Optical electrophysiology for probing function and pharmacology of voltage-gated ion channels

Voltage-gated ion channels mediate electrical dynamics in excitable tissues and are an important class of drug targets. Channels can gate in sub-millisecond timescales, show complex manifolds of conformational states, and often show state-dependent pharmacology. Mechanistic studies of ion channels typically involve sophisticated voltage-clamp protocols applied through manual or automated electrophysiology. Here, we develop all-optical electrophysiology techniques to study activity-dependent modulation of ion channels, in a format compatible with high-throughput screening. Using optical electrophysiology, we recapitulate many voltage-clamp protocols and apply to Nav1.7, a channel implicated in pain. Optical measurements reveal that a sustained depolarization strongly potentiates the inhibitory effect of PF-04856264, a Nav1.7-specific blocker. In a pilot screen, we stratify a library of 320 FDA-approved compounds by binding mechanism and kinetics, and find close concordance with patch clamp measurements. Optical electrophysiology provides a favorable tradeoff between throughput and information content for studies of NaV channels, and possibly other voltage-gated channels. DOI: http://dx.doi.org/10.7554/eLife.15202.00

Fatores considerados pela população como mais importantes para manutenção da saúde

OBJECTIVE: To analyze factors that adults and elderly individuals regard as the most important for health maintenance. METHODS: A cross-sectional study performed with 4,060 adults and 4,003 elderly individuals in areas covered by 240 primary health units in the Brazilian Southern and Northeastern regions, in 2005. A card with pictures and sentences about seven factors associated with the risk of non-communicable diseases and health problems was shown to individuals so they should point out the most relevant factor for health. These factors were as follows: to maintain a healthy diet, to exercise regularly, to avoid excessive drinking, to have regular medical check-ups, not to smoke, to maintain the ideal weight, and to control or avoid stress. Adjusted analysis was carried out by Poisson regression, with calculations of adjusted prevalence ratios, respective 95% confidence intervals and significance values, using Wald tests for heterogeneity and linear trend. RESULTS: Factors most frequently indicated by adults were the following: to maintain a healthy diet (33.8%), to exercise regularly (21.4%) and not to smoke (13.9%). Among the elderly, factors most frequently reported were: to maintain a healthy diet (36.7%), not to smoke (17.7%) and to have regular medical check-ups (14.2%). Differences among factors mentioned were observed, according to geographical region, and demographic, socioeconomic and health variables. CONCLUSIONS: The majority of adults and elderly individuals of both regions recognize and indicate the need to maintain a healthy diet and not to smoke as the most important health maintenance measures. Health education strategies should consider these characteristics to promote specific measures to be adopted for each population segment.OBJETIVO: Analisar os fatores que adultos e idosos consideram como mais importantes para manutenção da saúde. MÉTODOS: Estudo transversal realizado com 4.060 adultos e 4.003 idosos residentes em áreas de abrangência de 240 unidades básicas de saúde das regiões Sul e Nordeste, em 2005. Um cartão com figuras e frases referentes a sete fatores relacionados com o risco de doenças e agravos não transmissíveis era mostrado aos indivíduos para que indicassem o fator mais relevante para a saúde. Os fatores eram: manter uma alimentação saudável, fazer exercício físico regularmente, não tomar bebidas alcoólicas em excesso, realizar consultas médicas regularmente, não fumar, manter o peso ideal e controlar ou evitar o estresse. As análises foram ajustadas por regressão de Poisson com cálculo de razões de prevalência ajustadas, intervalos com 95% de confiança, e valores de significância usando os Testes de Wald para heterogeneidade e tendência linear. RESULTADOS: Os fatores mais freqüentemente indicados pelos adultos foram: alimentação saudável (33,8%), realizar exercício físico (21,4%) e não fumar (13,9%). Entre os idosos, os fatores mais relatados foram: alimentação saudável (36,7%), não fumar (17,7%) e consultar o médico regularmente (14,2%). Foram observadas diferenças entre os fatores citados conforme a região geográfica, variáveis demográficas, socioeconômicas e de saúde. CONCLUSÕES: A maioria de adultos e idosos, de ambas regiões, reconhece e indica a necessidade de manter uma alimentação saudável e de não fumar como medidas mais importantes para manutenção da saúde. Estratégias de educação em saúde devem considerar essas características dos indivíduos para estimular medidas específicas a serem adotadas para cada segmento populacional.OBJETIVO: Analizar los factores que adultos y ancianos consideran como más importantes para mantenimiento de la salud. MÉTODOS: Estudio transversal realizado con 4.060 adultos y 4.003 ancianos residentes en áreas que abarcan 240 unidades básicas de salud de las regiones Sur y Noreste de Brasil, en 2005. Una tarjeta con figuras y frases referentes a siete factores relacionados con el riesgo de enfermedades y agravios no transmisibles era mostrada a los individuos para que indicaran el factor más relevante para la salud. Los factores eran: mantener una alimentación saludable, hacer ejercicio físico regularmente, no tomar bebidas alcohólicas en exceso, realizar consultas médicas regularmente, no fumar, mantener el peso ideal y controlar o evitar el estrés. Los análisis fueron ajustados por regresión de Poisson con cálculo de tasas de prevalencia ajustadas, intervalos con 95% de confianza, y valores de significancia usando las pruebas de Wald para heterogeneidad y tendencia linear. RESULTADOS: Los factores más frecuentemente indicados por los adultos fueron: alimentación saludable (33,8%), realizar ejercicio físico (21,4%) y no fumar (13,9%). Entre los ancianos, los factores más relatados fueron: alimentación saludable (36,7%), no fumar (17,7%) y consultar el médico regularmente (14,2%). Fueron observadas diferencias entre los factores citados conforme a la región geográfica, variables demográficas, socioeconómicas y de salud. CONCLUSIONES: La mayoría de los adultos y ancianos, de ambas regiones, reconoce e indica la necesidad de mantener una alimentación saludable y de no fumar como medidas más importantes para mantenimiento de la salud. Estrategias de educación en salud deben considerar esas características de los individuos para estimular medidas específicas a ser adoptadas para cada segmento poblacional

The Virtual Sociality of Rights: The Case of Women\u27s Rights are Human Rights

This essay traces the relationship between activists and academics involved in the campaign for women\u27s rights as human rights as a case study of the relationship between different classes of what I call knowledge professionals self-consciously acting in a transnational domain. The puzzle that animates this essay is the following: how was it that at the very moment at which a critique of rights and a reimagination of rights as rights talk proved to be such fertile ground for academic scholarship did the same rights prove to be an equally fertile ground for activist networking and lobbying activities? The paper answers this question with respect to the work of self-reflexivity in creating a virtual sociality of rights

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 Ã 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 Ã 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Effects of Memory Association Devices and Attention Tasks on Name Recall Abilities in Individuals with Dementia: Memory Alone Versus a Combination of Memory and Attention

Individuals with dementia constitute the fastest-growing clinical population in speech-language pathology. Cognitive deficits present in dementia adversely affect overall communication abilities, and a specific skill compromised is name recall ability. Various memory training strategies have yielded somewhat positive results for name recall ability. As attention is also affected, a combination of memory and attention tasks might result in further gains. In this study, three individuals with dementia participated in seven sessions measuring name recall abilities for unfamiliar individuals. A multiple-baseline design was used to compare name recall abilities for different conditions. Results were compared to a concurrent study, in which three participants completed attention tasks and a combination of memory and attention tasks. Participants obtained fluctuating scores across sessions, with no group trend evident relative to the introduction of experimental conditions. One participant showed a positive trend during combined sessions. Participants in the concurrent study received scores with a general increasing trend. Limitations to the study are discussed, along with possible clinical implications