

EBF1 plays a crucial role in early adipogenesis; however, despite high expression in mature adipocytes, its function in these cells is currently unknown. To identify direct and indirect EBF1 targets in fat, we undertook a combination of transcriptional profiling of EBF1-deficient adipocytes and genome-wide EBF1 location analysis. Our results indicate that many components of metabolic and inflammatory pathways are positively and directly regulated by EBF1, including PI3K/AKT, MAPK, and STAT1 signaling. Accordingly, we observed significant reduction ofmultiple signaling events in EBF1 knockdown cells as well as a reduction in insulin-stimulated glucose uptake and lipogenesis. Inflammatory signaling, gene expression, and secretion of inflammatory cytokines were also significantly affected by loss of EBF1 in adipocytes, although ChIP-sequencing results suggest that these actions are indirect.We also found that EBF1 occupies some 35,000 sites in adipocytes, most of which occur in enhancers. Significantly, comparison with three other published EBF1 ChIP-sequencing data sets in B-cells reveals both gene- and cell type-specific patterns of EBF1 binding. These results advance our understanding of the transcriptional mechanisms regulating signaling pathways in mature fat cells and indicate that EBF1 functions as a key integrator of signal transduction, inflammation, and metabolism. [ABSTRACT FROM AUTHOR]

Abstract: Thresholds for the perception of vibration on the hand reduce with increasing area of excitation when the thresholds are mediated by the Pacinian channel (a phenomenon known as spatial summation) but thresholds are generally independent of the area of excitation when they are mediated by non-Pacinian channels. The effect of the area of excitation on vibrotactile thresholds at the sole of the foot has not been thoroughly investigated. In the study reported in this paper, thresholds for the perception of 20Hz vibration and 160Hz vibration were determined on the foot (at the big toe (hallux), the medial (inside) ball, the lateral (outside) ball, and the heel) and on the hand (at the thenar eminence and at the fingertip) in 12 male subjects using four probe diameters: 1mm (0.19cm2 excitation area), 3mm (0.38cm2), 6mm (0.78mm2) and 10mm (1.53cm2) with a 2mm gap between the vibrating probe and a fixed surround. On both the hand and the foot, thresholds for the perception of 160Hz vibration decreased as the probe diameter increased. There was no overall consistent change in thresholds for the perception of 20Hz vibration. Thresholds for the perception of 160Hz vibration were lowest at the fingertip and highest at the big toe. Thresholds for 20Hz vibration were also lowest at the fingertip. It is concluded that on the sole of the foot there is evidence of spatial summation in the perception of 160Hz vibration, mediated by the Pacinian channel, but not in the perception of 20Hz vibration, mediated by a non-Pacinian channel. The findings show that vibrotactile thresholds at the foot obtained with different areas of excitation, or an unknown area of excitation, should not be compared. It is concluded that there is a need to standardise methods of measuring the vibrotactile thresholds at the foot that are obtained for clinical applications. [Copyright &y& Elsevier]

Ribulose-bisphosphate carboxylase/oxygenase (Rubisco) activase uses the energy from ATP hydrolysis to remove tight binding inhibitors from Rubisco, thus playing a key role in regulating photosynthesis in plants. Although several structures have recently added much needed structural information for different Rubisco activase enzymes, the arrangement of these subunits in solution remains unclear. In this study, we use a variety of techniques to show that Rubisco activase forms a wide range of structures in solution, ranging from monomers to much higher order species, and that the distribution of these species is highly dependent on protein concentration. The data support a model in which Rubisco activase forms an open spiraling structure rather than a closed hexameric structure. At protein concentrations of 1 μM, corresponding to the maximal activity of the enzyme, Rubisco activase has an oligomeric state of 2-4 subunits. We propose a model in which Rubisco activase requires at least 1 neighboring subunit for hydrolysis of ATP. [ABSTRACT FROM AUTHOR]

Abstract: Lateral acceleration causes discomfort but how the discomfort depends on the frequency of acceleration or characteristics of seating is poorly understood. Using magnitude estimation, twelve male subjects rated the discomfort caused by lateral oscillation at eight frequencies (0.2–1.0 Hz) across four seating conditions (a rigid seat and a train seat, both with and without backrests). Discomfort increased with increasing frequency of lateral acceleration in a similar manner for all four seating conditions. However, at all frequencies and with both seats there was less discomfort when sitting with backrest support than without. Least discomfort occurred on the train seat with backrest and greatest discomfort on the rigid seat without backrest. Current standards predict an additive effect of backrest on vibration discomfort, but the findings show that low frequency lateral acceleration can cause less discomfort when sitting with a backrest than when sitting on the same seat without a backrest. [Copyright &y& Elsevier]

Abstract: With the possibility of future fresh water shortages increasing, a methodology that incorporates climatic and anthropogenic factors is needed. This research estimates future water availability in the Lower Cape Fear basin using changes in climate, land use, and population growth. The USGS Thornthwaite monthly water balance model is used with estimates of climate change and land use change parameters to assess future water resources based on predicted monthly fluxes of the water balance. The southern United States is a rapidly growing region. Trends present in the population data are used to produce future estimates of population for the basin. Precipitation and temperature estimates based on Intergovernmental Panel on Climate Change (IPCC) predictions and current climatology are inputs to the model. Projected increases in impervious surface cover due to population growth and urbanization are incorporated through the model runoff factor. Water stress indicators are used to categorize the sub-watersheds as water rich, water stressed, or water scarce. Scenarios incorporating regional predictions of climate change indicate a decrease in summer soil moisture minima and increases in summer water deficits. Ensemble runs indicate a shift toward water stress in the Lower Cape Fear River basin, due to a warming climate as well as increased demand. While climate change has a significant impact on water resources, population growth was found to have the most substantial impact. The methods and findings have application to water managers at local and regional levels. [Copyright &y& Elsevier]

Abstract: Current methods for evaluating seat vibration to predict vibration discomfort assume the same frequency weightings and axis multiplying factors can be used at the seat surface and the backrest irrespective of the backrest inclination. This experimental study investigated the discomfort arising from whole-body vertical vibration when sitting on a rigid seat with no backrest and with a backrest inclined at 0° (upright), 30°, 60°, and 90° (recumbent). Within each of these five postures, 12 subjects judged the discomfort caused by vertical sinusoidal whole-body vibration (at frequencies from 1 to 20 Hz at magnitudes from 0.2 to 2.0 m s−2 r.m.s.) relative to the discomfort produced by a reference vibration (8 Hz at 0.4 m s−2 r.m.s.). With 8-Hz vertical vibration, the subjects also judged vibration discomfort with each backrest condition relative to the vibration discomfort with no backrest. The locations in the body where discomfort was experienced were determined for each frequency at two vibration magnitudes. Equivalent comfort contours were determined for the five conditions of the backrest and show how discomfort depends on the frequency of vibration, the presence of the backrest, and the backrest inclination. At frequencies greater than about 8 Hz, the backrest increased vibration discomfort, especially when inclined to 30°, 60°, or 90°, and there was greater discomfort at the head or neck. At frequencies around 5 and 6.3 Hz there was less vibration discomfort when sitting with an inclined backrest. [Copyright &y& Elsevier]

Abstract: Few studies have compared the discomfort caused by vibration in different directions, and few have investigated the vibration discomfort of standing people. This study was designed to compare the discomfort experienced by standing people exposed to sinusoidal vibration in the fore-and-aft, lateral, and vertical directions. Using the method of magnitude estimation, 12 subjects estimated the discomfort caused by 4-Hz sinusoidal vibration at 10 different magnitudes. At 4 Hz, subjects were less sensitive to lateral vibration than to fore-and-aft vibration (Ky /Kx  = 0.71), and more sensitive to vertical vibration than to horizontal vibration (Kz /Kx  = 1.95; Kz /Ky  = 2.77). Previous findings showing how the discomfort of standing people depends on the frequency of fore-and-aft, lateral, and vertical vibration were used to define frequency weightings that reflect relative sensitivity to vibration in each direction. The frequency weightings differ from those appropriate for seated people, and differ from the weightings for standing people in current standards that were mostly derived from understanding of the discomfort of seated people. [Copyright &y& Elsevier]

Abstract: When using vibrotactile thresholds to investigate neuropathy in the fingers, the indentation of a vibrating probe, and the force applied to a static surround around a vibrating probe, affect thresholds. This study was designed to investigate the effects on vibrotactile perception thresholds at the sole of the foot of probe indentation (i.e. height of a vibrating probe relative to a static surround) and the force applied to the static surround. Thresholds at 20Hz (expected to be mediated by the NP I channel) and at 160Hz (expected to be mediated by the Pacinian channel) were obtained at the hallux (i.e. greater toe) and the ball of the foot on 14 healthy subjects. In one condition, the height of the vibrating probe was varied to 0, 1, 2, 3, and 4mm above a static surround with 4-N force applied to the surround. In a second condition, the force applied to the surround was varied to 1, 2, 3, 4, 5, and 6N while using a probe height of 1mm. Thresholds at 20Hz decreased with increasing probe height from 0 to 1mm but showed no significant variation between 2, 3, and 4mm at either the hallux or the ball of the foot. Thresholds at 160Hz decreased with increasing probe height from 0 to 4mm at both the hallux and the ball of the foot. Thresholds at 20Hz obtained with 1-N surround force were higher than thresholds obtained with 2N, but there was no significant difference with surround forces from 2 to 6N at either the hallux or the ball of the foot. Thresholds at 160Hz were unaffected by variations in surround force at the ball of the foot but tended to decrease with increasing force at the hallux. It is concluded that a vibrating probe flush with a static surround, and a surround force in the range 2–4N, are appropriate when measuring vibrotactile thresholds at the hallux and the ball of the foot with a 6-mm diameter contactor and a 2-mm gap to the static surround. [Copyright &y& Elsevier]

Abstract: The reactions of ethylene glycol and 1,2-propanediol have been studied on Pd(111) using temperature programmed desorption (TPD) and high resolution electron energy loss spectroscopy (HREELS). Both molecules initially decompose through O–H activation, forming ethylenedioxy (–OCH2CH2O–) and 1,2-propanedioxy (–OCH2CH(CH3)O–) surface intermediates. For ethylene glycol, increases in thermal energy lead to dehydrogenation and formation of carbonyl species at both oxygen atoms. The resulting glyoxal (O═CHCH═O) either desorbs molecularly or reacts through one of two competing pathways. The favored pathway proceeds via C–C bond scission, dehydrogenation, and decarbonylation to form carbon monoxide and hydrogen. In a minor pathway, small amounts of glyoxal undergo C–O bond scission and recombination with surface hydrogen to form ethylene and water. The same reaction mechanism occurs for 1,2-propanediol after methyl elimination and formation of glyoxal. However, this is accompanied by a minor pathway involving a methylglyoxal (O=CHC(CH3)=O) intermediate. The prevalence of the dehydrogenation/decarbonylation pathway in the current work is consistent with the high selectivity for C–C scission in the aqueous phase reforming of polyols on supported Pd catalysts. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: : Amyloid fibrils and amyloid-like structures are implicated in atherosclerosis via macrophage activation and inflammation. A common property of amyloid-like structures is their ability to induce thioflavin T (ThT) fluorescence. We measured ThT fluorescence in serum and related these levels to traditional cardiovascular risk factors and non-invasive measures of vascular dysfunction (elasticity). In addition, chemically modified serum components that contribute to serum ThT fluorescence were explored and identified. Design, Methods, and Results: : Sera from 105 people, including 35 healthy subjects, and 70 high cardiovascular risk patients (36 with rheumatoid arthritis and 34 with systemic lupus erythrematosus) showed an 8.75-fold variation in induced ThT fluorescence. Although mean (±SD) ThT fluorescence did not differ significantly between groups (controls 0.97±0.26, RA 1.12±0.45, and SLE 0.74±0.23), the combined data set showed significant inverse correlation (p =0.046) between ThT fluorescence tertiles and small artery elasticity. Correlation was also found between ThT fluorescence tertiles and LDL-cholesterol, total-cholesterol, and C-reactive protein. Floatation fractionation of apoB containing lipoproteins showed that ThT reactivity in this fraction correlated with both serum oxidised-LDL and LDL-cholesterol levels. However, approximately 94% of ThT reactivity in serum was associated with the non-apoB containing serum fraction, with the majority of ThT fluorescence associated with albumin. Incubation of purified albumin with glucose or with methylglyoxal induced ThT fluorescence, suggesting that glycated or chemical adducts of albumin contribute to the variation in ThT fluorescence of human serum. Conclusions: : We propose that the detection of these adducts in serum using ThT fluorescence measurements may provide a marker for chemically modified protein structures that could assist the assessment of cardiovascular disease risk. [Copyright &y& Elsevier]

Abstract: Vehicle drivers receive tactile feedback from steering-wheel vibration that depends on the frequency and magnitude of the vibration. From an experiment with 12 subjects, equivalent comfort contours were determined for vertical vibration of the hands at two positions with three grip forces. The perceived intensity of the vibration was determined using the method of magnitude estimation over a range of frequencies (4–250Hz) and magnitudes (0.1–1.58ms−2 r.m.s.). Absolute thresholds for vibration perception were also determined for the two hand positions over the same frequency range. The shapes of the comfort contours were strongly dependent on vibration magnitude and also influenced by grip force, indicating that the appropriate frequency weighting depends on vibration magnitude and grip force. There was only a small effect of hand position. The findings are explained by characteristics of the Pacinian and non-Pacinian tactile channels in the glabrous skin of the hand. [Copyright &y& Elsevier]

Abstract: We report the synthesis of (2E,5E)-4-oxoheptadienedioic acid and (2E)-4-oxoheptenedioic acid and evaluation of both diester and diacid analogues as inhibitors of bacterial dihydrodipicolinate synthase. Enzyme kinetic studies allowed the determination of second-order rate constants of inactivation; and substrate co-incubation studies have shown the inhibitors act at the active-site. Mass spectrometric analyses have further explored the enzyme–inhibitor interaction and determined the sites of enzyme alkylation. [Copyright &y& Elsevier]

To understand the molecular mechanisms underlying transcriptional activation of fatty-acid synthase (FAS), we examined the relationship between upstream stimulatory factor (USF) and SREBP-1c, two transcription factors that we have shown previously to be critical for FAS induction by feeding/insulin. Here, by using a combination of tandem affinity purification and coimmunoprecipitation, we demonstrate, for the first time, that USF and SREBP-1 interact in vitro and in vivo. Glutathione S-transferase pulldown experiments with various USF and sterol regulatory element-binding protein (SREBP) deletion constructs indicate that the basic helix-loop-helix domain of USF interacts directly with the basic helix-loop-helix and an N-terminal region of SREBP-1c. Furthermore, cotransfection of USF and SREBP-1c with an FAS promoter-luciferase reporter construct in Drosophila SL2 cells results in highly synergistic activation of the FAS promoter. We also show similar cooperative activation of the mitochondrial glycerol-3-phosphate acyltransferase promoter by USF and SREBP-1c. Chromatin immunoprecipitation analysis of mouse liver demonstrates that USF binds constitutively to the mitochondrial glycerol 3-phosphate acyltransferase promoter during fasting/refeeding in vivo, whereas binding of SREBP-1 is observed only during refeeding, in a manner identical to that of the FAS promoter. In addition, we show that the synergy we have observed depends on the activation domains of both proteins and that mutated USF or SREBP lacking the N-terminal activation domain could inhibit the transactivation of the other. Closely positioned E-boxes and sterol regulatory elements found in the promoters of several lipogenic genes suggest a common mechanism of induction by feeding/insulin. [ABSTRACT FROM AUTHOR]

Dihydrodipicolinate synthase (DHDPS, E.C. 4.2.1.52) mediates the first unique reaction of (S)-lysine biosynthesis in plants and microbes—the condensation of (S)-aspartate-β-semialdehyde ((S)-ASA) and pyruvate. It has been shown that DHDPS is partially feedback inhibited by (S)-lysine; it is suggested that this mechanism regulates flux through the DAP biosynthetic pathway. Others have characterised DHDPS from Escherichia coli with respect to (S)-lysine inhibition. They have concluded that, with respect to pyruvate, the first substrate of the reaction, DHDPS shows uncompetitive inhibition: as such, they further suggest that (S)-lysine inhibits DHDPS via interaction with the binding site for the second substrate, (S)-ASA. Yet, this finding is based on the assumption that (S)-lysine is a fully uncompetitive inhibitor. In light of crystallographic studies, which lead to the proposal that (S)-lysine affects the putative proton-relay of DHDPS, we re-evaluated the inhibition mechanism of DHDPS with respect to (S)-lysine by incorporating the observed hyperbolic inhibition. Our data showed that lysine is not an uncompetitive inhibitor, but a mixed inhibitor when pyruvate and (S)-lysine concentrations were varied. Thus, consistent with the crystallographic data, (S)-lysine must have an effect on the initial steps of the DHDPS reaction, including the binding of pyruvate and Schiff base formation. [Copyright &y& Elsevier]

We compared the binding properties of selective muscarinic antagonists with their potencies for antagonizing muscarinic responses in Chinese hamster ovary (CHO) cells expressing M2 and M3 muscarinic receptors in combination and in isolation. When measured by the competitive displacement of [3H]N-methylscopolamine binding to CHO cells expressing both M2 and M3 muscarinic receptors (CHO M2+M3 cells), the competition curves of the subtype-selective muscarinic antagonists were consistent with a two-site model. One site exhibited binding properties identical to those of CHO M2 cells, whereas the other site exhibited properties like those of CHO M3 cells. Oxotremorine-M, a muscarinic agonist, elicited a robust, pertussis toxin-insensitive stimulation of phosphoinositide hydrolysis in both CHO M3 and CHO M2+M3 cells, but not in CHO M2 cells. The pharmacological antagonism of the phosphoinositide response exhibited similar properties in both CHO M3 and CHO M2+M3 cells. Oxotremorine-M elicited a pertussis toxin-sensitive, robust inhibition of forskolin-stimulated cyclic AMP (cAMP) accumulation in both CHO M2 and CHO M2+M3 cells and a less robust inhibition in CHO M3 cells. At higher concentrations, oxotremorine-M elicited an increase in cAMP accumulation over the maximal inhibition noted at lower concentrations in both CHO M3 and CHO M2+M3 cells. Following pertussis toxin treatment, only the stimulatory phase of the cAMP response to oxotremorine-M was observed in CHO M2, CHO M3, and CHO M2+M3 cells. The pharmacological antagonism of the cAMP response in CHO M2+M3 cells resembled that expected for a response mediated independently by both M2 and M3 receptors. [Copyright &y& Elsevier]

Background: Chronic and inescapable trauma is implicated in the stress-induced analgesia (SIA) response.Methods: A sample of 27 chronically battered women was compared with 28 trauma-exposed nonbattered women on their SIA response at 1 month postindex assault.Results: For the battered women sample, the SIA response at 1 month postindex assault was found to significantly predict an increase in posttraumatic stress disorder-related hyperarousal at 3 months postindex assault. Furthermore, the battered women showed a significant increase in depression symptoms from 1 to 3 months postindex assault compared with the nonbattered women, who showed a significant decrease.Conclusions: The findings suggest that the chronic and inescapable nature of trauma exposure in the battered women might account for an SIA response that is qualitatively different from that seen in the nonbattered women. It is suggested that the mechanism underlying the SIA response in battered women might be opioid mediated and that it might be responsible for the significant prediction of physiologic hyperarousal. Furthermore, this hyperarousal might moderate the relationship between the SIA response and depression. [ABSTRACT FROM AUTHOR]

Reductions in vehicle vibration that may contribute to improvements in overall vehicle ride could individually be too small to be detected by drivers or passengers. This study investigated the 'difference threshold' (the difference in magnitude between two stimuli which is just sufficient for their difference to be detected) required for a change in vehicle ride to be perceived and whether this was consistent with Weber's Law. Ten male and 10 female subjects sat in a car seat and were exposed to four different reproductions of the vertical vibration recorded on the seat of a car. Three of the stimuli had the same waveform recorded while the car traversed a tarmac surface. This waveform was reproduced using three different magnitudes of vibration at the seat: 0.2, 0.4 and 0.8 m s(-2) r.m.s. (Wb weighted). The other stimulus was recorded with the car traversing a 'pavé' surface that gave a different waveform that was reproduced at a magnitude of 0.4 m s(-2) r.m.s. (Wb weighted). There were significant differences in the absolute difference thresholds measured using the same waveform at the three different magnitudes. When the difference thresholds were expressed in relative terms (the proportion by which two stimuli must differ in magnitude to be discriminated), the relative difference thresholds were approximately 13%, and independent of both the vibration magnitude and the vibration waveform. The results are therefore consistent with Weber's Law. No consistent differences were observed between the responses of male and female subjects. [ABSTRACT FROM AUTHOR]

Emotional engagement when recollecting a trauma memory is considered a key element of effective trauma-focused therapy. Research has shown that reduced physiological reactivity during trauma recall is associated with worse treatment outcomes for posttraumatic stress disorder (PTSD), but this has yet to be examined in a cognitively oriented treatment. This study examined whether pretreatment heart rate (HR) reactivity during trauma recall predicts PTSD symptom improvement and treatment dropout during Cognitive Processing Therapy (CPT) for PTSD. Participants were 142 women with PTSD secondary to interpersonal violence enrolled in one of two clinicals trials. HR reactivity reflected the mean increase in HR after listening to two 30-s scripts of the trauma memory prior to treatment. Linear mixed-effects models showed the effect of HR reactivity on change in total PTSD symptoms was not significant, but lower HR reactivity predicted less improvement in reexperiencing and avoidance and was associated with increased dropout. Findings suggest pretreatment physiological reactivity to the trauma memory may be a prognostic indicator of some elements of treatment response in CPT. Results tentatively support the importance of emotional activation during trauma recall in cognitive treatment of PTSD, though more research is needed to clarify how low HR reactivity impacts treatment. • Women with PTSD (n = 142) received 12 sessions of cognitive processing therapy (CPT). • Prior to treatment, heart rate reactivity (HRR) during trauma recall was measured. • Lower HRR predicted less improvement in reexperiencing and avoidance during CPT. • Lower HRR also predicted greater study and treatment dropout. • No association between pretreatment HRR and total PTSD symptom change was found. [ABSTRACT FROM AUTHOR]

Abstract: Has the current US space policy improved the USA''s overall strategic position? Does it affect favorably international partnerships? These questions are examined in terms of security, political economy, and influence. In today''s context, where there are more space players, more options, more potential for unintended consequences, and higher stakes, unilateral action is more limited in its effectiveness than in earlier times. Surveying current US space policy, it is not clear that data-driven, analytically based decisions are being made to affect positively national independence, innovation, market creation, and international perceptions of the USA as a trustworthy partner. More promising are the steps taken to bolster a predictable space operational environment and economic competitiveness. Ultimately, in order to achieve American excellence and leadership, a ‘closed loop’ on the policy system is needed, to gauge regularly and systematically whether the US is achieving the desired national outcomes. [Copyright &y& Elsevier]

• A series of experiments tests if working memory predicts ability to prioritize study. • High working memory leads to slightly better prioritization. • Experience at prioritizing leads to more marked improvements across all subjects. People with larger working memory capacity exhibit enhanced free recall. One explanation for this relationship is that the strategies that people bring to the task of learning and retrieving are superior in learners with high working memory. There is ample evidence that learners with high working memory do indeed bring better strategies to both encoding and retrieval, but as yet little evidence of whether higher working memory is related to greater effectiveness in prioritizing information across materials that differ in value. Using the value-directed remembering paradigm of Castel, Benjamin, Watkins, and Craik (2002), we examined whether learners with high working memory capacity show a particular advantage in remembering materials that are of high value. Across four experiments, we found that high working memory capacity led to a selective preference for remembering high-valued word pairs, but the effect was very modest and does not provide a complete picture of the relationship between working memory and recall. [ABSTRACT FROM AUTHOR]

Abstract The apolipoprotein family is a set of highly conserved proteins characterized by the presence of amphipathic α-helical sequences that mediate lipid binding. Paradoxically, this family of proteins is also prominent among the proteins known to form amyloid fibrils, characterized by extensive cross-β structure. Several apolipoproteins including apolipoprotein (apo) A-I, apoA-II and apoC-II accumulate in amyloid deposits of atherosclerotic lesions. This review illustrates the role of lipid-apolipoprotein interactions in apolipoprotein folding and aggregation with a specific focus on human apoC-II, a well-studied member of the family. In the presence of high concentrations of micellar lipid mimetics apoC-II adopts a stable and predominantly α-helical structure, similar to other members of the family and presumed to be the structure of apoC-II in circulating plasma lipoproteins. In contrast, lipid-free apoC-II aggregates to form long amyloid fibrils with a twisted ribbon-like morphology. Detailed structural analyses identify a letter G-like conformation as the basic building block within these fibrils. Phospholipids at submicellar concentrations accelerate apoC-II fibril formation by promoting the formation of a discrete tetrameric intermediate. Conversely, several small molecule lipid-mimetics inhibit apoC-II fibril formation at submicellar concentrations, inducing well-defined dimers unable to further aggregate. Finally, low concentrations of phospholipid micelles and bilayers induce the slow formation of amyloid fibrils with distinct rod-like fibril morphology. These studies highlight the diversity of lipid effects on apolipoprotein amyloid formation and reveal a conformational adaptability that could underlie the widespread occurrence of apolipoproteins in amyloid deposits and atheroma. Highlights • Apolipoproteins are prominent in the list of proteins known to form amyloid in vivo. • Lipids alter the rate of formation and final structure of apolipoprotein amyloid. • These effects may play roles in pathology of atherosclerosis and systemic amyloidoses. • We review the complex effects of lipid on amyloid formation by apolipoprotein C-II. [ABSTRACT FROM AUTHOR]

Biodynamic responses of the seated human body are usually measured and modelled assuming a single point of vibration excitation. With vertical vibration excitation, this study investigated how forces are distributed over the body-seat interface. Vertical and fore-and-aft forces were measured beneath the ischial tuberosities, middle thighs, and front thighs of 14 subjects sitting on a rigid flat seat in three postures with different thigh contact while exposed to random vertical vibration at three magnitudes. Measures of apparent mass were calculated from transfer functions between the vertical acceleration of the seat and the vertical or fore-and-aft forces measured at the three locations, and the sum of these forces. When sitting normally or sitting with a high footrest, vertical forces at the ischial tuberosities dominated the vertical apparent mass. With feet unsupported to give increased thigh contact, vertical forces at the front thighs were dominant around 8 Hz. Around 3–7 Hz, fore-and-aft forces at the middle thighs dominated the fore-and-aft cross-axis apparent mass. Around 8–10 Hz, fore-and-aft forces were dominant at the ischial tuberosities with feet supported but at the front thighs with feet unsupported. All apparent masses were nonlinear: as the vibration magnitude increased the resonance frequencies decreased. With feet unsupported, the nonlinearity in the apparent mass was greater at the front thighs than at the ischial tuberosities. It is concluded that when the thighs are supported on a seat it is not appropriate to assume the body has a single point of vibration excitation. [ABSTRACT FROM AUTHOR]

To assess whether extra-oesophageal symptoms are predictive of oesophageal malignancy. A prospective, single-centre cross-sectional questionnaire study at a tertiary referral unit for oesophageal cancer using the Comprehensive Reflux Symptoms Scale (CReSS) questionnaire tool. Respondents with oesophageal malignancy were compared with historical cohorts undergoing airway examination or upper gastrointestinal endoscopy and found to have benign diagnoses. We developed a model for predicting oesophageal cancer using linear discriminant analysis and logistic regression, assessed by Monte Carlo cross validation. Respondents with oesophageal malignancy (n = 146; mean age 70.5; male: female, 71:29) were compared with those undergoing airway examination (n = 177) and upper gastrointestinal endoscopy (n = 351), found to have benign diagnoses. No single questionnaire item, or group of co-varying items (factors), reliably discriminated oesophageal cancer from other diagnoses. Individual items which suggested higher risk of oesophageal malignancy included dysphagia (area under the curve (AUC) 0.68), low appetite (AUC 0.66), and early satiety (AUC 0.58). Conversely, throat pain (AUC 0.38), bloating (AUC 0.38) and heartburn (AUC 0.37) were inversely related to cancer risk. A forward stepwise regression analysis including a subset of 12 CReSS questionnaire items together with age and sex derived a model predictive of oesophageal malignancy in this cohort (AUC 0.89). We demonstrate a model comprised of 12 questionnaire items and 2 demographic parameters as a potential predictive tool for oesophageal malignancy diagnosis in this study population. Translating this model for predicting oesophageal malignancy in the general population is a valuable topic for future research. • Oesophageal malignancy remains a diagnostic challenge, often presenting late. • Extra-oesophageal symptoms are not cancer referral criteria in the United Kingdom. • Symptoms can be characterised with the Comprehensive Reflux Symptoms Scale (CReSS). • Extra-oesophageal symptoms may be useful to predict risk of oesophageal malignancy. • This could be used to risk stratify patients for upper gastrointestinal endoscopy. [ABSTRACT FROM AUTHOR]

The aggregation of α-synuclein (α-syn) into amyloid fibrils is associated with neurodegenerative diseases, collectively referred to as the α-synucleinopathies. In vivo, molecular chaperones, such as the small heat-shock proteins (sHsps), normally act to prevent protein aggregation; however, it remains to be determined how aggregation-prone α-syn evades sHsp chaperone action leading to its disease-associated deposition. This work examines the molecular mechanism by which two canonical sHsps,αB-crystallin (αB-c) and Hsp27, interact with aggregation-prone α-syn to prevent its aggregation in vitro. Both sHsps are very effective inhibitors of α-syn aggregation, but no stable complex between the sHsps andα-syn was detected, indicating that the sHsps inhibit α-syn aggregation via transient interactions. Moreover, the ability of these sHsps to prevent α-syn aggregation was dependent on the kinetics of aggregation; the faster the rate of aggregation (shorter the lag phase), the less effective the sHsps were at inhibiting fibril formation of α-syn. Thus, these findings indicate that the rate at whichα-syn aggregates in cells may be a significant factor in how it evades sHsp chaperone action in the α-synucleinopathies. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated whether the method for eliciting vibration-induced oVEMPs could be improved by applying vibration directly to the teeth, and how vibration-induced oVEMP responses depend on the duration of the applied vibration. Methods: In 10 participants, a hand-held shaker was used to present 100-Hz vibration tone pips to the teeth via a customised bite-bar or to other parts of the head. oVEMP potentials were recorded in response to vibration in three orthogonal directions and five stimulus durations (10-180 ms). The oVEMP responses were analysed in terms of the peak latency onset, peak-to-peak amplitude, and the quality of the trace. Results: Vibration applied to the teeth via the bite-bar produced oVEMPs that were more consistent, of higher quality and of greater amplitude than those evoked by vibration applied to the head. Results: Longer duration stimuli produced longer duration oVEMP responses. Results: One cycle duration stimuli produced responses that were smaller in amplitude and lower quality than the longer stimulus durations. Conclusions: Application of vibration via the teeth using a bite-bar is an effective means of producing oVEMPs. Conclusions: A 1-cycle stimulus is not optimal to evoke an oVEMP because it produces less robust responses than those of longer stimulus duration. Conclusions: A positive relationship between the duration of the stimulus and the response is consistent with the notion that the vibration-induced oVEMP is an oscillatory response to the motion of the head, rather than being a simple reflex response that occurs when the stimulus exceeds a threshold level of stimulation. [ABSTRACT FROM AUTHOR]

Apolipoprotein A-I (apoA-I) is the major component of high density lipoproteins and plays a vital role in reverse cholesterol transport. Lipid-free apoA-I is the main constituent of amyloid deposits found in atherosclerotic plaques, an acquired type of amyloidosis, whereas its N-terminal fragments have been associated with a hereditary form, known as familial apoA-I amyloidosis. Here, we identified and verified four “aggregation-prone” segments of apoA-I with amyloidogenic properties, utilizing electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy and polarized light microscopy. These segments may act as conformational switches, possibly controlling the transition of the α-helical apoA-I content into the “cross-β” architecture of amyloid fibrils. A structural model illuminating the structure of amyloid fibrils formed by the N-terminal fragments of apoA-I is proposed, indicating that two of the identified chameleon segments may play a vital part in the formation of amyloid fibrils in familial apoA-I amyloidosis. [ABSTRACT FROM AUTHOR]

Abstract: The motions of vessels may interfere with crew activities and well-being, but the relationships between motion and the experiences of crew are not well-established. Crew responses to motions of a floating production and storage offshore vessel at a fixed location in the North Sea were studied over a 5-month period to identify any changes in crew difficulties and symptoms associated with changes in vessel motion. Ship motions in all six axes (fore-aft, lateral, vertical, roll, pitch, and yaw) were recorded continuously over the 5-month period while 47 crew completed a total of 1704 daily diary entries, a participation rate of 66–78% of the crew complement. The dominant oscillations had frequencies of around 0.1Hz, producing magnitudes of translational oscillation in accommodation areas of up to about 0.7ms−2 r.m.s., depending on the weather, and magnitudes up to three times greater in some other areas. The daily diaries gave ratings of difficulties with tasks, effort level, motion sickness, health symptoms, fatigue, and sleep. Problems most strongly associated with vessel motions were difficulties with physical tasks (balancing, moving and carrying), and sleep problems. Physical and mental tiredness, cognitive aspects of task performance, and stomach awareness and dizziness were also strongly associated with motion magnitude. There was a vomiting incidence of 3.1%, compared with a predicted mean vomiting incidence of 9.3% for a mixed population of unadapted adults. It is concluded that crew difficulties increase on days when vessel motions increase, with some activities and responses particularly influenced by vessel motions. [Copyright &y& Elsevier]

Two studies examined the contributing factors for panic symptoms following trauma. In Study 1, survivors of sexual and nonsexual assaults (N=105) were assessed at 2 weeks postcrime. Prior trauma, psychiatric history, crime characteristics, and peritraumatic dissociation were assessed. Posttraumatic panic was modestly predicted by childhood sexual abuse (CSA) experiences, a history of Anxiety and Depression, and peritraumatic dissociation. Childhood physical abuse (CPA), Adult Victimization, crime variables, and a prior history of Substance Use disorders and posttraumatic stress disorder (PTSD) were not implicated. In Study 2, the role of peritraumatic panic in predicting later arousal was also examined in a similar sample who were assessed within 6 weeks of their trauma (N=93). Presence of significant arousal during trauma predicted frequency of posttrauma panic attacks, but not its severity. In contrast to Study 1, prior history of PTSD, perception of life threat, and the index trauma being a sexual assault all predicted posttrauma panic, whereas prior trauma exposure and depression did not. These findings are discussed in terms of cognitive and arousal factors that may influence posttrauma panic. [Copyright &y& Elsevier]

Background: Minimally invasive thoracic surgery causes significant postoperative pain. Erector spinae plane (ESP) block and serratus anterior plane (SAP) block promise effective thoracic analgesia compared with systemically administered opioids, but have never been compared in terms of terms of quality of recovery and overall morbidity after minimally invasive thoracic surgery.Methods: Sixty adult patients undergoing minimally invasive thoracic surgery were randomly assigned to receive either single-shot ESP or SAP block before surgery using levobupivacaine 0.25%, 30 ml. The primary outcome was quality of patient recovery at 24 h, using the Quality of Recovery-15 (QoR-15) scale. Secondary outcomes included area under the curve (AUC) of pain verbal rating scale (VRS) over time, time to first opioid analgesia, postoperative 24 h opioid consumption, in-hospital comprehensive complication index (CCI) score and hospital stay.Results: The QoR-15 score was higher among ESP patients compared with those in the SAP group, mean (standard deviation): 114 (16) vs 102 (22) (P=0.02). Time (min) to first i.v. opioid analgesia in recovery was 32.6 (20.6) in ESP vs 12.7 (9.5) in SAP (P=0.003). AUC at rest was 92 (31) mm h-1vs 112 (35) in ESP and SAP (P=0.03), respectively, whereas AUC on deep inspiration was 107 mm h-1 (32) vs 129 (32) in ESP and SAP (P=0.01), respectively. VRS pain on movement in ESP and SAP at 24 h was, median (25-75% range): 4 (2-4) vs 5 (3-6) (P=0.04), respectively. Opioid consumption at 24 h postoperatively was 29 (31) vs 39 (34) (P=0.37). Median (25-75%) CCI in ESP and SAP was 1 (0-2) vs 4 (0-26) (P=0.03), whereas hospital stay was 3 (2-6) vs 6 (3-9) days (P=0.17), respectively.Conclusion: Compared with SAP, ESP provides superior quality of recovery at 24 h, lower morbidity, and better analgesia after minimally invasive thoracic surgery.Clinical Trial Registration: NCT03862612. [ABSTRACT FROM AUTHOR]

Small heat-shock proteins (sHSPs) are ubiquitously expressed molecular chaperones that inhibit amyloid fibril formation; however, their mechanisms of action remain poorly understood. sHSPs comprise a conserved a-crystallin domain flanked by variable N- and C-terminal regions. To investigate the functional contributions of these three regions, we compared the chaperone activities of various constructs of human αB-crystallin (HSPB5) and heat-shock 27-kDa protein (Hsp27, HSPB1) during amyloid formation by α-synuclein and apolipoprotein C-II. Using an array of approaches, including thioflavin T fluorescence assays and sedimentation analysis, we found that the N-terminal region of Hsp27 and the terminal regions of aBcrystallin are important for delaying amyloid fibril nucleation and for disaggregating mature apolipoprotein C-II fibrils. We further show that the terminal regions are required for stable fibril binding by both sHSPs and for mediating lateral fibril– fibril association, which sequesters preformed fibrils into large aggregates and is believed to have a cytoprotective function. We conclude that although the isolated a-crystallin domain retains some chaperone activity against amyloid formation, the flanking domains contribute additional and important chaperone activities, both in delaying amyloid formation and in mediating interactions of sHSPs with amyloid aggregates. Both these chaperone activities have significant implications for the pathogenesis and progression of diseases associated with amyloid deposition, such as Parkinson's and Alzheimer's diseases. [ABSTRACT FROM AUTHOR]

Interleukin (IL) 11 activates multiple intracellular signaling pathways by forming a complex with its cell surface α-receptor, IL-11Rα, and the β-subunit receptor, gp130. Dysregulated IL-11 signaling has been implicated in several diseases, including some cancers and fibrosis. Mutations in IL-11Rα that reduce signaling are also associated with hereditary cranial malformations. Here we present the first crystal structure of the extracellular domains of human IL-11Rα and a structure of human IL-11 that reveals previously unresolved detail. Disease-associated mutations in IL-11Rα are generally distal to putative ligand-binding sites. Molecular dynamics simulations showed that specific mutations destabilize IL-11Rα and may have indirect effects on the cytokine-binding region. We show that IL-11 and IL-11Rα form a 1:1 complex with nanomolar affinity and present a model of the complex. Our results suggest that the thermodynamic and structural mechanisms of complex formation between IL-11 and IL-11Rα differ substantially from those previously reported for similar cytokines. This work reveals key determinants of the engagement of IL-11 by IL-11Rα that may be exploited in the development of strategies to modulate formation of the IL-11-IL-11Rα complex. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) use a series of conserved microswitches to transmit signals across the cell membrane via an allosteric network encompassing the ligand-binding site and the G protein-binding site. Crystal structures of GPCRs provide snapshots of their inactive and active states, but poorly describe the conformational dynamics of the allosteric network that underlies GPCR activation. Here, we analyzed the correlation between ligand binding and receptor conformation of the α1A-adrenoreceptor, a GPCR that stimulates smooth muscle contraction in response to binding noradrenaline. NMR of [13C-H3]methionine-labeled α1A-adrenoreceptor variants, each exhibiting differing signaling capacities, revealed how different classes of ligands modulate the conformational equilibria of this receptor. [13C-H3]Methionine residues near the microswitches exhibited distinct states that correlated with ligand efficacies, supporting a conformational selection mechanism. We propose that allosteric coupling among the microswitches controls the conformation of the α1A-adrenoreceptor and underlies the mechanism of ligand modulation of GPCR signaling in cells. [ABSTRACT FROM AUTHOR]

In environments where glucose is limited, some pathogenic bacteria metabolize host-derived sialic acid as a nutrient source. N-Acetylmannosamine kinase (NanK) is the second enzyme of the bacterial sialic acid import and degradation pathway and adds phosphate to N-acetylmannosamine using ATP to prime the molecule for future pathway reactions. Sequence alignments reveal that Gram-positive NanK enzymes belong to the Repressor, ORF, Kinase (ROK) family, but many lack the canonical Zn-binding motif expected for this function, and the sugar-binding EXGH motif is altered to EXGY. As a result, it is unclear how they perform this important reaction. Here, we study the Staphylococcus aureus NanK (SaNanK), which is the first characterization of a Gram-positive NanK. We report the kinetic activity of SaNanK along with the ligand-free, N-acetylmannosamine-bound and substrate analog GlcNAc-bound crystal structures (2.33, 2.20, and 2.20 Å resolution, respectively). These demonstrate, in combination with small-angle X-ray scattering, that SaNanK is a dimer that adopts a closed conformation upon substrate binding. Analysis of the EXGY motif reveals that the tyrosine binds to the N-acetyl group to select for the "boat" conformation of N-acetylmannosamine. Moreover, SaNanK has a stacked arginine pair coordinated by negative residues critical for thermal stability and catalysis. These combined elements serve to constrain the active site and orient the substrate in lieu of Zn binding, representing a significant departure from canonical NanK binding. This characterization provides insight into differences in the ROK family and highlights a novel area for antimicrobial discovery to fight Gram-positive and S. aureus infections. [ABSTRACT FROM AUTHOR]

meso-Diaminopimelate decarboxylase catalyzes the decarboxylation of meso-diaminopimelate, the final reaction in the diaminopimelate L-lysine biosynthetic pathway. It is the only known pyridoxal-5-phosphate-dependent decarboxylase that catalyzes the removal of a carboxyl group from a D-stereocenter. Currently, only prokaryotic orthologs have been kinetically and structurally characterized. Here, using complementation and kinetic analyses of enzymes recombinantly expressed in Escherichia coli, we have functionally tested two putative eukaryotic meso-diaminopimelate decarboxylase isoforms from the plant species Arabidopsis thaliana. We confirm they are both functional meso-diaminopimelate decarboxylases, although with lower activities than those previously reported for bacterial orthologs. We also report in-depth X-ray crystallographic structural analyses of each isoform at 1.9 and 2.4 Å resolution. We have captured the enzyme structure of one isoform in an asymmetric configuration, with one ligand-bound monomer and the other in an apo-form. Analytical ultracentrifugation and smallangle X-ray scattering solution studies reveal that A. thaliana meso-diaminopimelate decarboxylase adopts a homodimeric assembly. On the basis of our structural analyses, we suggest a mechanism whereby molecular interactions within the active site transduce conformational changes to the active-site loop. These conformational differences are likely to influence catalytic activity in a way that could allow for D-stereocenter selectivity of the substrate meso-diaminopimelate to facilitate the synthesis of L-lysine. In summary, the A. thaliana gene loci At3g14390 and At5g11880 encode functional. meso-diaminopimelate decarboxylase enzymes whose structures provide clues to the stereochemical control of the decarboxylation reaction catalyzed by these eukaryotic proteins. [ABSTRACT FROM AUTHOR]

This work addresses the effect of the support on the performance of Pd-based catalysts for hydrodeoxygenation of different model molecules (phenol, m-cresol, anisole, guaiacol) in the vapor phase at 573 K. The activity and the selectivity to deoxygenated products strongly depended on the support, regardless the model molecule. For HDO of phenol and m-cresol, benzene and toluene were the dominant products on niobia supported catalysts, whereas cyclohexanone and methylcyclohexanone were the main compounds formed on Pd/SiO 2 . For HDO of anisole, demethoxylation reaction producing benzene is favored over Pd/Nb 2 O 5 catalyst, while demethylation is the preferred route over Pd/SiO 2 . Phenol and methanol were the main products observed for HDO of guaiacol over all catalysts but significant formation of benzene was detected over Pd/Nb 2 O 5 . The improved deoxygenation performance over the niobia supported catalysts is explained in terms of the oxophilic sites represented by Nb 4+ /Nb 5+ cations. These catalysts were also tested for HDO of pine pyrolysis vapors. All three catalysts were effective for reducing the total yield of oxygenated products. The extent of deoxygenation was highest over the Pd/Nb 2 O 5 and Pd/NbOPO 4 catalysts. The effectiveness of Pd/Nb 2 O 5 and Pd/NbOPO 4 for deoxygenation of real feeds is in good agreement with the model compound results and suggests that these catalysts are promising materials for the upgrading of pyrolysis vapors to produce hydrocarbon fuels. [ABSTRACT FROM AUTHOR]

[Display omitted] • Atomic layer-deposited TiO 2 onto Pt/Al 2 O 3 enhances production of jet fuel-range alkanes. • Ti cation sites created by reduction of the TiO 2 overcoats at highest examined surface coverage. • Conversion of key intermediate in HDO reaction increased upon creation of new Ti cation sites. The conversion of wet waste-derived volatile fatty acids into jet fuel-range hydrocarbons is a promising route for increasing the production of sustainable aviation fuel; however, the cost and moderate alkane selectivity of Pt-based hydrodeoxygenation catalysts present challenges for commercialization. To address this, we used atomic layer deposition to apply TiO 2 overcoats to Pt/Al 2 O 3 catalysts and create new interface sites that exhibited 8 times higher site time yield of the desirable n-alkane product than uncoated catalyst. Through TPR/TPD, XPS, CO DRIFTS, and DFT calculations, we found that the increased selectivity of the ALD-coated catalyst was due to the creation of O vacancies at the Pt-TiO 2 interface under reducing conditions, resulting in new Ti3+ acid sites near the active metal. Maximum conversion and alkane selectivity during HDO was achieved with an ALD-coated 0.5% wt Pt catalyst, indicating that TiO 2 ALD can be used to maximize the utility of precious-metal catalysts. [ABSTRACT FROM AUTHOR]

Oxidative stress is a key mechanism of the aging process that can cause damage to brain white matter and cognitive functions. Polymorphisms in the superoxide dismutase 2 ( SOD2) and catalase (CAT ) genes have been associated with abnormalities in antioxidant enzyme activity in the aging brain, suggesting a risk for enhanced oxidative damage to white matter and cognition among older individuals with these genetic variants. The present study compared differences in white matter microstructure and cognition among 96 older adults with and without genetic risk factors of SOD2 (rs4880) and CAT (rs1001179). Results revealed higher radial diffusivity in the anterior thalamic radiation among SOD2 CC genotypes compared to CT/TT genotypes. Further, the CC genotype moderated the relationship between the hippocampal cingulum and processing speed, though this did not survive multiple test correction. The CAT polymorphism was not associated with brain outcomes in this cohort. These results suggest that the CC genotype of SOD2 is an important genetic marker of suboptimal brain aging in healthy individuals. [ABSTRACT FROM AUTHOR]

• Catalytic Fast Pyrolysis (CFP) of woody biomass to produce hydrocarbon fuels. • Petroleum refinery co-hydroprocessing of CFP bio-intermediates. • Impact of chemical coproducts on economics and sustainability. • Impact of the source of hydrogen on sustainability. In this work we present model results for a scaled-up conceptual process informed by bench scale biomass catalytic fast pyrolysis (CFP) and hydrotreating experimental data. This process uses a Pt/TiO 2 catalyst during CFP, which produces a partially deoxygenated organic biocrude intermediate that is then hydroprocessed to a hydrocarbon fuel blendstock; the catalyst also enables high yields of acetone and methyl-ethyl-ketone (MEK) coproducts. Two options for hydroprocessing were modeled: (A) co-hydrotreating at a petroleum refinery using hydrogen sourced from steam reforming of natural gas and (B) standalone hydrotreating at a biorefinery using hydrogen sourced from CFP off gases. The results revealed that Case A was economically advantageous with a modeled minimum fuel selling price (MFSP) of $2.83/GGE or gallon gasoline equivalent (in 2016 US dollars), while the additional cost of standalone hydrotreating facilities in Case B increased the MFSP to $3.13/GGE. Conversely, greenhouse gas (GHG) emissions were lower for Case B (3.9 g CO 2 e/MJ) compared to Case A (21.5 g CO 2 e/MJ) due to the use of biogenic (Case B) and fossil-derived (Case A) hydrogen. In a third option (Case C), the requirements for separation and purification of acetone and MEK were removed from the refinery co-processing scenario (Case A) to evaluate the impacts of this process simplification. Elimination of these coproducts increased the MFSP to $3.21/GGE and GHG emissions to 35 g CO 2 e/MJ. These comparisons based on our detailed conceptual models provide economic and sustainability guidance regarding processing choices for future biorefineries. While refinery coprocessing using existing equipment and the production of relatively valuable coproducts can benefit the economics, the hydrogen-source and biogenic coproducts can have significant impacts on the sustainability of the process, and feasibility to use CFP off-gases or other renewable sources for hydrogen production can help lower GHG emissions. [ABSTRACT FROM AUTHOR]

Summary Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that belongs to the family of microtubule-associated proteins. Originally identified for its role in neurogenesis, DCLK1 has recently been shown to regulate biological processes outside of the CNS. DCLK1 is among the 15 most common putative driver genes for gastric cancers and is highly mutated across various other human cancers. However, our present understanding of how DCLK1 dysfunction leads to tumorigenesis is limited. Here, we provide evidence that DCLK1 kinase activity negatively regulates microtubule polymerization. We present the crystal structure of the DCLK1 kinase domain at 1.7 Å resolution, providing detailed insight into the ATP-binding site that will serve as a framework for future drug design. This structure also allowed for the mapping of cancer-causing mutations within the kinase domain, suggesting that a loss of kinase function may contribute to tumorigenesis. [ABSTRACT FROM AUTHOR]

Mixed alcohols are attractive oxygenated products of biomass-derived syngas because they may be catalytically converted to a range of hydrocarbon products, including liquid hydrocarbon fuels. Catalytic dehydration to form olefins is a potential first step in the conversion of C 2 –C 4 alcohols into longer-chain hydrocarbons. We describe here the physical and chemical characterization along with catalytic activity and selectivity of 4 Brønsted and Lewis acidic catalysts for the dehydration of two mixed alcohol feed streams that are representative of products from syngas conversion over K-CoMoS type catalysts (i.e., ethanol, 1-propanol, 1-butanol and 2-methyl-1-propanol). Specifically, a Lewis acidic Zr-incorporated mesoporous silicate (Zr-KIT-6), a commercial Al-containing mesoporous silicate (Al-MCM-41), a commercial microporous aluminosilicate (HZSM-5), and a commercial microporous silicoaluminophosphate (SAPO-34) were tested for mixed alcohol dehydration at 250, 300 and 350 °C. The zeolite materials exhibited high activity (>98% ethanol conversion) at all temperatures while the mesoporous materials only displayed significant activity (>10% ethanol conversion) at or above 300 °C. The turnover frequencies for ethanol dehydration at 300 °C decreased in the following order: HZSM-5 > SAPO-34 > Al-MCM-41 > Zr-KIT-6, suggesting that Brønsted acidic sites are more active than Lewis acidic sites for alcohol dehydration. At 300 °C, SAPO-34 produced the highest yield of olefin products from both a water-free ethanol rich feed stream and a C 3+ -alcohol rich feed stream containing water. Post-reaction characterization indicated changes in the Brønsted-to-Lewis acidic site ratios for Zr-KIT-6, Al-MCM-41 and HZSM-5. Ammonia temperature programmed desorption indicated that the acid sites of post-reaction samples could be regenerated following treatment in air. The post-reaction SAPO-34 catalyst contained more aromatic, methylated aromatic and polyaromatic compounds than its zeolite counterpart HZSM-5, while no aromatic compounds were observed on post-reaction Al-MCM-41 or Zr-KIT-6 catalysts. Olefin yield at 300 °C over SAPO-34 (>95%) was comparable to published values for the methanol-to-olefins process, indicating the potential industrial application of mixed alcohol dehydration. Furthermore, the olefin product distribution over SAPO-34 was tunable by the composition of the alcohol feed mixture. [ABSTRACT FROM AUTHOR]