Improved green and red GRAB sensors for monitoring dopaminergic activity in vivo.

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a large network of dopaminergic projections. To dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent G-protein-coupled receptor activation-based DA (GRABDA) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity and signal-to-noise ratio with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRABDA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions.

The good, the bad, and the environment: developing an area-based measure of access to health-promoting and health-constraining environments in New Zealand.

BACKGROUND: Accounting for the co-occurrence of multiple environmental influences is a more accurate reflection of population exposure than considering isolated influences, aiding in understanding the complex interactions between environments, behaviour and health. This study examines how environmental 'goods' such as green spaces and environmental 'bads' such as alcohol outlets co-occur to develop a nationwide area-level healthy location index (HLI) for New Zealand. METHODS: Nationwide data were collected, processed, and geocoded on a comprehensive range of environmental exposures. Health-constraining 'bads' were represented by: (i) fast-food outlets, (ii) takeaway outlets, (iii) dairy outlets and convenience stores, (iv) alcohol outlets, (v) and gaming venues. Health-promoting 'goods' were represented by: (i) green spaces, (ii) blue spaces, (iii) physical activity facilities, (iv) fruit and vegetable outlets, and (v) supermarkets. The HLI was developed based on ranked access to environmental domains. The HLI was then used to investigate socio-spatial patterning by area-level deprivation and rural/urban classification. RESULTS: Results showed environmental 'goods' and 'bads' co-occurred together and were patterned by area-level deprivation. The novel HLI shows that the most deprived areas of New Zealand often have the most environmental 'bads' and less access to environmental 'goods'. CONCLUSIONS: The index, that is now publicly available, is able to capture both inter-regional and local variations in accessibility to health-promoting and health-constraining environments and their combination. Results in this study further reinforce the need to embrace the multidimensional nature of neighbourhood and place not only when designing health-promoting places, but also when studying the effect of existing built environments on population health.

Spatial-temporal patterns of childhood immunization in New Zealand (2006-2017): an improving pattern but not for all?

BACKGROUND: Declining childhood immunization represents a serious public health problem globally and in New Zealand. To guide efforts to increase immunization coverage, this study monitors nationwide change in immunization coverage since the introduction of the National Immunisation Register (NIR) in 2005 and spatiotemporal patterns of immunization coverage from 2006 to 2017. METHODS: The study population consisted of 4 482 499 individual immunization records that were obtained from the NIR (2005-2017). Data on yearly and average immunization coverage in census area units (CAUs) in New Zealand were calculated by milestone age (6/8/12/18/24/60/144 months). Data for 2005 were excluded due to missing records in the introductory period of the NIR. We analyzed spatial and spatiotemporal patterns using Gi* and SaTScan methods. RESULTS: Immunization coverage improved since the introduction of the NIR in 2005, reaching a peak in 2014 and 2015 with a slight decrease in 2016 and 2017. Well and insufficiently immunized areas were identified with spatial autocorrelation analyses highlighting several hot- and cold-spots. Comparison of CAUs with neighbouring CAUs allowed for the identification of places where immunization coverage was significantly higher or lower than expected, over both time and space. CONCLUSION: We provide the first spatiotemporal analysis of childhood immunization in New Zealand that utilizes a large sample of over 4.4 million individual immunization records. Our spatial analyses enable policymakers to understand the development of childhood immunization coverage and make more effective prevention strategies in New Zealand.

Transport changes and COVID-19: From present impacts to future possibilities.

Changes in people's movement and travel behaviour have been apparent in many places during the COVID-19 pandemic, with differences seen at a range of spatial scales. These changes, occurring as a result of the COVID-19 'natural experiment', have afforded us an opportunity to reimagine how we might move in our day-to-day travels, offering a hopeful glimpse of possibilities for future policy and planning around transport. The nature and scale of changes in movement and transport resulting from the pandemic have shown we can shift travel behaviour with strong policy responses, which is especially important in the concurrent climate change crisis.

Learning from methylomes: epigenomic correlates of Populus balsamifera traits based on deep learning models of natural DNA methylation.

Epigenomes have remarkable potential for the estimation of plant traits. This study tested the hypothesis that natural variation in DNA methylation can be used to estimate industrially important traits in a genetically diverse population of Populus balsamifera L. (balsam poplar) trees grown at two common garden sites. Statistical learning experiments enabled by deep learning models revealed that plant traits in novel genotypes can be modelled transparently using small numbers of methylated DNA predictors. Using this approach, tissue type, a nonheritable attribute, from which DNA methylomes were derived was assigned, and provenance, a purely heritable trait and an element of population structure, was determined. Significant proportions of phenotypic variance in quantitative wood traits, including total biomass (57.5%), wood density (40.9%), soluble lignin (25.3%) and cell wall carbohydrate (mannose: 44.8%) contents, were also explained from natural variation in DNA methylation. Modelling plant traits using DNA methylation can capture tissue-specific epigenetic mechanisms underlying plant phenotypes in natural environments. DNA methylation-based models offer new insight into natural epigenetic influence on plants and can be used as a strategy to validate the identity, provenance or quality of agroforestry products.

Self-motion processing in visual and entorhinal cortices: inputs, integration, and implications for position coding.

The sensory signals generated by self-motion are complex and multimodal, but the ability to integrate these signals into a unified self-motion percept to guide navigation is essential for animal survival. Here, we summarize classic and recent work on self-motion coding in the visual and entorhinal cortices of the rodent brain. We compare motion processing in rodent and primate visual cortices, highlighting the strengths of classic primate work in establishing causal links between neural activity and perception, and discuss the integration of motor and visual signals in rodent visual cortex. We then turn to the medial entorhinal cortex (MEC), where calculations using self-motion to update position estimates are thought to occur. We focus on several key sources of self-motion information to MEC: the medial septum, which provides locomotor speed information; visual cortex, whose input has been increasingly recognized as essential to both position and speed-tuned MEC cells; and the head direction system, which is a major source of directional information for self-motion estimates. These inputs create a large and diverse group of self-motion codes in MEC, and great interest remains in how these self-motion codes might be integrated by MEC grid cells to estimate position. However, which signals are used in these calculations and the mechanisms by which they are integrated remain controversial. We end by proposing future experiments that could further our understanding of the interactions between MEC cells that code for self-motion and position and clarify the relationship between the activity of these cells and spatial perception.

The validation of the Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS) with deaf British sign language users in the UK.

BACKGROUND: There is no validated measure of positive mental well-being that is suitable for Deaf people who use a signed language such as British Sign Language (BSL). This impedes inclusion of this population in a range of research designed to evaluate effectiveness of interventions. The study aims were: (i) to translate the original English version of SWEMWBS into BSL and to test the SWEMWBS BSL with the Deaf population in the UK who use BSL; (ii) to examine its psychometric properties; and (iii) to establish the validity and reliability of the SWEMWBS BSL. METHODS: The SWEMWBS was translated into BSL following a six stage translation procedure and in consultation with the originators. The draft version was piloted with Deaf BSL users (n = 96) who also completed the CORE-OM BSL well-being subscale and the EQ-5D VAS BSL. Reliability was explored using Cronbach's alpha for internal consistency and ICC for test-retest reliability. Validity was explored by using Kendall's tau correction for convergent validity and an exploratory factor analysis for construct validity. RESULTS: The internal consistency for the reliability of the SWEMWBS BSL was found to be good and the test-retest one week apart showed an acceptable reliability. There was good convergent validity of the SWEMWBS BSL with the well-being subscale of the CORE-OM BSL and the EQ-5D VAS BSL. CONCLUSIONS: The SWEMWBS BSL can be used with a Deaf population of BSL users. This is the first validated version of a BSL instrument that focuses solely on positively phrased questions for measuring mental well-being.

Activity pacing: moving beyond taking breaks and slowing down.

This brief communication responds to the paper by Jeong and Cho (Qual Life Res 26(4):903-911, 2017) that has described activity pacing in limited terms of adjusting activities through going at a slower rate and taking breaks. Activity pacing was reported as not involving goal setting, in comparison to other strategies for long-term conditions such as Acceptance and Commitment Therapy. This brief communication aims to challenge this limited perception of activity pacing in light of numerous studies that recognise pacing to be a more complex strategy. Pacing is considered to be a multifaceted coping strategy, including broad themes of not only adjusting activities, but also planning activities, having consistent activity levels, acceptance of current abilities and gradually increasing activities, and one that includes goal setting as a key facet. It is essential that pacing is both defined and measured as a multifaceted strategy in order to assess the outcomes of pacing, and for meaningful comparisons with other strategies regarding efficacy for the management of long-term conditions.

The experiences of myocardial infarction patients readmitted within six months of primary percutaneous coronary intervention.

AIMS AND OBJECTIVES: To explore the experiences of patients readmitted due to potential ischaemic heart disease symptoms within six months of primary percutaneous coronary intervention. BACKGROUND: Following myocardial infarction and primary percutaneous coronary intervention, some patients experience potential ischaemic heart disease symptoms that may lead to readmission. Symptoms may be related to cardiac ischaemia, reduced psychological health or a comorbid condition. DESIGN: A qualitative study involving semistructured, in-depth interviews conducted once, mean 196 (50-384) days following readmission (at least six months following original ST-elevation myocardial infarction and primary percutaneous coronary intervention). This is the qualitative part of a mixed methods study. METHODS: Participants were purposefully selected, and concurrent sampling, data collection and data analysis were performed. Data were organised using framework analysis; constant comparative analysis involving deduction and induction led to identification of cogent themes and subthemes. RESULTS: Twenty-five participants (14 men, 27-79 years) experienced 1-4 readmissions; discharge diagnoses were cardiac, psychological, indeterminate, pulmonary and gastric. Three main themes emerged: (1) anxiety, uncertainty and inability to determine cause of symptoms, (2) fear of experiencing further myocardial infarction and (3) insufficient opportunity to validate self-construction of illness. CONCLUSION: Fear of dying or experiencing a further myocardial infarction led to patients seeking help at the time of potential ischaemic heart disease symptoms. Participants were anxious and lacked understanding regarding symptom attribution at the time of readmission and generally following their heart attack. Additionally, original heart attack symptoms were used as a comparator for future symptoms. Participants reported feeling well immediately after primary percutaneous coronary intervention but later experiencing fatigue and debilitation often linked to potential ischaemic heart disease symptoms. RELEVANCE TO CLINICAL PRACTICE: Increased education and information related to symptom attribution post-primary percutaneous coronary intervention and postreadmission are worthy of exploration and may lead to increased understanding and reassurance for this patient group.

Leaf size serves as a proxy for xylem vulnerability to cavitation in plantation trees.

Hybrid poplars are an important renewable forest resource known for their high productivity. At the same time, they are highly vulnerable to water stress. Identifying traits that can serve as indicators for growth performance remains an important task, particularly under field conditions. Understanding which trait combinations translate to improved productivity is key in order to satisfy the demand for poplar wood in an uncertain future climate. In this study, we compared hydraulic and leaf traits among five hybrid poplar clones at 10 plantations in central Alberta. We also assessed the variation of these traits between 2- to 3-year-old branches from the lower to mid-crown and current-year long shoots from the mid to upper crown. Our results showed that (1) hybrid poplars differed in key hydraulic parameters between branch type, (2) variation of hydraulic traits among clones was relatively large for some clones and less for others, and (3) strong relationships between measured hydraulic traits, such as vessel diameter, cavitation resistance, xylem-specific and leaf-specific conductivity and leaf area, were observed. Our results suggest that leaf size could serve as an additional screening tool when selecting for drought-tolerant genotypes in forest management and tree improvement programmes.

Olive Oil, Sunflower Oil or no Oil for Baby Dry Skin or Massage: A Pilot, Assessor-blinded, Randomized Controlled Trial (the Oil in Baby SkincaRE [OBSeRvE] Study).

Topical oils on baby skin may contribute to development of childhood atopic eczema. A pilot, assessor-blinded, randomized controlled trial assessed feasibility of a definitive trial investigating their impact in neonates. One-hundred and fifteen healthy, full-term neonates were randomly assigned to olive oil, sunflower oil or no oil, twice daily for 4 weeks, stratified by family history of atopic eczema. We measured spectral profile of lipid lamellae, trans-epidermal water loss (TEWL), stratum corneum hydration and pH and recorded clinical observations, at baseline, and 4 weeks post-birth. Recruitment was challenging (recruitment 11.1%; retention 80%), protocol adherence reasonable (79-100%). Both oil groups had significantly improved hydration but significantly less improvement in lipid lamellae structure compared to the no oil group. There were no significant differences in TEWL, pH or erythema/skin scores. The study was not powered for clinical significance, but until further research is conducted, caution should be exercised when recommending oils for neonatal skin.

Poplar trees reconfigure the transcriptome and metabolome in response to drought in a genotype- and time-of-day-dependent manner.

BACKGROUND: Drought has a major impact on tree growth and survival. Understanding tree responses to this stress can have important application in both conservation of forest health, and in production forestry. Trees of the genus Populus provide an excellent opportunity to explore the mechanistic underpinnings of forest tree drought responses, given the growing molecular resources that are available for this taxon. Here, foliar tissue of six water-deficit stressed P. balsamifera genotypes was analysed for variation in the metabolome in response to drought and time of day by using an untargeted metabolite profiling technique, gas chromatography/mass-spectrometry (GC/MS). RESULTS: Significant variation in the metabolome was observed in response the imposition of water-deficit stress. Notably, organic acid intermediates such as succinic and malic acid had lower concentrations in leaves exposed to drought, whereas galactinol and raffinose were found in increased concentrations. A number of metabolites with significant difference in accumulation under water-deficit conditions exhibited intraspecific variation in metabolite accumulation. Large magnitude fold-change accumulation was observed in three of the six genotypes. In order to understand the interaction between the transcriptome and metabolome, an integrated analysis of the drought-responsive transcriptome and the metabolome was performed. One P. balsamifera genotype, AP-1006, demonstrated a lack of congruence between the magnitude of the drought transcriptome response and the magnitude of the metabolome response. More specifically, metabolite profiles in AP-1006 demonstrated the smallest changes in response to water-deficit conditions. CONCLUSIONS: Pathway analysis of the transcriptome and metabolome revealed specific genotypic responses with respect to primary sugar accumulation, citric acid metabolism, and raffinose family oligosaccharide biosynthesis. The intraspecific variation in the molecular strategies that underpin the responses to drought among genotypes may have an important role in the maintenance of forest health and productivity.

Control of carbon flux to glutamate excretion in Klebsiella pneumoniae: the role of the indigenous plasmid and its encoded isocitrate dehydrogenase.

Klebsiella pneumoniae (NCTC, CL687/80) harbors a large indigenous plasmid (p(C3)), which in addition to encoding for citrate utilization, proline synthesis and glutamate excretion, it uniquely carries the structural gene (icd); encoding isocitrate dehydrogenase (ICDH). Flux analysis revealed that ICDH, despite its role in the generation of NADPH required for glutamate dehydrogenase, is not rate-limiting (controlling) in central metabolism as evidenced by a negative flux control coefficient and an adverse effect of overexpression (14-fold) on glutamate excretion. More significantly, however, this paper presents, for the first time, clear evidence that the accumulation of glutamate and its subsequent excretion is associated with the C3 plasmid-encoded regulatory elements, which trigger a shift-down in the activity of α-ketoglutarate dehydrogenase, both in the K. pneumoniae parental strain as well as in the E. coli exconjugants strains. This finding opens the door for the exploitation of regulatory elements as a tool for manipulating flux in microbial cell factories.

Apps and Adolescents: A Systematic Review of Adolescents' Use of Mobile Phone and Tablet Apps That Support Personal Management of Their Chronic or Long-Term Physical Conditions.

BACKGROUND: The prevalence of physical chronic or long-term conditions in adolescents aged 10-24 years is rising. Mobile phone and tablet mobile technologies featuring software program apps are widely used by these adolescents and their healthy peers for social networking or gaming. Apps are also used in health care to support personal condition management and they have considerable potential in this context. There is a growing body of literature on app use in health contexts, thereby making a systematic review of their effectiveness very timely. OBJECTIVE: To systematically review the literature on the effectiveness of mobile apps designed to support adolescents' management of their physical chronic or long-term conditions. METHODS: We conducted a review of the English-language literature published since 2003 in five relevant bibliographical databases using key search terms. Two independent reviewers screened titles and abstracts using data extraction and quality assessment tools. RESULTS: The search returned 1120 hits. Of the 19 eligible full-text papers, four met our review criteria, reporting one pilot randomized controlled trial and three pretest/post-test studies. Samples ranged from 4 to 18 participants, with a combined sample of 46 participants. The apps reported were targeted at type 1 diabetes, asthma, and cancer. Two papers provided data for calculating effect size. Heterogeneity in terms of study design, reported outcomes, follow-up times, participants' ages, and health conditions prevented meta-analyses. There was variation in whether adolescents received guidance in using the app or were solely responsible for navigating the app. Three studies reported some level of patient involvement in app design, development, and/or evaluation. Health professional involvement in the modelling stages of apps was reported in all studies, although it was not always clear whether specific clinical (as opposed to academic) expertise in working with adolescents was represented. The dearth of studies and the small overall sample size emphasizes the need for future studies of the development, evaluation, use, and effectiveness of mobile apps to support adolescents' personal management of their conditions. CONCLUSIONS: A key finding of the review is the paucity of evidence-based apps that exist, in contrast to the thousands of apps available on the app market that are not evidence-based or user or professional informed. Although we aimed to assess the effectiveness of apps, the dearth of studies meeting our criteria meant that we were unable to be conclusive in this regard. Based on the available evidence, apps may be considered feasible health interventions, but more studies involving larger sample sizes, and with patient and health professional input at all stages, are needed to determine apps' acceptability and effectiveness. This review provides valuable findings and paves the way for future rigorous development and evaluation of health apps for adolescents with chronic or long-term conditions.

Comprehensive multiphase NMR: a promising technology to study plants in their native state.

Nuclear magnetic resonance (NMR) spectroscopy is arguably one the most powerful tools to study the interactions and molecular structure within plants. Traditionally, however, NMR has developed as two separate fields, one dealing with liquids and the other dealing with solids. Plants in their native state contain components that are soluble, swollen, and true solids. Here, a new form of NMR spectroscopy, developed in 2012, termed comprehensive multiphase (CMP)-NMR is applied for plant analysis. The technology composes all aspects of solution, gel, and solid-state NMR into a single NMR probe such that all components in all phases in native unaltered samples can be studied and differentiated in situ. The technology is evaluated using wild-type Arabidopsis thaliana and the cellulose-deficient mutant ectopic lignification1 (eli1) as examples. Using CMP-NMR to study intact samples eliminated the bias introduced by extraction methods and enabled the acquisition of a more complete structural and metabolic profile; thus, CMP-NMR revealed molecular differences between wild type (WT) and eli1 that could be overlooked by conventional methods. Methanol, fatty acids and/or lipids, glutamine, phenylalanine, starch, and nucleic acids were more abundant in eli1 than in WT. Pentaglycine was present in A. thaliana seedlings and more abundant in eli1 than in WT.

Mutation altering the miR-184 seed region causes familial keratoconus with cataract.

MicroRNAs (miRNAs) bind to complementary sequences within the 3' untranslated region (UTR) of mRNAs from hundreds of target genes, leading either to mRNA degradation or suppression of translation. We found that a mutation in the seed region of miR-184 (MIR184) is responsible for familial severe keratoconus combined with early-onset anterior polar cataract by deep sequencing of a linkage region known to contain the mutation. The mutant form fails to compete with miR-205 (MIR205) for overlapping target sites on the 3' UTRs of INPPL1 and ITGB4. Although these target genes and miR-205 are expressed widely, the phenotype is restricted to the cornea and lens because of the very high expression of miR-184 in these tissues. Our finding highlights the tissue specificity of a gene network regulated by a miRNA. Awareness of the important function of miRNAs could aid identification of susceptibility genes and new therapeutic targets for treatment of both rare and common diseases.

Interplay between sucrose and folate modulates auxin signaling in Arabidopsis.

As sessile organisms growing in an ever-changing environment, plants must integrate multiple regulatory inputs to promote the appropriate developmental responses. One such nutritional signal is cellular sugar levels, which rise and fall throughout the day and affect a variety of developmental processes. To uncover signaling pathways that modulate sugar perception, compounds from the Library of Active Compounds in Arabidopsis were screened for the ability to perturb developmental responses to sucrose (Suc) in Arabidopsis (Arabidopsis thaliana) seedlings. This screen found that sulfonamides, which inhibit folate biosynthesis in plants, restrict hypocotyl elongation in a sugar-dependent fashion. Transcriptome analysis identified a small set of transcripts that respond to the interaction between sulfonamide and Suc, including a number of transcripts encoding Auxin/Indole-3-Acetic Acids, negative regulators of auxin signal transduction. Chemical inhibition of auxin transport or genetic disruption of auxin signaling relieved this interaction, suggesting that responses to these two nutritional stimuli are mediated by auxin. Reporter systems used to track auxin signaling and distribution showed enhanced activity in the vascular region of the hypocotyl in response to cotreatment of Suc and sulfonamide, yet no change in auxin abundance was observed. Taken together, these findings suggest that the interplay between Suc and folates acts to fine-tune auxin sensitivity and influences auxin distribution during seedling development.

PlaNet: combined sequence and expression comparisons across plant networks derived from seven species.

The model organism Arabidopsis thaliana is readily used in basic research due to resource availability and relative speed of data acquisition. A major goal is to transfer acquired knowledge from Arabidopsis to crop species. However, the identification of functional equivalents of well-characterized Arabidopsis genes in other plants is a nontrivial task. It is well documented that transcriptionally coordinated genes tend to be functionally related and that such relationships may be conserved across different species and even kingdoms. To exploit such relationships, we constructed whole-genome coexpression networks for Arabidopsis and six important plant crop species. The interactive networks, clustered using the HCCA algorithm, are provided under the banner PlaNet (http://aranet.mpimp-golm.mpg.de). We implemented a comparative network algorithm that estimates similarities between network structures. Thus, the platform can be used to swiftly infer similar coexpressed network vicinities within and across species and can predict the identity of functional homologs. We exemplify this using the PSA-D and chalcone synthase-related gene networks. Finally, we assessed how ontology terms are transcriptionally connected in the seven species and provide the corresponding MapMan term coexpression networks. The data support the contention that this platform will considerably improve transfer of knowledge generated in Arabidopsis to valuable crop species.