Bacterial Hsp70 resolves misfolded states and accelerates productive folding of a multi-domain protein

The ATP-dependent Hsp70 chaperones (DnaK in E. coli) mediate protein folding in cooperation with J proteins and nucleotide exchange factors (E. coli DnaJ and GrpE, respectively). The Hsp70 system prevents protein aggregation and increases folding yields. Whether it also enhances the rate of folding remains unclear. Here we show that DnaK/DnaJ/GrpE accelerate the folding of the multi-domain protein firefly luciferase (FLuc) 20-fold over the rate of spontaneous folding measured in the absence of aggregation. Analysis by single-pair FRET and hydrogen/deuterium exchange identified inter-domain misfolding as the cause of slow folding. DnaK binding expands the misfolded region and thereby resolves the kinetically-trapped intermediates, with folding occurring upon GrpE-mediated release. In each round of release DnaK commits a fraction of FLuc to fast folding, circumventing misfolding. We suggest that by resolving misfolding and accelerating productive folding, the bacterial Hsp70 system can maintain proteins in their native states under otherwise denaturing stress conditions. The Hsp70 system prevents protein aggregation and increases folding yields, but it is unknown whether it also enhances the rate of folding. Here the authors combine refolding assays, FRET and hydrogen/deuterium exchange-mass spectrometry measurements to study the folding of firefly luciferase and find that the bacterial Hsp70 actively promotes the folding of this multi-domain protein

Review

Molecular chaperones are highly conserved proteins that promote proper folding of other proteinsin vivo. Diverse chaperone systems assistde novoprotein folding and trafficking, the assembly of oligomeric complexes, and recovery from stress-induced unfolding. A fundamental function of molecular chaperones is to inhibit unproductive protein interactions by recognizing and protecting hydrophobic surfaces that are exposed during folding or following proteotoxic stress. Beyond this basic principle, it is now clear that chaperones can also actively and specifically accelerate folding reactions in an ATP-dependent manner. We focus on the bacterial Hsp70 and chaperonin systems as paradigms, and review recent work that has advanced our understanding of how these chaperones act as catalysts of protein folding

Hypofractionated image-guided radiotherapy for the treatment of acoustic neuromas: A dosimetrically acceptable alternative to stereotactic radiosurgery in a resource-constrained environment

Purpose: Treatment options for acoustic neuromas (ANs) are limited in low- and middle-income countries. The aim of this study was to investigate whether hypofractionated image-guided radiotherapy (IGRT) is a clinically acceptable treatment option for departments where no other radiosurgery options are available. Methods and materials: Fifteen dynamic conformal arc plans that had been clinically utilised were evaluated against the Radiation Therapy Oncology Group (RTOG) radiosurgery criteria and published indices. Analysis involved evaluating critical structure doses and the volume of normal tissue receiving 12 and 10 Gy single fraction equivalent dose (V12Eq and V10Eq). Results: Overall, there was only one RTOG protocol deviation in the whole patient group, where quality of coverage was compromised in order to achieve brainstem tolerance. Conformity indices were within clinically acceptable limits (CIPaddick ≥ 0.6) despite being inferior to the published Universitair Ziekenhuis Brussel (UZB) Gamma Knife and CyberKnife results (p < 0.0001). Homogeneity was superior to the Gamma Knife (p < 0.0001) and Novalis dynamic conformal arc (p = 0.0002) results. Gradient index results were inferior to all published techniques, but doses to the normal structures were well controlled with the exception of the cochlea. The V10Eq data showed increased sensitivity when compared with V12Eq. Conclusion: Dynamic arc IGRT allows for good coverage of AN lesions, but the dose fall-off is not as steep as that obtained with mainstream radiosurgery systems. Contouring and planning should include detailed critical structures analysis. For normal brain parenchyma analysis, V10Eq is a superior risk indicator when compared to V12Eq for this technique. Dynamic arc IGRT offers a dosimetrically acceptable treatment alternative for patients without serviceable hearing, in departments where there are no mainstream radiosurgery treatment options available

Risks of stillbirth and neonatal death with advancing gestation at term: A systematic review and meta-analysis of cohort studies of 15 million pregnancies.

BACKGROUND: Despite advances in healthcare, stillbirth rates remain relatively unchanged. We conducted a systematic review to quantify the risks of stillbirth and neonatal death at term (from 37 weeks gestation) according to gestational age. METHODS AND FINDINGS: We searched the major electronic databases Medline, Embase, and Google Scholar (January 1990-October 2018) without language restrictions. We included cohort studies on term pregnancies that provided estimates of stillbirths or neonatal deaths by gestation week. We estimated the additional weekly risk of stillbirth in term pregnancies that continued versus delivered at various gestational ages. We compared week-specific neonatal mortality rates by gestational age at delivery. We used mixed-effects logistic regression models with random intercepts, and computed risk ratios (RRs), odds ratios (ORs), and 95% confidence intervals (CIs). Thirteen studies (15 million pregnancies, 17,830 stillbirths) were included. All studies were from high-income countries. Four studies provided the risks of stillbirth in mothers of White and Black race, 2 in mothers of White and Asian race, 5 in mothers of White race only, and 2 in mothers of Black race only. The prospective risk of stillbirth increased with gestational age from 0.11 per 1,000 pregnancies at 37 weeks (95% CI 0.07 to 0.15) to 3.18 per 1,000 at 42 weeks (95% CI 1.84 to 4.35). Neonatal mortality increased when pregnancies continued beyond 41 weeks; the risk increased significantly for deliveries at 42 versus 41 weeks gestation (RR 1.87, 95% CI 1.07 to 2.86, p = 0.012). One additional stillbirth occurred for every 1,449 (95% CI 1,237 to 1,747) pregnancies that advanced from 40 to 41 weeks. Limitations include variations in the definition of low-risk pregnancy, the wide time span of the studies, the use of registry-based data, and potential confounders affecting the outcome. CONCLUSIONS: Our findings suggest there is a significant additional risk of stillbirth, with no corresponding reduction in neonatal mortality, when term pregnancies continue to 41 weeks compared to delivery at 40 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015013785

Nurturing the young shoots of talent: Using action research for exploration and theory building

This is an Author's Accepted Manuscript of an article published in European Early Childhood Education Research Journal, 19(4), 433-450, 2011, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/1350293X.2011.623515.This paper reports the outcomes of a set of action research projects carried out by teacher researchers in 14 local education authorities in England, working collaboratively with university tutors, over a period of three years. The common aim of all the projects was to explore practical ways of nurturing the gifts and talents of children aged four–seven years. The project was funded by the Department of Education and Skills in England as part of the government's gifted and talented programme. The project teachers felt that their understanding of issues relating to nurturing the gifts and talents of younger children was enhanced through their engagement in the project. It was possible to map the findings of the projects to the English government's National Quality Standards for gifted and talented education which include: (1) identification; (2) effective provision in the classroom; (3) enabling curriculum entitlement and choice; (4) assessment for learning; (5) engaging with community, families and beyond. The findings are also analysed within the framework of good practice in educating children in the first years of schooling. Participating practitioners felt that action research offered them a suitable methodology to explore the complexity of the topic of giftedness through cycles of planning, action and reflection and personal theory building

MicroRNA responses to acute resistance exercise protocols: a pilot study

INTRODUCTION: MicroRNAs (miRNAs) are non-coding RNAs that have an important role in regulating gene expression. Although circulating miRNAs are considered good markers of response to acute resistance training (RT) (1), change in expression according to the applied stimulus (e.g. high-intensity low-volume vs. low-intensity high-volume) has yet to be investigated. The aim of this study was therefore to evaluate the impact of RT protocols on circulating miRNA levels. We selected miRNA 29a, 128a, 486 as they have been previously shown to be implicated in skeletal muscle regeneration and structural adaptation (i.e. hypertrophy

Periodic points in random substitution subshifts

We study various aspects of periodic points for random substitution subshifts. In order to do so, we introduce a new property for random substitutions called the disjoint images condition. We provide a procedure for determining the property for compatible random substitutions—random substitutions for which a well-defined abelianisation exists. We find some simple necessary criteria for primitive, compatible random substitutions to admit periodic points in their subshifts. In the case that the random substitution further has disjoint images and is of constant length, we provide a stronger criterion. A method is outlined for enumerating periodic points of any specified length in a random substitution subshift

Variable-Pitch Rectangular Cross-section Radiofrequency Coils for the Nitrogen-14 Nuclear Quadrupole Resonance Investigation of Sealed Medicines Packets

This work was partly funded by a technology transfer award from the Wellcome Trust (U.K.). Additional funding was provided by the European Commission as part of 7th Framework Programme under Grant No. 261670

Going to sleep in the supine position is a modifiable risk factor for late pregnancy stillbirth; findings from the New Zealand multicentre stillbirth case-control study

Objective: Our objective was to test the primary hypothesis that maternal non-left, in particular supine going-to-sleep position, would be a risk factor for late stillbirth (≥28 weeks of gestation). Methods: A multicentre case-control study was conducted in seven New Zealand health regions, between February 2012 and December 2015. Cases (n=164) were women with singleton pregnancies and late stillbirth, without congenital abnormality. Controls (n=569) were women with on-going singleton pregnancies, randomly selected and frequency matched for health region and gestation. The primary outcome was adjusted odds of late stillbirth associated with self-reported going-to-sleep position, on the last night. The last night was the night before the late stillbirth was thought to have occurred or the night before interview for controls. Going to- sleep position on the last night was categorised as: supine, left-side, right-side, propped or restless. Multivariable logistic regression adjusted for known confounders. Results: Supine going-to-sleep position on the last night was associated with increased late stillbirth risk (adjusted odds ratios (aOR) 3.67, 95% confidence interval (CI) 1.74 to 7.78) with a population attributable risk of 9.4%. Other independent risk factors for late stillbirth (aOR, 95% CI) were: BMI (1.04, 1.01 to 1.08) per unit, maternal age ≥40 (2.88, 1.31 to 6.32), birthweight <10th customised centile (2.76, 1.59 to 4.80), and <6 hours sleep on the last night (1.81, 1.14 to 2.88). The risk associated with supine-going-to sleep position was greater for term (aOR 10.26, 3.00 to 35.04) than preterm stillbirths (aOR 3.12, 0.97 to 10.05). Conclusions: Supine going-to-sleep position is associated with a 3.7 fold increase in overall late stillbirth risk, independent of other common risk factors. A public health campaign encouraging women not to go-to-sleep supine in the third trimester has potential to reduce late stillbirth by approximately 9%

Chemical composition and antibacterial activity of essential oils from the medicinal plant Mentha cervina L. grown in Portugal

Mentha cervina is a medicinal plant traditionally used in Portugal in folk medicine, in different gastric disorders and inflammations of the respiratory tract. In order to validate those traditional uses, M. cervina essential oils (EOs) were characterized by GC and GC–MS and their antimicrobial activity was tested against 23 bacterial strains (including multiresistant strains). The EOs were dominated by the monoterpenes pulegone (52–75%), isomenthone (8–24%), limonene (4–6%), and menthone (1–2%). The antibacterial activity of these EOs was compared to that of the main components standards. The most effective antibacterial activity was expressed by the EOs against the Gram-negative bacteria, Escherichia coli and Acinetobacter baumanni, with MIC values of 1 mg/ml. The EOs complex mixtures were more active than the individual aromatic components supporting the hypothesis that the EOs antibacterial activity is a function of the synergistic effect of their different aromatic components. These results show the potential role of M. cervina EOs as antibacterial agents and validate the traditional use of this plant