The eukaryotic translation initiation factor 4AI (eIF4AI) is the prototypical DEAD-box RNA helicase. It has a “dumbbell” structure consisting of two domains connected by a flexible linker. Previous ...studies demonstrated that eIF4AI, in conjunction with eIF4H, bind to loop structures and repetitively unwind RNA hairpins. Here, we probe the conformational dynamics of eIF4AI in real time using single-molecule FRET. We demonstrate that eIF4AI/eIF4H complex can repetitively unwind RNA hairpins by transitioning between an eIF4AI “open” and a “closed” conformation using the energy derived from ATP hydrolysis. Our experiments directly track the conformational changes in the catalytic cycle of eIF4AI and eIF4H, and this correlates precisely with the kinetics of RNA unwinding. Furthermore, we show that the small-molecule eIF4A inhibitor hippuristanol locks eIF4AI in the closed conformation, thus efficiently inhibiting RNA unwinding. These results indicate that the large conformational changes undertaken by eIF4A during the helicase catalytic cycle are rate limiting.
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•The conformational dynamics of eIF4AI are directly probed by single-molecule FRET•EIF4AI undergoes large conformational transitions, while unwinding RNA hairpins•EIF4H binds to the N-terminal domain of eIF4AI when RNA hairpin is present•Hippuristanol locks eIF4AI in the closed conformation and inhibits RNA unwinding
Sun et al. use single molecule fluorescence to monitor the conformational dynamics of a key eukaryotic initiation factor eIF4AI. During RNA unwinding in the presence of eIF4H, eIF4AI transitions between two conformations, which facilitate substrate binding, RNA duplex unzipping, and a partial substrate release.
Aims. A multi-transition survey of HCN (sub-) millimeter line emission from a large sample of asymptotic giant branch (AGB) stars of different chemical type is presented. The data are analysed and ...circumstellar HCN abundances are estimated. The sample stars span a large range of properties such as mass-loss rate and photospheric C/O-ratio. The analysis of the new data allows for more accurate estimates of the circumstellar HCN abundances and puts new constraints on chemical models. Methods. In order to constrain the circumstellar HCN abundance distribution a detailed non-local thermodynamic equilibrium (LTE) excitation analysis, based on the Monte Carlo method, is performed. Effects of line overlaps and radiative excitation from dust grains are included. Results. The median values for the derived abundances of HCN (with respect to H2) are 3 × 10-5, 7 × 10-7 and 10-7 for carbon stars (25 stars), S-type AGB stars (19 stars) and M-type AGB stars (25 stars), respectively. The estimated sizes of the HCN envelopes are similar to those obtained in the case of SiO for the same sample of sources and agree well with previous results from interferometric observations, when these are available. Conclusions. We find that there is a clear dependence of the derived circumstellar HCN abundance on the C/O-ratio of the star, in that carbon stars have about two orders of magnitude higher abundances than M-type AGB stars, on average. The derived HCN abundances of the S-type AGB stars have a larger spread and typically fall in between those of the two other types, however, slightly closer to the values for the M-type AGB stars. For the M-type stars, the estimated abundances are much higher than what would be expected if HCN is formed in thermal equilibrium. However, the results are also in contrast to predictions from recent non-LTE chemical models, where very little difference is expected in the HCN abundances between the various types of AGB stars.
Context. The chemical evolution of asymptotic giant branch (AGB) stars is driven by repeated thermal pulses (TPs). The duration of a TP is only a few hundred years, whereas an inter-pulse period ...lasts 10 4 − 10 5 yr. Direct observations of TPs are hence unlikely. However, the detached shells seen in CO line emission that are formed as a result of a TP provide indirect constraints on the changes experienced by the star during the pulse. Aims. We aim to resolve the spatial and kinematic sub-structures in five detached-shell sources to provide detailed constraints for hydrodynamic models that describe the formation and evolution of the shells. Methods. We used observations of the 12 CO (1 − 0) emission towards five carbon-AGB stars with ALMA (Atacama Large Millimeter/submillimeter Array), including previously published observations of the carbon AGB star U Ant. The data have angular resolutions of 0″.3 to 1″ and a velocity resolution of 0.3 km s −1 . This enabled us to quantify spatial and kinematic structures in the shells. Combining the ALMA data with single-dish observations of the 12 CO (1 − 0) to 12 CO (4 − 3) emission towards the sources, we used radiative transfer models to compare the observed structures with previous estimates of the shell masses and temperatures. Results. The observed emission is separated into two distinct components: a more coherent, bright outer shell and a more filamentary, fainter inner shell. The kinematic information shows that the inner sub-shells move at a higher velocity relative to the outer sub-shells. The observed sub-structures reveal a negative velocity gradient outwards across the detached shells, confirming the predictions from hydrodynamical models. However, the models do not predict a double-shell structure, and the CO emission likely only traces the inner and outer edges of the shell, implying a lack of CO in the middle layers of the detached shell. Previous estimates of the masses and temperatures are consistent with originating mainly from the brighter subshell, but the total shell masses are likely lower limits. Also, additional structures in the form of partial shells outside the detached shell around V644 Sco, arcs within the shell of R Scl, and a partially filled shell for DR Ser indicate a more complicated evolution of the shells and mass-loss process throughout the TP cycle than previously assumed. Conclusions. The observed spatial and kinematical splittings of the shells appear consistent with results from the hydrodynamical models, provided the CO emission does not trace the H 2 density distribution in the shell but rather traces the edges of the shells. The hydrodynamical models predict very different density profiles depending on the evolution of the shells and the different physical processes involved in the wind-wind interaction (e.g. heating and cooling processes). It is therefore not possible to constrain the total shell mass based on the CO observations alone. Additional features outside and inside the shells complicate the interpretation of the data. Complementary observations of, for example, CI as a dissociation product of CO would be necessary to understand the distribution of CO compared to H 2 , in addition to new detailed hydrodynamical models of the pre-pulse, pulse, and post-pulse wind. Only a comprehensive combination of observations and models will allow us to constrain the evolution of the shells and the changes in the star during the thermal-pulse cycle.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects 0.5-1.0% of the population, and where many patients in spite of modern pharmacological treatment fail to reach remission. This ...affects physical as well as mental wellbeing and leads to severely reduced quality of life and reduced work capacity, thus yielding high individual as well as societal costs. As a complement to modern pharmacological treatment, lifestyle intervention should be evaluated as a treatment option. Scientific evidence exists for anti-inflammatory effects by single foods on RA, but no study exists where these foods have been combined to obtain maximum effect and thus offer a substantial improvement in patient life quality. The main goal of the randomized cross-over trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis) is to test the hypothesis that an anti-inflammatory diet intervention, compared to a regular diet, will decrease disease activity and improve quality of life in patients with stable established RA.
In total, 50 RA patients with moderate disease activity are randomized to receive initially either a portfolio diet based on several food items with suggested anti-inflammatory effects or a control diet during 2 × 10 weeks with 3 months wash-out between diets. Food bags are delivered weekly by a home food delivery chain and referred to as the fiber bag and the protein bag, respectively, to partially blind participants. Both groups continue with regular pharmacological treatment. Known food biomarkers will be analyzed to measure intervention compliance. Impact on disease severity (measured by DAS28, a composite score which predicts disability and progression of RA), risk markers for cardiovascular disease and quality of life are evaluated after each diet regimen. Metabolomics will be used to evaluate the potential to predict responders to dietary treatment. A health economic evaluation is also included.
The nutritional status of patients with RA often is poor and many ask their physician for diet advice. No evidence-based dietary guidelines for patients with RA exist because of the paucity of well-conducted sufficiently large diet intervention trials. ADIRA is an efficacy study and will provide evidence as to whether dietary treatment of RA can reduce disease activity and improve quality of life as well as reduce individual and societal costs.
ClinicalTrials.gov Registration Number: NCT02941055 .
The chronic inflammation in patients with rheumatoid arthritis (RA) increases the risk for cardiovascular diseases (CVD). The contribution of diet as a risk factor for CVD among these patients is ...however not fully understood. The aim of this study is to investigate if a proposed anti-inflammatory diet improves cardiovascular profile in weight stable patients with RA.
Patients (n = 50) with RA were included in a cross-over trial. They were randomized to either a diet rich in whole grain, fatty fish, nuts, vegetables and fruit and supplemented with probiotics, or a control diet resembling average nutritional intake in Sweden, for ten weeks. After a 4-month washout they switched diet. Participants received food bags and dietary guidelines. Primary outcome was triglyceride (TG) concentration. Secondary outcomes were total-, high density lipoprotein- (HDL) and low density lipoprotein- (LDL) cholesterol, Apolipoprotein-B100 and -A1, lipoprotein composition, plasma phospholipid fatty acids and blood pressure.
Forty-seven patients completed at least one period and they remained weight stable. There was a significant between-dietary treatment effect in TG and HDL-cholesterol concentration in favor of intervention (p = 0.007 and p = 0.049, respectively). Likewise, Apolipoprotein-B100/A1 ratio shifted toward a less atherogenic profile in favor of the intervention (p = 0.007). Plasma fatty acids increased in polyunsaturated- and decreased in monounsaturated- and saturated fatty acids between diet periods in favor of the intervention period.
Blood lipid profile improved indicating cardioprotective effects from an anti-inflammatory dietary intervention in patients with RA.
This trial is registered at ClinicalTrials.gov as NCT02941055 .
Recent observations at subarcsecond resolution, now possible also at submillimeter wavelengths, have shown intricate circumstellar structures around asymptotic giant branch (AGB) stars, mostly ...attributed to binary interaction. The results presented here are part of a larger project aimed at investigating the effects of a binary companion on the morphology of circumstellar envelopes (CSEs) of AGB stars.
AGB stars are characterized by intense stellar winds that build CSEs around the stars. Here, the CO(
= 3→2) emission from the CSE of the binary S-type AGB star W Aql has been observed at subarcsecond resolution using ALMA. The aim of this paper is to investigate the wind properties of the AGB star and to analyse how the known companion has shaped the CSE.
The average mass-loss rate during the creation of the detected CSE is estimated through modelling, using the ALMA brightness distribution and previously published single-dish measurements as observational constraints. The ALMA observations are presented and compared to the results from a 3D smoothed particle hydrodynamics (SPH) binary interaction model with the same properties as the W Aql system and with two different orbital eccentricities. Three-dimensional radiative transfer modelling is performed and the response of the interferometer is modelled and discussed.
The estimated average mass-loss rate of W Aql is
= 3.0×10
M
yr
and agrees with previous results based on single-dish CO line emission observations. The size of the emitting region is consistent with photodissociation models. The inner 10″ of the CSE is asymmetric with arc-like structures at separations of 2-3″ scattered across the denser sections. Further out, weaker spiral structures at greater separations are found, but this is at the limit of the sensitivity and field of view of the ALMA observations.
The CO(
= 3→2) emission is dominated by a smooth component overlayed with two weak arc patterns with different separations. The larger pattern is predicted by the binary interaction model with separations of ~10″ and therefore likely due to the known companion. It is consistent with a binary orbit with low eccentricity. The smaller separation pattern is asymmetric and coincides with the dust distribution, but the separation timescale (200 yrs) is not consistent with any known process of the system. The separation of the known companions of the system is large enough to not have a very strong effect on the circumstellar morphology. The density contrast across the envelope of a binary with an even larger separation will not be easily detectable, even with ALMA, unless the orbit is strongly asymmetric or the AGB star has a much larger mass-loss rate.
Restricting intake of FODMAPs (Fermentable Oligo-, Di-, Monosaccharides and Polyols) is used as treatment for irritable bowel syndrome (IBS). However, whether habitual FODMAP consumption correlates ...to symptom severity, and if this relationship differs among IBS subtypes, is unclear. The aim was to study the relationship between habitual FODMAP intake and symptom severity. A total of 189 patients with IBS-IBS with constipation (IBS-C)
= 44 (22.3%), IBS with diarrhea (IBS-D)
= 54 (27.4%), mixed IBS (IBS-M)
= 46 (23.4%) and unsubtyped IBS (IBS-U)
= 46 (23.4%)-recorded food intake during four days. Symptom severity was measured with the IBS severity scoring system (IBS-SSS). For FODMAP intake, a lower lactose intake was noted among women with IBS-D,
= 0.009. In women, there was a statistically significant relationship between energy-adjusted FODMAP intake and IBS-SSS (r = 0.21,
= 0.003). This was mainly driven by the subtype IBS-U, where excess fructose intake accounted for 19.9% of explained variance in IBS-SSS (
= 0.007). This study demonstrates small differences in FODMAP intake among IBS patients with different subtypes. Association between IBS symptoms and FODMAP intake was most prominent in unsubtyped IBS. However, patients who are intolerant to certain FODMAPs may already have reduced their FODMAP intake, and this warrants future cohort or experimental studies to uncover.
Rheumatoid Arthritis (RA) is an autoimmune disease affecting peripheral joints. Chronic activation of inflammatory pathways results in decreased function and the development of comorbidities, such as ...loss of lean mass while retaining total body mass. The objective of this report was to assess whether dietary manipulation affects body composition in patients with RA as a secondary outcome. Fifty patients were included in a randomized controlled crossover trial testing a proposed anti-inflammatory Mediterranean-style diet compared to a Western diet. Body composition was measured by bioelectrical impedance spectroscopy in patients without implants (n = 45). Regardless of treatment, fat-free mass increased and fat mass percentage decreased during weight stability, but no differences between intervention and control in the whole group (n = 42, all p > 0.20) were found. Interaction analysis revealed that participants who were non-employed (n = 15) significantly decreased in fat mass (−1.767 kg; 95% CI: −3.060, −0.475, p = 0.012) and fat mass percentage (−1.805%; 95% CI: −3.024, −0.586, p = 0.008) from the intervention compared to the control period. A Mediterranean-style diet improved body composition in non-employed participants (n = 15). The group as a whole improved regardless of dietary allocation, indicating a potential to treat rheumatoid cachexia by dietary manipulation.
A genotyping assay for the Ion Torrent Ion PGM platform was developed for fast and cost‐effective targeted genotyping of key single nucleotide polymorphisms (SNPs) earlier identified using a ...genome‐wide SNP array in Atlantic salmon Salmo salar. The method comprised a simple primer design step for multiplex‐polymerase chain reaction (PCR), followed by two rounds of Ion Torrent Ion PGM sequencing to empirically evaluate marker efficiency in large multiplexes and to optimise or exclude them when necessary. Of 282 primer pairs initially tested, 217 were successfully amplified, indicating good amplification success (>75%). These markers included the sdy partial gene product to determine genetic sex, as well as three additional modules comprising SNPs for assessing neutral genetic variation (NSNP = 150), examining functional genetic variation associated with sea age at maturity (NSNP = 5), and for performing genetic subpopulation assignment (NSNP = 61). The assay was primarily developed to monitor long‐term genetic changes in S. salar from the Teno River, but modules are likely suitable for application in a wide range of S. salar populations. Furthermore, the fast and versatile assay development pipeline offers a strategy for developing targeted sequencing assays in any species.
Abstract
Background
There is a shortage of high-quality studies regarding choice of mesh in open anterior inguinal hernia repair in relation to long-term chronic pain. The authors hypothesized that ...heavyweight compared with lightweight mesh causes increased postoperative pain.
Methods
An RCT was undertaken between 2007 and 2009 at two sites in Sweden. Men aged 25 years or older with an inguinal hernia evaluated in the outpatient clinic were randomized in an unblinded fashion to heavyweight or lightweight mesh for open anterior inguinal hernia repair. Data on pain affecting daily activities, as measured by the Short-Form Inguinal Pain Questionnaire 9–12 years after surgery, were collected as the primary outcome. Differences between groups were evaluated by generalized odds and numbers needed to treat.
Results
A total of 412 patients were randomized; 363 were analysed with 320 questionnaires sent out. A total of 271 questionnaires (84.7 per cent) were returned; of these, 121 and 150 patients were in the heavyweight and lightweight mesh groups respectively. Pain affecting daily activities was more pronounced in patients randomized to heavyweight versus lightweight mesh (generalized odds 1.33, 95 per cent c.i. 1.10 to 1.61). This translated into a number needed to treat of 7.06 (95 per cent c.i. 4.28 to 21.44). Two reoperations for recurrence were noted in the heavyweight mesh group, and one in the lightweight mesh group.
Conclusion
A large-pore lightweight mesh causes significantly less pain affecting daily activities a decade after open anterior inguinal hernia repair. Registration number: NCT00451893 (http://www.clinicaltrials.gov).
This expertise-based, parallel-group RCT regarding choice of mesh in open anterior inguinal hernia repair in relation to long-term chronic pain was undertaken between 2007 and 2009. Some 271 patients were analysed. Pain affecting daily activities was more pronounced in patients who had surgery with heavyweight versus lightweight mesh (generalized odds 1.33, 95 per cent c.i. 1.10 to 1.61). This translated into a number needed to treat of 7.06 (95 per cent c.i. 4.28 to 21.44).
Long term outcomes
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