An epigenome-wide association study of total serum immunoglobulin E concentration.

Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations--with a meta-analysis false discovery rate less than 10(-4)--between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.

A multidisciplinary evaluation of suspected, non-confirmed cases of COVID-19 including chest CT, as compared to World Health Organization recommendations.

AIM: To report an audit of the evaluation of suspected, unconfirmed cases of COVID-19 including chest computed tomography (CT), as compared to World Health Organization recommendations. METHODS: A clinical audit was undertaken examining the evaluation of patients with suspected COVID-19 with negative SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) results, with comparison to WHO recommendations. A retrospective chart review was undertaken for 90 patients examining investigations, in particular CT, used to clarify the diagnosis. RESULTS: Ninety patients underwent additional investigation. Seventy-five per cent adherence to WHO recommendations was observed. Fifty-two men (57.78%) and 38 (42.22%) women were investigated, with a median age of 69 years (range 20-96 years). Seventy-nine chest CT examinations demonstrated positive, indeterminate, and negative rates for COVID-19 of 3.79%, 24.1%, and 72.15% respectively. Three patients had discordant swab results with initially negative and subsequently positive results for SARS-CoV-2, resulting in false-negative rates of 5.1% for those retested. Combining discordant RT-PCR swab results, positive radiology, and patients treated as COVID-19-positive due to indeterminate radiology and highly consistent symptoms, resulted in a false-negative rate for initial SARS-CoV-2 RT-PCR swabs of 16.67%. CONCLUSION: Seventy-five per cent compliance with relevant WHO guidance and a false-negative rate for initial swabs of 16.67% was demonstrated. Further evidence is needed to fully determine the utility of chest CT in the diagnosis of COVID-19 in the context of initial false-negative RT-PCR results.

Correction: High-Resolution Phenotypic Landscape of the RNA Polymerase II Trigger Loop.

[This corrects the article DOI: 10.1371/journal.pgen.1006321.].

Capacity building for dementia care in community care services: a mixed methods approach.

BACKGROUND: The prevalence of dementia is surging that results in huge service demand in the community care services. Dementia care competence of staff working in these settings is fundamental of the care quality. This project aims to examine the effects of staff training on their competence for the anticipated challenges in dementia care and explore how the training influence their care practices. METHODS: This study adopted a mixed methods triangulation design, including a prospective multi-center study with pre-test post-test evaluations and a narrative analysis of the participants' reflective essays. Seventeen experienced health and social care professionals were trained as trainers at the Dementia Services Development Centre of the University of Stirling, UK. The trainers provided local facilitator training to staff members by using training materials that were culturally adapted to the local context. The facilitators were required to deliver 12 two-hour in-service training sessions for 6 months to their colleagues in a small group format in their respective workplace. Eventually a total of 1347 staff members from community care centers, day care centers, outreach teams and care homes of 70 non-government organizations in Hong Kong participated in the study between April 2017 and December 2018. Validated instruments were used to measure knowledge, attitude, sense of competence in dementia care and job satisfaction at the baseline and at 12-month follow-up. All participants were required to write a reflective essay to describe their experiences in dementia care by the end of the training. RESULTS: A total of 1264 participants, including 195 facilitators and 1069 learners, completed all assessment were included for analysis. Significant improvements were observed in all outcomes at the 12-month follow-up assessment (Ps ≤ .001). The magnitude of improvements in attitudes was the largest. The findings also showed that the effects of the training program significantly varied across different groups of learners in terms of age, occupation, work and training experience. CONCLUSIONS: This community-wide large-scale project provided evidence that the train-the-trainer model and reflective learning are effective means to facilitate situated learning that promote awareness and understanding of dementia, and consequently enhance sustainability of changes in care practices.

Effect of pollutant source location on air pollutant dispersion around a high-rise building.

This article investigates the dispersion of airborne pollutants emitted from different locations near a high-rise building. A Computational Fluid Dynamics (CFD) model for simulating the wind flow field and the pollutant dispersion was developed and validated by wind tunnel data. Then the spreading of the pollutant emitted from different locations to a rectangular-shaped high-rise residential (HRR) building was numerically studied. The pollutant source location was set in a wide range of the position angle and distance between the source and the building. It was found that the pollutant concentration on the building decreases with an increase in the emission distance whereas the effect of the position angle is more complicated. Interestingly, there is a critical range of the position angle from which the emitted pollutants will not spread to the building in a significant way. The effect of the source location was linked to the wind flow field around the building, particularly with several major flows. The vertical distributions of the pollutant concentration on different faces were also investigated, and it was found that these are more affected by the vertical flow near each face. Finally, a mathematical model was developed to evaluate the pollutant concentration as a function of the emission distance and position angle. These findings are helpful to the understanding of the dispersion of airborne pollutants around high-rise buildings and the related hazard management in urban design.

How to foster informed decision making about food supplements: results from an international Delphi study.

Food supplement use can have beneficial and detrimental effects, making informed decisions about supplement use important. How these decisions are made and which communication strategies can stimulate informed decision making is unclear. This study identified the important characteristics of (i) informed decision making about food supplement use and (ii) important factors indicating how to communicate about food supplements to foster informed decision making. An online three-round Delphi study was conducted. International experts within the field of (risk) communication about food supplements or related fields were recruited via email. The participants' age ranged from 25 to 69 years, and sample sizes for the three rounds were 38, 89 and 51, respectively. Experts indicated that for making an informed decision about food supplement use one needs to have knowledge of their positive and negative effects, the ability to compare these effects, knowing alternatives besides supplements, feeling informed, and feeling able (self-efficacious) to make the decision and making the decision voluntarily. Important communication strategies mentioned were: provision of information about positive and negative effects and the nature of these effects including scientific evidence, ensuring information is easily accessible, well ordered, tailored and provided by a trustworthy, credible and independent source.

High-Resolution Phenotypic Landscape of the RNA Polymerase II Trigger Loop.

The active sites of multisubunit RNA polymerases have a "trigger loop" (TL) that multitasks in substrate selection, catalysis, and translocation. To dissect the Saccharomyces cerevisiae RNA polymerase II TL at individual-residue resolution, we quantitatively phenotyped nearly all TL single variants en masse. Three mutant classes, revealed by phenotypes linked to transcription defects or various stresses, have distinct distributions among TL residues. We find that mutations disrupting an intra-TL hydrophobic pocket, proposed to provide a mechanism for substrate-triggered TL folding through destabilization of a catalytically inactive TL state, confer phenotypes consistent with pocket disruption and increased catalysis. Furthermore, allele-specific genetic interactions among TL and TL-proximal domain residues support the contribution of the funnel and bridge helices (BH) to TL dynamics. Our structural genetics approach incorporates structural and phenotypic data for high-resolution dissection of transcription mechanisms and their evolution, and is readily applicable to other essential yeast proteins.

Evidence for a New Component of High-Energy Solar Gamma-Ray Production.

The observed multi-GeV γ-ray emission from the solar disk-sourced by hadronic cosmic rays interacting with gas and affected by complex magnetic fields-is not understood. Utilizing an improved analysis of the Fermi-LAT data that includes the first resolved imaging of the disk, we find strong evidence that this emission is produced by two separate mechanisms. Between 2010 and 2017 (the rise to and fall from solar maximum), the γ-ray emission was dominated by a polar component. Between 2008 and 2009 (solar minimum) this component remained present, but the total emission was instead dominated by a new equatorial component with a brighter flux and harder spectrum. Most strikingly, although six γ rays above 100 GeV were observed during the 1.4 yr of solar minimum, none were observed during the next 7.8 yr. These features, along with a 30-50 GeV spectral dip which will be discussed in a companion paper, were not anticipated by theory. To understand the underlying physics, Fermi-LAT and HAWC observations of the imminent cycle 25 solar minimum are crucial.

Does life story work improve psychosocial well-being for older adults in the community? A quasi-experimental study.

BACKGROUND: Previous studies have demonstrated that life story work has positive effects when used on older adults. This study aimed to examine the effect of life story work on the general mental well-being, self-esteem, and life satisfaction of older adults by comparing two groups - one with and one without depressive symptoms. METHODS: A quasi-experimental design was adopted in this study. One hundred and twenty-three adults aged 60 or above were recruited from community centers through convenience sampling. They were allocated into two groups based on their level of depressive symptomatology as measured by the Geriatric Depression Scale (GDS). The intervention was to produce a written life story with pictures and memorabilia in four to six semi-structured sessions facilitated by trained volunteers. The outcome measures included general mental well-being (General Health Questionnaire, GHQ), life satisfaction (Life Satisfaction Scale Index A, LSI-A), and self-esteem (Rosenberg's Self-esteem Scale, RSES). Data were collected at baseline (T0), immediately post-intervention (T1), and at the 3-month follow-up (T2). Generalized estimating equations were used to examine the effect of the intervention on the outcomes. RESULTS: There was a significant interaction effect between the two groups at T1 (ß = 0.244, p < 0.05) with improvements in the GHQ observed in the group with depressive symptomology. No significant time and interaction effects were seen on the LSI-A and RSES. The Friedman test was also used to examine whether the intervention itself would have any effects on the GDS score, with two groups combined. A reduction in the mean GDS score was found to be close to reaching a level of significance (χ2 = 5.912, p = 0.052). CONCLUSION: The findings of this study provided some preliminary evidence that life story work was effective at improving the general mental well-being of community-dwelling older adults with depressive symptomology. Because older adults with different levels of depressive symptoms might respond differently to life story work interventions, our findings offer interesting directions for future studies - for instance, on what population would benefit the most from Life Story Work and what would be the mechanism that renders Life Story Work effective.

Anaerobic biosynthesis of the lower ligand of vitamin B12.

Vitamin B12 (cobalamin) is required by humans and other organisms for diverse metabolic processes, although only a subset of prokaryotes is capable of synthesizing B12 and other cobamide cofactors. The complete aerobic and anaerobic pathways for the de novo biosynthesis of B12 are known, with the exception of the steps leading to the anaerobic biosynthesis of the lower ligand, 5,6-dimethylbenzimidazole (DMB). Here, we report the identification and characterization of the complete pathway for anaerobic DMB biosynthesis. This pathway, identified in the obligate anaerobic bacterium Eubacterium limosum, is composed of five previously uncharacterized genes, bzaABCDE, that together direct DMB production when expressed in anaerobically cultured Escherichia coli. Expression of different combinations of the bza genes revealed that 5-hydroxybenzimidazole, 5-methoxybenzimidazole, and 5-methoxy-6-methylbenzimidazole, all of which are lower ligands of cobamides produced by other organisms, are intermediates in the pathway. The bza gene content of several bacterial and archaeal genomes is consistent with experimentally determined structures of the benzimidazoles produced by these organisms, indicating that these genes can be used to predict cobamide structure. The identification of the bza genes thus represents the last remaining unknown component of the biosynthetic pathway for not only B12 itself, but also for three other cobamide lower ligands whose biosynthesis was previously unknown. Given the importance of cobamides in environmental, industrial, and human-associated microbial metabolism, the ability to predict cobamide structure may lead to an improved ability to understand and manipulate microbial metabolism.

Clinical characteristics and quality of life of older adults with cognitive impairment in Macao.

BACKGROUND: Little is known about the characteristics of older adults with cognitive impairment in Macao. This study aimed to determine the prevalence of cognitive impairment and the quality of life (QOL) of older adults living in the community and nursing homes. METHODS: A consecutive sample of 413 subjects (199 from the community; 214 from nursing homes) was recruited and interviewed using standardized instruments. Cognition was measured with the Repeatable Battery for the Assessment of Neuropsychological Status and QOL with the brief version of the World Health Organization Quality of Life instrument. RESULTS: Altogether 87 subjects (21.0%) had cognitive impairment. On multivariate analyses, advanced age (P < 0.001, OR = 1.06, 95%CI: 1.03-1.1) and depressive symptoms (P = 0.03, OR = 1.07, 95%CI: 0.005-1.1) were positively associated with cognitive impairment. Married marital status (P = 0.01, OR = 0.3, 95%CI: 0.1-0.7) and higher education level (P < 0.001, OR = 0.1, 95%CI: 0.06-0.3) were negatively associated with cognitive impairment. After the confounders were controlled for, cognitive impairment was significantly associated with the lower psychological (F (11,412) = 6.3, P = 0.01) and social relationship domains of QOL (F (11,412) = 4.0, P = 0.04). CONCLUSION: Cognitive impairment was found to be common in community-dwelling and nursing home resident older adults in Macao. Given cognitive impairment's negative impact on QOL, appropriate strategies should be implemented to improve access to treatment in this population.

Beyond Recovery.

It is a worldwide trend that more households are having pets or companion animals. Hence, there has been an increasing number of animal lovers experience companion animal loss bereavement. This form of bereavement has not been explored in Chinese societies. We conducted a qualitative study using in-depth interviews with 31 animal lovers and recruited through convenience and snowball sampling in Hong Kong. Companion animal loss bereavement appears to share similar features to other forms of bereavement but also has its unique features. The intensity of grief seemed to be affected by factors like the strength of the human-animal bond, lack of empathy from closed ones, being married without children, and euthanasia decision. Although the bereavement was distressful for many of our participants, many of them gradually achieved personal growth from their loss experience. We have identified seven common themes from the interview data and through self-reliance, social-supported, or professional-supported coping behaviors, people bereaved by animal loss can achieve growth from their experience. This study shows that postbereavement growth is possible from pet loss bereavement when appropriate coping strategies are adopted by the bereaved but some professional help may be needed.

Sinorhizobium fredii†HH103 bacteroids are not terminally differentiated and show altered O-antigen in nodules of the Inverted Repeat-Lacking Clade legume Glycyrrhiza uralensis.

In rhizobial species that nodulate inverted repeat-lacking clade (IRLC) legumes, such as the interaction between Sinorhizobium meliloti and Medicago, bacteroid differentiation is driven by an endoreduplication event that is induced by host nodule-specific cysteine rich (NCR) antimicrobial peptides and requires the participation of the bacterial protein BacA. We have studied bacteroid differentiation of Sinorhizobium fredii HH103 in three host plants: Glycine max, Cajanus cajan and the IRLC legume Glycyrrhiza uralensis. Flow cytometry, microscopy analyses and viability studies of bacteroids as well as confocal microscopy studies carried out in nodules showed that S. fredii HH103 bacteroids, regardless of the host plant, had deoxyribonucleic acid (DNA) contents, cellular sizes and survival rates similar to those of free-living bacteria. Contrary to S. meliloti, S. fredii HH103 showed little or no sensitivity to Medicago NCR247 and NCR335 peptides. Inactivation of S. fredii HH103 bacA neither affected symbiosis with Glycyrrhiza nor increased bacterial sensitivity to Medicago NCRs. Finally, HH103 bacteroids isolated from Glycyrrhiza, but not those isolated from Cajanus or Glycine, showed an altered lipopolysaccharide. Our studies indicate that, in contrast to the S. meliloti-Medicago model symbiosis, bacteroids in the S. fredii HH103-Glycyrrhiza symbiosis do not undergo NCR-induced and bacA-dependent terminal differentiation.

Dark Matter Velocity Spectroscopy.

Dark matter decays or annihilations that produce linelike spectra may be smoking-gun signals. However, even such distinctive signatures can be mimicked by astrophysical or instrumental causes. We show that velocity spectroscopy-the measurement of energy shifts induced by relative motion of source and observer-can separate these three causes with minimal theoretical uncertainties. The principal obstacle has been energy resolution, but upcoming experiments will have the precision needed. As an example, we show that the imminent Astro-H mission can use Milky Way observations to separate possible causes of the 3.5-keV line. We discuss other applications.

Predicting DNA methylation level across human tissues.

Differences in methylation across tissues are critical to cell differentiation and are key to understanding the role of epigenetics in complex diseases. In this investigation, we found that locus-specific methylation differences between tissues are highly consistent across individuals. We developed a novel statistical model to predict locus-specific methylation in target tissue based on methylation in surrogate tissue. The method was evaluated in publicly available data and in two studies using the latest IlluminaBeadChips: a childhood asthma study with methylation measured in both peripheral blood leukocytes (PBL) and lymphoblastoid cell lines; and a study of postoperative atrial fibrillation with methylation in PBL, atrium and artery. We found that our method can greatly improve accuracy of cross-tissue prediction at CpG sites that are variable in the target tissue [R(2) increases from 0.38 (original R(2) between tissues) to 0.89 for PBL-to-artery prediction; from 0.39 to 0.95 for PBL-to-atrium; and from 0.81 to 0.98 for lymphoblastoid cell line-to-PBL based on cross-validation, and confirmed using cross-study prediction]. An extended model with multiple CpGs further improved performance. Our results suggest that large-scale epidemiology studies using easy-to-access surrogate tissues (e.g. blood) could be recalibrated to improve understanding of epigenetics in hard-to-access tissues (e.g. atrium) and might enable non-invasive disease screening using epigenetic profiles.

A post-antibiotic era looms: can plant natural product research fill the void?

Antimicrobial resistance is increasing among certain pathogenic bacteria to the extent that treatment efficacy is no longer always assured. According to the CDC, as few as six new antibiotics have been released for use over the past 30 years. Resistance has already been observed to each of these. Eleven plant natural products have been approved for therapeutic use during the same period--none of them being antimicrobial agents. We have learned through experience that some microorganisms will inevitably overcome antibiotic treatment in certain situations, and then spread. It is clear that the rate of new antimicrobial development is insufficient to meet our current and future needs, which should be addressed in order to guarantee the effective future of antimicrobial chemotherapy. However, in recent years there has been an increase in the number of peer-reviewed reports of antimicrobial efficacy among plant-derived secondary metabolites. A limitation with these reports is the wide range of modified in vitro methods used to determine antimicrobial efficacy of these products, showing an absence of the type of standardisation that is the norm when testing the efficacy of single- or combined-agent conventional antimicrobials in the laboratory, thereby making inter-study comparison difficult. Overall, despite the large diversity in preparation and testing strategies used currently for natural product plant-derived antimicrobials, our investigations suggest that the field shows promise in the provision of novel antimicrobial agents, even as exemplified by our selected example, Inula helenium (Elecampane).

The Role of Speech and Language Therapy in Assessing and Managing Pharyngo-esophageal Diverticula.

This study explores the contribution of Speech and Language Therapists (SLTs) to the assessment and management of patients presenting on videofluoroscopic swallow studies (VFSS) with a suspected pharyngo-oesophageal diverticulum. Records for all patients who attended for VFSS in an acute hospital over an eleven-year period were examined (N = 1820). Twenty patients were identified on VFSS as having a suspected diverticulum. Symptoms suggestive of a diverticulum were found during both bedside clinical examination and radiographic examination e.g. respiratory difficulties (n = 15; 75%), voice changes (n = 14; 70/0). VFSS confirmed a reduced risk of aspiration for 14 patients (70%) using a combination of fluid modification (n = 9; 45%), food modification (n = 13; 65%) and swallow strategies (n = 14; 70%). VFSS confirmed aspiration directly related to the diverticulum in 11 patients (55%). Findings indicate that SLTs have the opportunity to identify potential diverticula and implement behavioural management to reduce associated health risks. This is of particular importance to patients who are awaiting, or cannot undergo, surgical repair of their diverticulum.

Who are the healthy active seniors? A cluster analysis.

BACKGROUND: This paper reports a cluster analysis of a sample recruited from a randomized controlled trial that explored the effect of using a life story work approach to improve the psychological outcomes of older people in the community. METHODS: 238 subjects from community centers were included in this analysis. After statistical testing, 169 seniors were assigned to the active ageing (AG) cluster and 69 to the inactive ageing (IG) cluster. RESULTS: Those in the AG were younger and healthier, with fewer chronic diseases and fewer depressive symptoms than those in the IG. They were more satisfied with their lives, and had higher self-esteem. They met with their family members more frequently, they engaged in more leisure activities and were more likely to have the ability to move freely. CONCLUSION: In summary, active ageing was observed in people with better health and functional performance. Our results echoed the limited findings reported in the literature.

Laboratory evolution of E. coli with a natural vitamin B12 analog reveals roles for cobamide uptake and adenosylation in methionine synthase-dependent growth.

The majority of bacteria use cobamides as cofactors for methionine synthesis or other diverse metabolic processes. Cobamides are a structurally diverse family of cofactors related to vitamin B12 (cobalamin), and most bacteria studied to date grow most robustly with particular cobamides. Because different environments contain varying abundances of distinct cobamides, bacteria are likely to encounter cobamides that do not function efficiently for their metabolism. Here, we performed a laboratory evolution of a cobamide-dependent strain of Escherichia coli with pseudocobalamin (pCbl), a cobamide that E. coli uses less effectively than cobalamin for MetH-dependent methionine synthesis, to identify genetic adaptations that lead to improved growth with less-preferred cobamides. After propagating and sequencing nine independent lines and validating the results by constructing targeted mutations, we found that increasing expression of the outer membrane cobamide transporter BtuB is beneficial during growth under cobamide-limiting conditions. Unexpectedly, we also found that overexpression of the cobamide adenosyltransferase BtuR confers a specific growth advantage in pCbl. Characterization of this phenotype revealed that BtuR and adenosylated cobamides contribute to optimal MetH-dependent growth. Together, these findings improve our understanding of how bacteria expand their cobamide-dependent metabolic potential.

MAP3K8 is a potential therapeutic target in airway epithelial inflammation.

BACKGROUND: We have previously discovered clusters of sequentially negative and positive modulators of acute inflammation during cytokine stimulation in epithelial cells and identified potential targets for therapy within these clusters. MAP3K8 is a druggable kinase that we found to be a hub of a principal interaction network. We describe here the results of MAP3K8 knockdown in the A549 lung cancer cell line, the BEAS-2B epithelial cell line and normal human bronchial epithelial (NHBE) cells following IL-1ß stimulation. We analysed signalling transduction and global gene expression after IL-1ß stimulation with and without MAP3K8 knockdown, quantifying levels of the inflammatory cytokines IL-6, IL-8 and RANTES levels by qPCRs and/or by ELISAs. We also examined potential small molecule inhibitors for MAP3K8 in the same models. RESULTS: IL-1ß significantly and consistently increased MAP3K8 expression after 2 h in A549, BEAS-2B and NHBE cells. Phosphorylation of MAP3K8 occurred at 20 min after IL-1ß stimulation and MAP3K8 protein was degraded at 30 min. MAP3K8 knockdown significantly reduced IL-6, IL-8 levels after IL-1ß stimulation and yielded a 10-fold enhancement of the anti-inflammatory effects of dexamethasone. Phosphorylation of ERK1/2 (P-ERK1/2) and phosphorylation of SAPK/JNK (P-SAPK/JNK) decreased at 30 min after IL-1ß stimulation with MAP3K8 knockdown. The combination of dexamethasone and MAP3K8 knockdown resulted in greater inhibition of phosphorylated ERK1/2 and SAPK/JNK. Nineteen genes including MMP1, MMP3, MMP10, ITGB8, LAMC2 and PLAT (P corrected < 0.01 respectively) demonstrated a distinct altered temporal response to IL-1ß following suppression of MAP3K8. However, putative MAP3K8 inhibitors including Tpl2-1, Tpl2-2 and GSK2222867A only showed inhibition of IL-6 and IL-8 production at a high dose. CONCLUSIONS: These results confirm that MAP3K8 is a key mediator of the early inflammatory response and that it is a potential target in inflammatory diseases. However, current tool compounds do not effectively inhibit its effects.