Visuomotor Origins of Covert Spatial Attention

AbstractCovert spatial attention produces biases in perceptual performance and neural processing of behaviorally relevant stimuli in the absence of overt orienting movements. The neural mechanism that gives rise to these effects is poorly understood. This paper surveys past evidence of a relationship between oculomotor control and visual spatial attention and more recent evidence of a causal link between the control of saccadic eye movements by frontal cortex and covert visual selection. Both suggest that the mechanism of covert spatial attention emerges as a consequence of the reciprocal interactions between neural circuits primarily involved in specifying the visual properties of potential targets and those involved in specifying the movements needed to fixate them

Petrology and oxygen isotopic composition of large igneous inclusions in ordinary chondrites: Early solar system igneous processes and oxygen reservoirs

Large (>3.5 mm and up to 4 cm across) igneous inclusions poor in metal and sulfide are a minor but not uncommon component in ordinary chondrites, and have implications for the nature of physiochemical and melting processes in the early solar system. We obtained petrographic-chemical data for forty-two large igneous inclusions in ordinary chondrites of various groups (H, L, LL) and petrographic types (3-6) and oxygen isotope data for a subset of twelve of these inclusions and their host chondrites. Different inclusions formed both before and after the thermal metamorphism experienced by their host chondrites. The bulk chemical compositions of the inclusions vary broadly around whole-rock chondrite composition, comprise four main chemical types and some other variants, and show little evidence of having formed as igneous differentiates. Oxygen isotope compositions overlap ordinary chondrite compositions and are related to inclusion chemical type. Most prevalent in type 3 and 4 chondrites are inclusions, often droplets, of the vapor-fractionated (Vfr) chemical type, either enriched in refractory lithophile elements, or depleted in volatile lithophile elements, or both. These inclusions have low Δ17O (∼0.1-0.6‰) and high δ18O (∼4-8‰) values and formed in reservoirs with Δ17O lower than their hosts, primarily as evaporative melts and mixtures that probably experienced kinetic isotopic fractionation. Another chemical type (Unfr+K) has unfractionated abundances of lithophile elements except for being strongly enriched in K, a signature also found in some impact melts from melt rocks and melt breccias. These inclusions formed by impact melting of chondritic material and accompanying K enrichment. Inclusions with unfractionated (Unfr) lithophile element abundances are present in type 3-6 chondrites and are prevalent in type 5 and 6. Some are spatially associated with coarse metal-sulfide nodules in the chondrites and likely formed by in situ impact melting. Others were melted prior to thermal metamorphism and were chemically but not isotopically homogenized during metamorphism; they are xenoliths that formed in oxygen reservoirs different than the hosts in which they were metamorphosed. The latter inclusions provide evidence for nebular or collisional mixing of primitive materials prior to thermal metamorphism of asteroid bodies, including transport of H-like source materials to the L body, LL-like source materials to the L body, and low-Δ17O materials to the LL body. Feldspar-rich (FldR) inclusions have compositions similar to melt pockets and could have formed by disequilibrium melting and concentration of feldspar during an impact event to form large droplets or large masses. Overall, the results of this study point to important and varied roles for both “planetary” impact melting and “nebular” evaporative melting processes to form different large igneous inclusions in ordinary chondrites. Chondrules may have formed by processes similar to those inferred for large inclusions, but there are important differences in the populations of these objects

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of sufferingwithin commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

A Multi-Country Analysis on Potential Adaptive Mechanisms to Cold and Heat in a Changing Climate

Background: Temporal variation of temperature-health associations depends on the combination of two pathways: pure adaptation to increasingly warmer temperatures due to climate change, and other attenuation mechanisms due to non-climate factors such as infrastructural changes and improved health care. Disentangling these pathways is critical for assessing climate change impacts and for planning public health and climate policies. We present evidence on this topic by assessing temporal trends in cold- and heat-attributable mortality risks in a multi-country investigation. Methods: Trends in country-specific attributable mortality fractions (AFs) for cold and heat (defined as below/ above minimum mortality temperature, respectively) in 305 locations within 10 countries (1985–2012) were estimated using a two-stage time-series design with time-varying distributed lag non-linear models. To separate the contribution of pure adaptation to increasing temperatures and active changes in susceptibility (non-climate driven mechanisms) to heat and cold, we compared observed yearly-AFs with those predicted in two counterfactual scenarios: trends driven by either (1) changes in exposure-response function (assuming a constant temperature distribution), (2) or changes in temperature distribution (assuming constant exposure-response relationships). This comparison provides insights about the potential mechanisms and pace of adaptation in each population. Results: Heat-related AFs decreased in all countries (ranging from 0.45–1.66% to 0.15–0.93%, in the first and last 5-year periods, respectively) except in Australia, Ireland and UK. Different patterns were found for cold (where AFs ranged from 5.57–15.43% to 2.16–8.91%), showing either decreasing (Brazil, Japan, Spain, Australia and Ireland), increasing (USA), or stable trends (Canada, South Korea and UK). Heat-AF trends were mostly driven by changes in exposure-response associations due to modified susceptibility to temperature, whereas no clear patterns were observed for cold. Conclusions: Our findings suggest a decrease in heat-mortality impacts over the past decades, well beyond those expected from a pure adaptation to changes in temperature due to the observed warming. This indicates that there is scope for the development of public health strategies to mitigate heat-related climate change impacts. In contrast, no clear conclusions were found for cold. Further investigations should focus on identification of factors defining these changes in susceptibility

Early childhood epilepsies:epidemiology, classification, aetiology, and socio-economic determinants

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216–263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251–357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139–233), χ2 odds ratio = 1.7 (95% CI 1.3–2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations

Improving the selectivity of photocatalytic NOx abatement through improved O2 reduction pathways using Ti0.909W0.091O2Nx semiconductor nanoparticles : from characterisation to photocatalytic performance

Peer reviewedPostprin

Trends in utilization and costs of BRCA testing among women aged 18–64 years in the United States, 2003–2014

Purpose We examined 12-year trends in BRCA testing rates and costs in the context of clinical guidelines, national policies, and other factors. Methods We estimated trends in BRCA testing rates and costs from 2003 to 2014 for women aged 18–64 years using private claims data and publicly reported revenues from the primary BRCA testing provider. Results The percentage of women with zero out-of-pocket payments for BRCA testing increased during 2013–2014, after 7 years of general decline, coinciding with a clarification of Affordable Care Act coverage of BRCA genetic testing. Beginning in 2007, family history accounted for an increasing proportion of women with BRCA tests compared with personal history, coinciding with BRCA testing guidelines for primary care settings and direct-to-consumer advertising campaigns. During 2013–2014, BRCA testing rates based on claims grew at a faster rate than revenues, following 3 years of similar growth, consistent with increased marketplace competition. In 2013, BRCA testing rates based on claims increased 57%, compared with 11% average annual increases over the preceding 3 years, coinciding with celebrity publicity. Conclusion The observed trends in BRCA testing rates and costs are consistent with possible effects of several factors, including the Affordable Care Act, clinical guidelines and celebrity publicity

A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer

Despite substantial improvements in the treatment landscape of prostate cancer, the evolution of hormone therapy-resistant and metastatic prostate cancer remains a major cause of cancer-related death globally. The mainstay of treatment for advanced prostate cancer is targeting of androgen receptor signaling, including androgen deprivation therapy plus second-generation androgen receptor blockade (e.g., enzalutamide, apalutamide, darolutamide), and/or androgen synthesis inhibition (abiraterone). While these agents have significantly prolonged the lives of patients with advanced prostate cancer, is nearly universal. This therapy resistance is mediated by diverse mechanisms, including both androgen receptor-dependent mechanisms, such as androgen receptor mutations, amplifications, alternative splicing, and amplification, as well as non-androgen receptor-mediated mechanisms, such as lineage plasticity toward neuroendocrine-like or epithelial-mesenchymal transition (EMT)-like lineages. Our prior work identified the EMT transcriptional regulator Snail as critical to hormonal therapy resistance and is commonly detected in human metastatic prostate cancer. In the current study, we sought to interrogate the actionable landscape of EMT-mediated hormone therapy resistant prostate cancer to identify synthetic lethality and collateral sensitivity approaches to treating this aggressive, therapy-resistant disease state. Using a combination of high-throughput drug screens and multi-parameter phenotyping by confluence imaging, ATP production, and phenotypic plasticity reporters of EMT, we identified candidate synthetic lethalities to Snail-mediated EMT in prostate cancer. These analyses identified multiple actionable targets, such as XPO1, PI3K/mTOR, aurora kinases, c-MET, polo-like kinases, and JAK/STAT as synthetic lethalities in Snail+ prostate cancer. We validated these targets in a subsequent validation screen in an LNCaP-derived model of resistance to sequential androgen deprivation and enzalutamide. This follow-up screen provided validation of inhibitors of JAK/STAT and PI3K/mTOR as therapeutic vulnerabilities for both Snail+ and enzalutamide-resistant prostate cancer