PAX6 mutations: genotype-phenotype correlations

BACKGROUND: The PAX6 protein is a highly conserved transcriptional regulator that is important for normal ocular and neural development. In humans, heterozygous mutations of the PAX6 gene cause aniridia (absence of the iris) and related developmental eye diseases. PAX6 mutations are archived in the Human PAX6 Allelic Variant Database, which currently contains 309 records, 286 of which are mutations in patients with eye malformations. RESULTS: We examined the records in the Human PAX6 Allelic Variant Database and documented the frequency of different mutation types, the phenotypes associated with different mutation types, the contribution of CpG transitions to the PAX6 mutation spectrum, and the distribution of chain-terminating mutations in the open reading frame. Mutations that introduce a premature termination codon into the open reading frame are predominantly associated with aniridia; in contrast, non-aniridia phenotypes are typically associated with missense mutations. Four CpG dinucleotides in exons 8, 9, 10 and 11 are major mutation hotspots, and transitions at these CpG's account for over half of all nonsense mutations in the database. Truncating mutations are distributed throughout the PAX6 coding region, except for the last half of exon 12 and the coding part of exon 13, where they are completely absent. The absence of truncating mutations in the 3' part of the coding region is statistically significant and is consistent with the idea that nonsense-mediated decay acts on PAX6 mutant alleles. CONCLUSION: The PAX6 Allelic Variant Database is a valuable resource for studying genotype-phenotype correlations. The consistent association of truncating mutations with the aniridia phenotype, and the distribution of truncating mutations in the PAX6 open reading frame, suggests that nonsense-mediated decay acts on PAX6 mutant alleles

The Imaging and Cognition Genetics Conference 2011, ICG 2011: A Meeting of Minds

In June 2011, 70 researchers from the disciplines of cognitive science, genetics, psychology, psychiatry, neurobiology, and computer science gathered in Os, Norway, for the first Imaging and Cognition Genetics meeting. The aim of the conference was to discuss progress, enhance collaboration, and maximize the sharing of resources within this new field. In this Perspective, we summarize the major themes that emerged from ICG 2011. The first is the importance of defining cognitive and imaging phenotypes and endophenotypes suitable for genetic analysis. These can come from differential psychology, cognitive science, structural MRI, tractography, and functional imaging. The second theme is the emergence of new methods for the analysis of complex traits. These include advanced computational and statistical techniques for analyzing complex datasets, and new ways of interpreting data from genome-wide association studies, such as jointly evaluating the contribution of SNPs in specific genes and pathways rather than considering single SNPs in isolation. The final theme is the importance of establishing functional correlates of newly identified genetic variants

A screen for proteins that interact with PAX6: C-terminal mutations disrupt interaction with HOMER3, DNCL1 and TRIM11

BACKGROUND: The PAX6 protein is a transcriptional regulator with a key role in ocular and neurological development. Individuals with heterozygous loss-of-function mutations in the PAX6 gene have malformations of the eye and brain. Little is known about the interactions of PAX6 with other proteins, so we carried out a systematic screen for proteins that interact with PAX6. RESULTS: We used bioinformatics techniques to characterise a highly conserved peptide at the C-terminus of the PAX6 protein. Yeast two-hybrid library screens were then carried out to identify brain-expressed proteins that interact with the C-terminal peptide and with the entire PAX6 proline-serine-threonine-rich domain. Three novel PAX6-interacting proteins were identified: the post-synaptic density (PSD) protein HOMER3, the dynein subunit DNCL1, and the tripartite motif protein TRIM11. Three C-terminal PAX6 mutations, previously identified in patients with eye malformations, all reduced or abolished the interactions. CONCLUSION: Our preliminary data suggest that PAX6 interacts with HOMER3, DNCL1 and TRIM11. We propose that the interaction of PAX6 with HOMER3 and DNCL1 is a mechanism by which synaptic activation could lead to changes in neuronal transcriptional activity, and that some of the neural anomalies in patients with PAX6 mutations could be explained by impaired protein-protein interactions

Discriminação do perfil aromático de cafés e misturas industriais de acordo com o valor cromático

Different polymeric phases have been used in order to perform roasted coffee aroma analysis although not in a systematic way. Variations in the type of SPME polymer and sample composition make experimental results interpretation difficult and may hinder coffee blend differentiation. In the present work, static headspace solid phase microextraction using carboxen/polydimethylsiloxane polymeric fibre (HS-SPME(CAR/PDMS)) followed by gas chromatography-mass spectrometry (GC-MS), revealed the best analytical performance to characterize the aroma profile of coffees and industrial blends with different chromaticvalues (64.9, 70.6, 75.3, 86.1 and 89.6). The most relevant classes of aroma compounds founded were pyrroles, ketones, pyrazines, furans, phenolics, pyridines, alcohols and acids, independent of the degree of roasting. By combining the analytical methodology with principal component analysis (HS-SPME (CAR/PDMS)/GC-MS/PCA), important aroma compounds such as 2-furancarboxaldehyde, 2-furanmethanol and acetic acid, allows to discriminate the different degrees of roasting, from light (chromatic value 89.6) to dark(chromatic value 64.9) roast. The proposed analytical approach may help to build aroma profile databases to allow a better evaluation of coffee blend quality, and in controlling the industrial roasting processes.Diferentes fases poliméricas têm sido utilizadas, a fim de realizar-se a análise do aroma do café torrado, embora isso não tenha sido feito de forma sistemática. Variações no tipo de polímero de SPME, bem como na composição da amostra tornam a interpretação dos resultados experimentais difícil o que pode inclusive interferir em tentativas de diferenciação de diferentes misturas de café. No presente trabalho, a microextração de fase sólida para análise estática de “espaço-de-cabeça”, utilizando o polímero carboxen/polidimetilsiloxano (HS-SPME (CAR/PDMS)), associada a cromatografia gasosa acoplada a espectrometria de massa (GC-MS), revelou o melhor desempenho analítico na caracterização do perfil aromático de cafés e misturas industriais, com diferentes valores cromáticos (64,9, 70,6, 75,3, 86,1 e 89,6). As classes de compostos aromáticos mais importantes identificadas nos cafés foram: pirróis, cetonas, pirazinas, furanos, fenóis, piridinas, álcoois e ácidos, independentemente do grau de torra. Aocombinar a metodologia analítica com a análise de componentes principais (HS-SPME (CAR/PDMS)/GC-MS/PCA), verificou-se que os compostos aromáticos furancarboxaldeído, 2-furanmethanol e ácido acético permitem discriminar os diferentes graus de torrefação. A abordagem proposta neste estudo pode ajudar a construir bases de dados de perfis aromáticos de uma maneira mais robusta,permitindo uma melhor avaliação da qualidade de misturas de café e melhor controle do processo industrial de torração

Getting rights right: implementing 'Martha's Rule'

The UK government has recently committed to adopting a new policy —dubbed ‘Martha’s Rule’— which has been characterized as providing patients the right to rapidly access a second clinical opinion in urgent or contested cases. Support for the rule emerged following the death of Martha Mills in 2021, after doctors failed to admit her to intensive care despite concerns raised by her parents. We argue that framing this issue in terms of patient rights is not productive, and should be avoided. Insofar as the ultimate goal of ‘Martha’s Rule’ is the provision of a clinical service that protects patient safety, an approach that focuses on the obligations of the health system —rather than the individual rights of patients— will better serve this goal. We outline an alternative approach that situates rapid clinical review as part of a suite of services aimed at enhancing and protecting patient care. This approach would make greater progress towards addressing the difficult systemic issues that Martha’s Rule does not, while also better engaging with the constraints of clinical practice

The Potential of Tree and Shrub Legumes in Agroforestry Systems

Climate variability and changes are utmost important primary drivers of biological processes. They are intimately associated with a wide array of abiotic stresses, highlighting the vulnerability of ecosystems and endangering biodiversity. Nitrogen‐fixing trees and shrubs (NFTSs) constitute a unique group of plants for their wide range of applications at the environmental, social and economic levels. In this chapter, we review and analyse the potential of this group of legumes in agroforestry towards sustainable agriculture in Africa. In the first part, the intertwined pillar of sustainable agriculture is brought forward under the context of growing population and climate changes. The second part addresses general aspects of legumes, including botany and the symbiosis with rhizobia. The third part includes the application of NFTS as N‐fertilizers in agroforestry, highlighting the importance of an accurate choice of the crop(s)/NFTS combination(s) and cropping type (intercropping, multistrata or fallows). The implementation of agroforestry systems with NFTS should be supported by fundamental research strategies such as stable isotopes and systems biology and preceded by experimental assays, in order to identify the factors promoting N‐losses and to design appropriate management strategies that synchronize legume‐N availability with the crop demand

Objective assessment of dietary patterns by use of metabolic phenotyping:A randomised, controlled, crossover trial

BACKGROUND: Accurate monitoring of changes in dietary patterns in response to food policy implementation is challenging. Metabolic profiling allows simultaneous measurement of hundreds of metabolites in urine, the concentrations of which can be affected by food intake. We hypothesised that metabolic profiles of urine samples developed under controlled feeding conditions reflect dietary intake and can be used to model and classify dietary patterns of free-living populations. METHODS: In this randomised, controlled, crossover trial, we recruited healthy volunteers (aged 21–65 years, BMI 20–35 kg/m(2)) from a database of a clinical research unit in the UK. We developed four dietary interventions with a stepwise variance in concordance with the WHO healthy eating guidelines that aim to prevent non-communicable diseases (increase fruits, vegetables, whole grains, and dietary fibre; decrease fats, sugars, and salt). Participants attended four inpatient stays (72 h each, separated by at least 5 days), during which they were given one dietary intervention. The order of diets was randomly assigned across study visits. Randomisation was done by an independent investigator, with the use of opaque, sealed, sequentially numbered envelopes that each contained one of the four dietary interventions in a random order. Participants and investigators were not masked from the dietary intervention, but investigators analysing the data were masked from the randomisation order. During each inpatient period, urine was collected daily over three timed periods: morning (0900–1300 h), afternoon (1300–1800 h), and evening and overnight (1800–0900 h); 24 h urine samples were obtained by pooling these samples. Urine samples were assessed by proton nuclear magnetic resonance ((1)H-NMR) spectroscopy, and diet-discriminatory metabolites were identified. We developed urinary metabolite models for each diet and identified the associated metabolic profiles, and then validated the models using data and samples from the INTERMAP UK cohort (n=225) and a healthy-eating Danish cohort (n=66). This study is registered with ISRCTN, number ISRCTN43087333. FINDINGS: Between Aug 13, 2013, and May 18, 2014, we contacted 300 people with a letter of invitation. 78 responded, of whom 26 were eligible and invited to attend a health screening. Of 20 eligible participants who were randomised, 19 completed all four 72 h study stays between Oct 2, 2013, and July 29, 2014, and consumed all the food provided. Analysis of (1)H-NMR spectroscopy data indicated that urinary metabolic profiles of the four diets were distinct. Significant stepwise differences in metabolite concentrations were seen between diets with the lowest and highest metabolic risks. Application of the derived metabolite models to the validation datasets confirmed the association between urinary metabolic and dietary profiles in the INTERMAP UK cohort (p<0·0001) and the Danish cohort (p<0·0001). INTERPRETATION: Urinary metabolite models developed in a highly controlled environment can classify groups of free-living people into consumers of diets associated with lower or higher non-communicable disease risk on the basis of multivariate metabolite patterns. This approach enables objective monitoring of dietary patterns in population settings and enhances the validity of dietary reporting. FUNDING: UK National Institute for Health Research and UK Medical Research Council

Training needs for staff providing remote services in general practice: a mixed-methods study

Background Contemporary general practice includes many kinds of remote encounter. The rise in telephone, video and online modalities for triage and clinical care requires clinicians and support staff to be trained, both individually and as teams, but evidence-based competencies have not previously been produced for general practice. Aim To identify training needs, core competencies, and learning methods for staff providing remote encounters. Design and setting Mixed-methods study in UK general practice. Method Data were collated from longitudinal ethnographic case studies of 12 general practices; a multi-stakeholder workshop; interviews with policymakers, training providers, and trainees; published research; and grey literature (such as training materials and surveys). Data were coded thematically and analysed using theories of individual and team learning. Results Learning to provide remote services occurred in the context of high workload, understaffing, and complex workflows. Low confidence and perceived unmet training needs were common. Training priorities for novice clinicians included basic technological skills, triage, ethics (for privacy and consent), and communication and clinical skills. Established clinicians’ training priorities include advanced communication skills (for example, maintaining rapport and attentiveness), working within the limits of technologies, making complex judgements, coordinating multi-professional care in a distributed environment, and training others. Much existing training is didactic and technology focused. While basic knowledge was often gained using such methods, the ability and confidence to make complex judgements were usually acquired through experience, informal discussions, and on-the-job methods such as shadowing. Whole-team training was valued but rarely available. A draft set of competencies is offered based on the findings. Conclusion The knowledge needed to deliver high-quality remote encounters to diverse patient groups is complex, collective, and organisationally embedded. The vital role of non-didactic training, for example, joint clinical sessions, case-based discussions, and in-person, whole-team, on-the-job training, needs to be recognised

Level and determinants of county health system technical efficiency in Kenya: two stage data envelopment analysis.

BACKGROUND: Improving health system efficiency is a key strategy to increase health system performance and accelerate progress towards Universal Health Coverage. In 2013, Kenya transitioned into a devolved system of government granting county governments autonomy over budgets and priorities. We assessed the level and determinants of technical efficiency of the 47 county health systems in Kenya. METHODS: We carried out a two-stage data envelopment analysis (DEA) using Simar and Wilson's double bootstrap method using data from all the 47 counties in Kenya. In the first stage, we derived the bootstrapped DEA scores using an output orientation. We used three input variables (Public county health expenditure, Private county health expenditure, number of healthcare facilities), and one outcome variable (Disability Adjusted Life Years) using 2018 data. In the second stage, the bias corrected technical inefficiency scores were regressed against 14 exogenous factors using a bootstrapped truncated regression. RESULTS: The mean bias-corrected technical efficiency score of the 47 counties was 69.72% (95% CI 66.41-73.01%), indicating that on average, county health systems could increase their outputs by 30.28% at the same level of inputs. County technical efficiency scores ranged from 42.69% (95% CI 38.11-45.26%) to 91.99% (95% CI 83.78-98.95%). Higher HIV prevalence was associated with greater technical inefficiency of county health systems, while higher population density, county absorption of development budgets, and quality of care provided by healthcare facilities were associated with lower county health system inefficiency. CONCLUSIONS: The findings from this analysis highlight the need for county health departments to consider ways to improve the efficiency of county health systems. Approaches could include prioritizing resources to interventions that will reduce high chronic disease burden, filling structural quality gaps, implementing interventions to improve process quality, identifying the challenges to absorption rates and reforming public finance management systems to enhance their efficiency

Location of chlorogenic acid biosynthesis pathway and polyphenol oxidase genes in a new interspecific anchored linkage map of eggplant

© Gramazio et al.; licensee BioMed Central. 2014. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated