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BACKGROUND: Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment.METHODS: We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (pFINDINGS: From a GWAS of 9714 cases and 48 471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the Human Leukocyte Antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and the FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2,203 cases and 17,627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino-acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease.INTERPRETATION: Novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.

Funder: British Lung Foundation, Funder: National Institute for Health Research (NIHR), Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351, Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

The use of biomarkers to measure immune responses in serum is crucial for understanding population-level exposure and susceptibility to human pathogens. Advances in sample collection, multiplex testing, and computational modeling are transforming serosurveillance into a powerful tool for public health program design and response to infectious threats. In July 2018, 70 scientists from 16 countries met to perform a landscape analysis of approaches that support an integrated serosurveillance platform, including the consideration of issues for successful implementation. Here, we summarize the group's insights and proposed roadmap for implementation, including objectives, technical requirements, ethical issues, logistical considerations, and monitoring and evaluation.

Aquatic primary production is the foundation of many river food webs. Dams change the physical template of rivers, often driving food webs toward greater reliance on aquatic primary production. Nonetheless, the effects of regulated flow regimes on primary production are poorly understood. Load following is a common dam flow management strategy that involves subdaily changes in water releases proportional to fluctuations in electrical power demand. This flow regime causes an artificial tide, wetting and drying channel margins and altering river depth and water clarity, all processes that are likely to affect primary production. In collaboration with dam operators, we designed an experimental flow regime whose goal was to mitigate negative effects of load following on ecosystem processes. The experimental flow contrasted steady-low flows on weekends with load following flows on weekdays. Here, we quantify the effect of this experimental flow on springtime gross primary production (GPP) 90-to-425 km downstream of Glen Canyon Dam on the Colorado River, AZ, USA. GPP during steady-low flows was 41% higher than during load following flows, mostly owing to nonlinear reductions in sediment-driven turbidity. The experimental flow increased weekly GPP even after controlling for variation in weekly mean discharge, demonstrating a negative effect of load following on GPP. We estimate that this environmental flow increased springtime carbon fixation by 0.27 g C m−2 d−1, which is ecologically meaningful considering median C fixation in 356 US rivers of 0.44 g C m−2 d−1 and the fact that native fish populations in this river are food-limited.

White asparagus (A. officinalis) is a popular vegetable consumed worldwide and its cooked spears are appreciated for their distinct flavour profile. During asparagus harvesting, around one-third of the total material is usually discarded. This significant waste stream partially consists of the stem bases which are cut off to produce spears with the same desired length for delivery to the supermarket. This waste stream could become a valuable resource of food ingredients. Asparagus waste was used to generate an asparagus concentrate, and this was spray-dried in different carrier formulations in which maltodextrin was partially replaced by cellulose-based carriers, i.e. asparagus fibre, citrus fibre or microcrystalline cellulose. Powders obtained from feed solutions with an initial solids content of 40 % w/w showed better physical properties and aroma retention than 30 % w/w. Partial replacement of maltodextrin by cellulose-based carriers resulted in powders with similar physical properties to the control and did not detrimentally influence the aroma profiles as analysed by headspace solid-phase microextraction and gas chromatography-mass spectrometry. Aroma analysis was focused on asparagus key volatiles based on previous studies. This research showed that fibre obtained from asparagus waste streams could potentially be used as a carrier to produce spray-dried asparagus powder with retained key asparagus odorants such as 2-methoxy-3-isopropyl pyrazine. Valorisation of these materials could reduce the amount of agricultural waste while generating aroma-rich natural food products.

The use of biomarkers to measure immune responses in serum is crucial for understanding population-level exposure and susceptibility to human pathogens. Advances in sample collection, multiplex testing, and computational modeling are transforming serosurveillance into a powerful tool for public health program design and response to infectious threats. In July 2018, 70 scientists from 16 countries met to perform a landscape analysis of approaches that support an integrated serosurveillance platform, including the consideration of issues for successful implementation. Here, we summarize the group's insights and proposed roadmap for implementation, including objectives, technical requirements, ethical issues, logistical considerations, and monitoring and evaluation.

Unemployment recoveries in the US have been inexorable. Between 1948 and 2019, the annual reduction in the unemployment rate during cyclical recoveries was fairly tightly distributed around 0.1 log points per year. The economy seems to have an irresistible force toward restoring full employment. In the aftermath of a recession, unless another crisis intervenes, unemployment continues to glide down. Occasionally, unemployment rises rapidly during an economic crisis, while most of the time, unemployment declines slowly and smoothly at a near-constant proportional rate. We show that similar properties hold for other measures of the US unemployment rate and for the unemployment rates of many other emerging and advanced countries.

Potential workers are classified as unemployed if they seek work but are not working. The unemployed population contains two groups—those with jobs and those without jobs. Those with jobs are on furlough or temporary layoff. This group expanded tremendously in April 2020, at the trough of the pandemic recession. They wait out periods of non-work with the understanding that their jobs still exist and that they will be recalled. We show that the resulting temporary-layoff unemployment mostly dissipated by the end of 2020. Potential workers without jobs constitute what we call jobless unemployment. Shocks that elevate jobless unemployment have much more persistent effects. Historical major adverse shocks, such as the financial crisis in 2008, created mostly jobless unemployment and consequently caused extended periods of elevated unemployment. Jobless unemployment reached its pandemic peak in November 2020, at 4.9%, modest by historical standards, and has declined at a faster-than-historical pace since.

Our client has a common manufacturing task of producing flanges with precisely located bolt holes. Precision is paramount as the bolt holes in one flange have to mate to another within a tolerance of several thousandths of an inch. Currently, the flange indexing process is laborious and time-consuming, involving the use of charts for a variety of flange sizes as well as the use of inexact measurement tools available in a fabrication shop. Our objective is to reduce the time and manpower this process requires, while maintaining precision and repeatability. Our design utilizes a high resolution rotary encoder coupled to a digital counter to precisely monitor and display the distance travelled by the indexer. An integral marking system makes it easy to precisely mark the location of bolt holes. The encoder mount can also be adjusted to follow a path offset from the centerline depending on the location of the desired bolt holes. Our design is portable, durable, and simple for a single person to operate with a limited amount of training.

En la reseña bibliográfica sobre el libro de Adela Cortina: "Las fronteras de la persona. El valor de los animales, la dignidad de los humanos" (Taurus, Madrid, 2009), el Profesor Robert Hall, Facultad de Filosofía de la Universidad Autónoma de Querétaro y de la West Virginia State University, esboza los argumentos que Adela Cortina hace con referencia a la relación entre los humanos y los animales. Publicado originalmente en Dianoia, el resumen proporciona una visión interna de las fortalezas y de las debilidades de los argumentos de la autora. De acuerdo con Hall, Cortina presenta tres posturas con respecto a la consideración ética de los animales: 1) Aceptar a los animales no humanos en el núcleo de la ética en pie de igualdad con los seres humanos; 2) Incluir a los animales en la ética pero introduciendo una gradación en la relevancia moral; y 3) Dejar las cosas como están debido a la falta de evidencia para cambiar la clasificación actual. Hall puntualiza que el argumento en favor de la segunda postura que realiza Cortina, (incluir a los animales dentro de los argumentos éticos) lo hace prácticamente a través de la negación de las otras dos posturas en vez de estructurar un argumento concreto en favor de la segunda postura. Cortina argumenta que los rasgos únicos e inalienables de los humanos los coloca en una condición dentro de la ética por encima de los animales no humanos. Como consecuencia, Cortina argumenta que los animales tienen valores pero no derechos, una posición en la cual Hall argumenta, deja a los animales no humanos, intencionadamente o no intencionadamente, al capricho de los derechos humanos. In his review of Adele Cortina's Las fronteras de la persona. El valor de los animales, la dignidad de los humanos (Taurus, Madrid, 2009), Professor Robert Hall from the Faculty of Philosophy of the University of West Virginia and Universidad Autónoma de Querétaro, sketches the arguments Cortina makes with regards to the relationship between humans and animals. Originally published in Dianoia, the summary provides an insightful take on the strengths and weaknesses of the author's arguments. According to Hall, Cortina presents three options for considering animals in the ethical system: first to accept non-human animals on the same terms as humans; second to include animals into the ethical argument, though with a certain moral gradation; and third to leave the situation as it is due to lack of evidence to change the current classification. Hall notes that while Cortina argues in favor of including animals into ethical arguments, she does so mostly via negation of the other two options rather than by structuring an argument in favor of the second. Cortina argues that inalienable and unique human traits put them on an ethical footing above non-human animals. As a result, Cortina argues that animals have values, but not rights, a position which, Hall argues, leaves them, whether intentionally or unintentionally, at the whims of human rights.

Background: In 2017, the Metabolomics Society conducted a survey among its members to assess the degree of its current success, define opportunities for improving its service to the community and make plans to establish future goals and direction of the Society. Methods: A 32-question online survey was sent via e-mail to all Metabolomics Society members as of 19 June 2017 (n = 644). In addition to the direct e-mails, the link to access the survey was made available through social media. The survey was open until 10 August 2017. Question-specific data were reported using the summary data generated by SurveyMonkey and additional stratified analyses performed using Stata 15. Results: The number of respondents was 394 (61%) with 348 (88%) completing the multiple-choice questions in survey. Metabolomics Society annual meetings, networking and the opportunity to join the global metabolomics community were among the most important benefits expressed by the Metabolomics Society members. Conclusions: The survey collected the first data focusing on membership issues from Society members. The Society should focus on collecting and monitoring of demographic data during the membership registration process; continuing to support the early-career members of the Society; and developing initiatives that focus on member networking to retain and increase Society membership.

Over the past century, a wide variety of poorly dated sediments that unconformably overlie pre-Neogene rocks in Sulawesi have been assigned to the Celebes Molasse and interpreted as post-orogenic rocks deposited after a major collision. New data from fieldwork and laboratory studies, including mineralogical, palaeontological and zircon geochronological analyses, provide the basis for a new Neogene stratigraphy and show that sediments assigned to the Celebes Molasse have significant variations in age, environment of deposition, composition and sedimentation history. Identified unconformities in the (1) Early Miocene (c. 23 Ma), (2) Middle Miocene (c. 15 Ma), (3) Mio-Pliocene (c. 6–5.3 Ma), and (4 and 5) Pleistocene (c. 1.8 and 0.1 Ma) separate Lower Miocene, Middle to Upper Miocene, Pliocene, Pleistocene and Holocene mega-sequences. These mega-sequences resulted from Early Miocene collision followed by extension, driven by subduction rollback, causing both uplift and subsidence, in contrast to previous interpretations of multiple collisions. Nanyang Technological University Published version This research was a project of the SE Asia Research Group (SEARG) supported by a consortium of oil companies who funded the PhD of the first author. This research was supported by the Earth Observatory of Singapore and comprises EOS contribution number 381.

Species and hybrids of Eucalyptus are the world's most widely planted hardwood trees. They are cultivated across a wide range of latitudes and therefore environmental conditions. In this context, comprehensive metabolomics approaches have been used to assess how different temperature regimes may affect the metabolism of three species of Eucalyptus, E. dunnii, E. grandis and E. pellita. Young plants were grown for 53 d in the greenhouse and then transferred to growth chambers at 10°C, 20°C or 30°C for another 7 d. In all three species the leaf chlorophyll content was positively correlated to temperature, and in E. pellita the highest temperature also resulted in a significant increase in stem biomass. Comprehensive metabolomics was performed using untargeted gas chromatography mass spectrometry (GC‐MS) and liquid chromatography (LC)‐MS. This approach enabled the comparison of the relative abundance of 88 polar primary metabolites from GC‐MS and 625 semi‐polar secondary metabolites from LC‐MS. Using principal components analysis, a major effect of temperature was observed in each species which was larger than that resulting from the genetic background. Compounds mostly affected by temperature treatment were subsequently selected using partial least squares discriminant analysis and were further identified. These putative annotations indicated that soluble sugars and several polyphenols, including tannins, triterpenes and alkaloids were mostly influenced.

Supplemental material, Supplemental_File_B for Amicus cum Laude: Ethnodramatic Inquiry Regarding Sharing Mental Health in College by Robert D. Hall in Qualitative Health Research

Pebble-bed fuelled, molten salt-cooled nuclear reactors (PB-FHRs) involve interactions between a fluid coolant phase, solid particle fuel phase and neutron interactions enabling fission of nuclear fuel for heat production. As these three aspects are highly interdependent, this work presents a three-way coupled methodology for simulation of PB-FHRs to provide a robust analysis tool for detailed analysis of such reactor designs. Computational fluid dynamics (CFD) techniques are implemented for simulation of the coolant fluid’s flow and temperature fields. Discrete element methods (DEM) are used to model individual pebble fuel elements present within the core, focusing on particle-particle interactions and structures formed within packed beds of mono-sized spheres. Modelling of the interaction between these two phases is realised through a two-way coupled methodology and open-source codes. Additional to the interaction of the fluid and pebble phases, consideration of the neutronic interactions resulting in nuclear heating of the fuel pebbles is included. The Monte Carlo neutron transport method is employed for determination of the fission rate distribution for PB-FHR geometries. Inclusion of the neutronics results within the CFD and DEM solvers, and vice versa, results in three-way coupled multiphysics simulations for PB-FHRs. This work has been built up over successively more complex simulations, starting with CFD-DEM replication of an isothermal pebble re-circulation experiment and culminating in the three-way coupled simulation of a true PB-FHR design. Additional analysis focusing on the neutronic behaviour of the PB-FHR geometry for various geometric and material property configurations is also presented. It was found that the multiplication factor of PB-FHRs with a free surface of pebbles within the core region are highly influenced on the shape of this free surface. The three-way coupling methodology was shown to provide detailed representations of PB-FHR geometries in a timely manner without the need for simplification of the geometry or material properties. This allowed for detailed analysis of coolant, fuel pebble and neutronic properties throughout the core region. The results obtained demonstrate the suitability for use as an accurate design tool.

Current Musicology, No 6 (1968): Current Musicology

Contact: A Journal for Contemporary Music (1971-1988), No 7 (1974): Contact: A Journal for Contemporary Music

Contact: A Journal for Contemporary Music (1971-1988), No 8 (1974): Contact: A Journal for Contemporary Music

BackgroundFew genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.MethodsIn this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10−6 in stage 1. We set genome-wide significance at p less than 5 × 10−8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.FindingsWe included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88–0·93; p=1·76 × 10−10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06–1·12; p=2·32 × 10−8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08–1·16; p=3·06 × 10−9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10−5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).InterpretationWe found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.

Chronic respiratory diseases are a major cause of morbidity and mortality. Asthma and chronic obstructive pulmonary disease (COPD) combined affect over 500 million people worldwide. While environmental factors are important in disease progression, asthma and COPD have long been known to be heritable with genetic components playing an important role in the risk of developing disease. Identification of genetic variation contributing to disease progression is important for a number of reasons including identification of risk alleles, understanding underlying disease mechanisms and development of novel therapies. Genome?wide association studies (GWAS) have been successful in identifying many loci associated with lung function, COPD and asthma. In recent years, meta?analyses and improved imputation have facilitated the growth of GWAS in terms of numbers of subjects and the number of single nucleotide polymorphisms (SNP) that can be interrogated. As a consequence, there has been a significant increase in the number of signals associated with asthma, COPD and lung function. SNP that have shown association with lung function reassuringly show a significant overlap with SNP associated with COPD giving a glimpse at pathways that may be involved in COPD mechanisms including genes in, for example, developmental pathways. In asthma, association signals are often in or near genes involved in both adaptive and innate immune response pathways, epithelial cell homeostasis and airway structural changes. The challenges now are translating these genetic signals into a new understanding of lung biology, understanding how variants impact health and disease and how they may provide opportunities for therapeutic intervention.

The Bay of Bengal (BoB) plays a fundamental role in controlling the weather systems that make up the South Asian summer monsoon system. In particular,the southern BoB has cooler sea surface temperature (SST) that influence ocean-atmosphere interaction and impact on the monsoon. Compared to the southeast, the southwestern BoB is cooler, more saline, receives much less rain, and is influenced by the Summer Monsoon Current(SMC). To examine the impact of these features on the monsoon, the BoB Boundary Layer Experiment (BoBBLE) was jointly undertaken by India and the UK during June–July 2016. Physical and bio-geochemical observations were made using a CTD, five ocean gliders, a uCTD, a VMP, two ADCPs, Argo floats, drifting buoys, meteorological sensors and upper air radiosonde balloons. The observations were made along a zonal section at 8◦N between 85.3◦E and 89◦E with a 10-day time series at 89◦E, 8◦N. This paper presents the new observed features of the southern BoB from the BoBBLE field program, supported by satellite data. Key results from the BoBBLE field campaign show the Sri Lanka Dome and the SMC in different stages of their seasonal evolution and two freshening events during which salinity decreased in the upper layer leading to the formation of thick barrier layers. BoBBLE observations were taken during a suppressed phase of the intraseasonal oscillation; they captured in detail the warming of the ocean mixed layer and preconditioning of the atmosphere to convection.

Current U.S. Navy combat system suites are ship class dependent. There are a variety of configurations that include sensors, weapons, and system interfaces to accomplish similar goals. The Navy Surface Warfare Center recommends developing combat system architectures utilizing reusable product line components. This recommendation is accomplished by applying model-based systems engineering and product line engineering to develop a combat system architecture with planned reuse of system components. Current U.S. Navy and European combat systems are reviewed as an introduction to the architecture and components of operational systems. Conducting functional decomposition and identifying commonalities of the reviewed combat systems allow for development of a system architecture following the Hatley-Pirbhai modeling framework. The system architecture helps identify system variability, which, in turn, is used to generate orthogonal variability models that are used to design the combat system product line. A product line orthogonal variability model features packaged variants for three proposed combat system tiers representing scalable capabilities. The benefits of a product line engineering approach are validated by a system-level Constructive Product Line Investment Model. This research provides a methodology and cost modeling tool for future combat system design as well as background for further research in combat system product line engineering. http://archive.org/details/utilizingamodelb1094559675 Lieutenant, United States Navy Approved for public release; distribution is unlimited.

Seismic travel-time tomography of the mantle under SE Asia reveals patterns of subduction-related seismic P-wave velocity anomalies that are of great value in helping to understand the region's tectonic development. We discuss tomography and tectonic interpretations of an area centred on Indonesia and including Malaysia, parts of the Philippines, New Guinea and northern Australia. We begin with an explanation of seismic tomography and causes of velocity anomalies in the mantle, and discuss assessment of model quality for tomographic models created from P-wave travel times. We then introduce the global P-wave velocity anomaly model UU-P07 and the tectonic model used in this paper and give an overview of previous interpretations of mantle structure. The slab-related velocity anomalies we identify in the upper and lower mantle based on the UU-P07 model are interpreted in terms of the tectonic model and illustrated with figures and movies. Finally, we discuss where tomographic and tectonic models for SE Asia converge or diverge, and identify the most important conclusions concerning the history of the region. The tomographic images of the mantle record subduction beneath the SE Asian region to depths of approximately 1600 km. In the upper mantle anomalies mainly record subduction during the last 10 to 25 Ma, depending on the region considered. We interpret a vertical slab tear crossing the entire upper mantle north of west Sumatra where there is a strong lateral kink in slab morphology, slab holes between c.200–400 km below East Java and Sumbawa, and offer a new three-slab explanation for subduction in the North Sulawesi region. There is a different structure in the lower mantle compared to the upper mantle and the deep structure changes from west to east. What was imaged in earlier models as a broad and deep anomaly below SE Asia has a clear internal structure and we argue that many features can be identified as older subduction zones. We identify remnants of slabs that detached in the Early Miocene such as the Sula slab, now found in the lower mantle north of Lombok, and the Proto-South China Sea slab now at depths below 700 km curving from northern Borneo to the Philippines. Based on our tectonic model we interpret virtually all features seen in upper mantle and lower mantle to depths of at least 1200 km to be the result of Cenozoic subduction.

Supplementary File: Calcium Imaging of GPCR Activation Using Arrays of Reverse Transfected HEK293 Cells in a Microfluidic System

Additional file 5. Table with primers used in this study. Table with primers used in this study.

Additional file 2. Growth and production time courses of extracellular product formation in S. cerevisiae strains PATW002, PATW011, and PATW012 in shake flask cultures. The strains were grown in shake-flasks with 50Â mL SMNar (1.5Â mM naringenin) and the OD600 and extracellular metabolite concentration of dihydrokaempferol (DHK), kaempferol and kaempferol 3-O-glucoside (K3G) expressed in ÂľM were measured by HPLC in supernatant of cultures in time.

The Bay of Bengal (BoB) plays a fundamental role in controlling the weather systems that make up the South Asian summer monsoon system. In particular, the southern BoB has cooler sea surface temperatures (SST) that influence ocean–atmosphere interaction and impact the monsoon. Compared to the southeastern BoB, the southwestern BoB is cooler, more saline, receives much less rain, and is influenced by the summer monsoon current (SMC). To examine the impact of these features on the monsoon, the BoB Boundary Layer Experiment (BoBBLE) was jointly undertaken by India and the United Kingdom during June–July 2016. Physical and biogeochemical observations were made using a conductivity–temperature–depth (CTD) profiler, five ocean gliders, an Oceanscience Underway CTD (uCTD), a vertical microstructure profiler (VMP), two acoustic Doppler current profilers (ADCPs), Argo floats, drifting buoys, meteorological sensors, and upper-air radiosonde balloons. The observations were made along a zonal section at 8°N between 85.3° and 89°E with a 10-day time series at 8°N, 89°E. This paper presents the new observed features of the southern BoB from the BoBBLE field program, supported by satellite data. Key results from the BoBBLE field campaign show the Sri Lanka dome and the SMC in different stages of their seasonal evolution and two freshening events during which salinity decreased in the upper layer, leading to the formation of thick barrier layers. BoBBLE observations were taken during a suppressed phase of the intraseasonal oscillation; they captured in detail the warming of the ocean mixed layer and the preconditioning of the atmosphere to convection.

Plants accumulate secondary metabolites to adapt to environmental conditions. These compounds, here exemplified by the purple-colored anthocyanins, are accumulated upon high temperatures, UV-light, drought, and nutrient deficiencies, and may contribute to tolerance to these stresses. Producing compounds is often part of a more broad response of the plant to changes in the environment. Here we investigate how a transcription-factor-mediated program for controlling anthocyanin biosynthesis also has effects on formation of specialized cell structures and changes in the plant root architecture. A systems biology approach was developed in tomato (

Along the river network, water, sediment, and nutrients are transported, cycled, and altered by coupled hydrological and biogeochemical processes. Our current understanding of the rates and processes controlling the cycling and removal of dissolved inorganic nutrients in river networks is limited due to a lack of empirical measurements in large, (nonwadeable), rivers. The goal of this paper was to develop a coupled hydrological and biogeochemical process model to simulate nutrient uptake at the network scale during summer base flow conditions. The model was parameterized with literature values from headwater streams, and empirical measurements made in 15 rivers with varying hydrological, biological, and topographic characteristics, to simulate nutrient uptake at the network scale. We applied the coupled model to 15 catchments describing patterns in uptake for three different solutes to determine the role of rivers in network-scale nutrient cycling. Model simulation results, constrained by empirical data, suggested that rivers contributed proportionally more to nutrient removal than headwater streams given the fraction of their length represented in a network. In addition, variability of nutrient removal patterns among catchments was varied among solutes, and as expected, was influenced by nutrient concentration and discharge. Net ammonium uptake was not significantly correlated with any environmental descriptor. In contrast, net daily nitrate removal was linked to suspended chlorophyll a (an indicator of primary producers) and land use characteristics. Finally, suspended sediment characteristics and agricultural land use were correlated with net daily removal of soluble reactive phosphorus, likely reflecting abiotic sorption dynamics. Rivers are understudied relative to streams, and our model suggests that rivers can contribute more to network-scale nutrient removal than would be expected based upon their representative fraction of network channel length.

Artificial intelligence methods have often been applied to perform specific functions or tasks in the cyber-defense realm. However, as adversary methods become more complex and difficult to divine, piecemeal efforts to understand cyber-attacks, and malware-based attacks in particular, are not providing sufficient means for malware analysts to understand the past, present and future characteristics of malware. In this paper, we present the Malware Analysis and Attributed using Genetic Information (MAAGI) system. The underlying idea behind the MAAGI system is that there are strong similarities between malware behavior and biological organism behavior, and applying biologically inspired methods to corpora of malware can help analysts better understand the ecosystem of malware attacks. Due to the sophistication of the malware and the analysis, the MAAGI system relies heavily on artificial intelligence techniques to provide this capability. It has already yielded promising results over its development life, and will hopefully inspire more integration between the artificial intelligence and cyber--defense communities.

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20–1.27), P = 5.05 × 10−49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

El desafío de Regan para dar reconocimiento moral y legal a los animales pareció extremo a mucha gente. Implica que los animales no humanos son totalmente iguales a los animales humanos, por lo cual muchos consideraron extrema la postura de Regan. El desafío de Regan continúa: si es dificil, considerar a los animales no humanos como personas ante la ley ¿qué estatus debemos atribuirles? Tanto los bioeticistas como los filósofos del derecho siguen luchando con este problema. "La solución" más común es que debemos reconocer jurídicamente a los animales como seres sensibles o sintientes, aunque nadie sabe exactamente qué implicaciones tiene esta nueva categoría. Por otra parte, algunos filósofos han sugerido que el asunto de nuestras obligaciones para con los animales es una relación política y que tenemos que considerar varias categorías de relación dependiendo de la historia y el contexto cultural de nuestras relaciones con ellos. Regan's challenge to give moral and legal recognition to animals seemed extreme to many people. It implies that the nonhuman animals are totally equal to the human animals, which is why many considered extreme the position of Regan. Regan's challenge continues today: if it is difficult to consider non-human animals as people before the law, what status should we attribute to them? Both bioethicists and legal philosophers continue to struggle with this problem. The most common solution is that we must recognize animals as sentient or sensitive beings, although no one knows exactly what the implications of this new category are. On the other hand, some philosophers have suggested that the issue of our obligations to animals is a political relationship and that we have to consider several categories of relationship depending on the history and cultural context of our relationships with them.

Today, all major central banks pay or collect interest on reserves, and stand ready to use the interest rate as an instrument of monetary policy. We show that by paying an appropriate rate on reserves, the central bank can pin the price level uniquely to a target. The essential idea is to index reserves to the market interest rate, the price level, and the target price level in a way that creates a contractionary financial force if the price level is above the target and an expansionary force if below. Our payment-on-reserves policy process does not require terminal conditions like Taylor rules, exogenous fiscal surpluses like the fiscal theory of the price level, liquidity preference as in quantity theories, or local approximations as in new Keynesian models. The process accommodates liquidity services from reserves, segmented financial markets where only some institutions can hold reserves, and nominal rigidities. We believe it would be easy to implement.

The 50-year commemoration of S.N. De's seminal 1959 publication in Nature provides an opportunity to reflect on scientific discovery, recognition, and public health. De's paper marked the first major conceptual advance in cholera research since 1884, when Robert Koch definitively identified Der Kommabazillus as the aetiological agent of cholera. Unfortunately, Koch reported that systemic toxinosis and multi-organ failure led to severe dehydrating diarrhoea, thereby mistaking cause for effect. As a consequence, while work on other microbial pathogens advanced into the development of vaccines and therapeutics, cholera research languished as scientists injected animals parenterally in decades of futile effort to develop an animal model of diarrhoea. This fundamental misconception in cholera pathogenesis was swept away when S.N. De used ligated loops of rabbit ileum to demonstrate lumenal fluid accumulation in the presence of Vibrio cholerae culture filtrates. After some delay, De's observation of a diarrhoeagenic exotoxin became the founding principle of modern cholera research, vaccination, and treatment; and a burst of discovery saw V. cholerae transformed into the enteric pathogen best understood at the molecular level. The scientific basis for orally administering vaccines to induce mucosal immunity was established, and the success of oral rehydration, what has been described as one of the 20 th century's most important medical advances, was explained. Nobel laureate Joshua Lederberg wrote of De's iconoclastic creativity, experimental skill, and observational mastery, and many other leaders in the field concurred. De was nominated for the Nobel Prize in Physiology or Medicine more than once. But despite the passage of half a century from De's work, cholera remains a frustrating problem: we are clearly missing something. In reviewing the scientific and programmatic impact of S.N. De on cholera, it is clear that a defining victory against the disease is achievable, but only if basic scientific discoveries are relentlessly driven towards progress in public health.

Ecosystem metabolism, that is, gross primary productivity (GPP) and ecosystem respiration (ER), controls organic carbon (OC) cycling in stream and river networks and is expected to vary predictably with network position. However, estimates of metabolism in small streams outnumber those from rivers such that there are limited empirical data comparing metabolism across a range of stream and river sizes. We measured metabolism in 14 rivers (discharge range 14–84 m3 s−1) in the Western and Midwestern United States (US). We estimated GPP, ER, and gas exchange rates using a Lagrangian, 2-station oxygen model solved in a Bayesian framework. GPP ranged from 0.6–22 g O2 m−2 d−1 and ER tracked GPP, suggesting that autotrophic production supports much of riverine ER in summer. Net ecosystem production, the balance between GPP and ER was 0 or greater in 4 rivers showing autotrophy on that day. River velocity and slope predicted gas exchange estimates from these 14 rivers in agreement with empirical models. Carbon turnover lengths (that is, the distance traveled before OC is mineralized to CO2) ranged from 38 to 1190 km, with the longest turnover lengths in high-sediment, arid-land rivers. We also compared estimated turnover lengths with the relative length of the river segment between major tributaries or lakes; the mean ratio of carbon turnover length to river length was 1.6, demonstrating that rivers can mineralize much of the OC load along their length at baseflow. Carbon mineralization velocities ranged from 0.05 to 0.81 m d−1, and were not different than measurements from small streams. Given high GPP relative to ER, combined with generally short OC spiraling lengths, rivers can be highly reactive with regard to OC cycling. © 2015, Springer Science+Business Media New York.

Seismic travel-time tomography of the mantle under SE Asia reveals patterns of subduction-related seismic P-wave velocity anomalies that are of great value in helping to understand the region's tectonic development. We discuss tomography and tectonic interpretations of an area centred on Indonesia and including Malaysia, parts of the Philippines, New Guinea and northern Australia. We begin with an explanation of seismic tomography and causes of velocity anomalies in the mantle, and discuss assessment of model quality for tomographic models created from P-wave travel times. We then introduce the global P-wave velocity anomaly model UU-P07 and the tectonic model used in this paper and give an overview of previous interpretations of mantle structure. The slab-related velocity anomalies we identify in the upper and lower mantle based on the UU-P07 model are interpreted in terms of the tectonic model and illustrated with figures and movies. Finally, we discuss where tomographic and tectonic models for SE Asia converge or diverge, and identify the most important conclusions concerning the history of the region. The tomographic images of the mantle record subduction beneath the SE Asian region to depths of approximately 1600. km. In the upper mantle anomalies mainly record subduction during the last 10 to 25. Ma, depending on the region considered. We interpret a vertical slab tear crossing the entire upper mantle north of west Sumatra where there is a strong lateral kink in slab morphology, slab holes between c.200-400. km below East Java and Sumbawa, and offer a new three-slab explanation for subduction in the North Sulawesi region. There is a different structure in the lower mantle compared to the upper mantle and the deep structure changes from west to east. What was imaged in earlier models as a broad and deep anomaly below SE Asia has a clear internal structure and we argue that many features can be identified as older subduction zones. We identify remnants of slabs that detached in the Early Miocene such as the Sula slab, now found in the lower mantle north of Lombok, and the Proto-South China Sea slab now at depths below 700. km curving from northern Borneo to the Philippines. Based on our tectonic model we interpret virtually all features seen in upper mantle and lower mantle to depths of at least 1200. km to be the result of Cenozoic subduction.

The Affordable Care Act has caused and continues to cause sweeping changes throughout the health system in the United States. Poorly explained, complex, controversial, confusing, and subject to continuous legal and regulatory definition, the law stands as a hallmark piece of legislation that will change the health sector in America forever. This article summarizes the Affordable Care Act with a focus on children, families, and disparities. Also provided is the context of the current system of health care coverage in the United States.

Nutrient transformation processes such as assimilation, dissimilatory transformation, and sorption to sediments are prevalent in benthic zones of headwater streams, but may also occur in the water column. The river continuum concept (RCC) predicts that water column processes become increasingly important with increasing stream size. We predicted that water column nutrient uptake increases with stream size, mirroring carbon/energy dynamics predicted by the RCC. We measured water column uptake of ammonium ( NH+4NH4+ ), nitrate ( NO−3NO3− ), and soluble reactive phosphorus (SRP) in 1st through 5th order stream and river reaches (discharge: 50–68,000 L s−1) in three watersheds ranging from 70 % developed lands. We found that water column volumetric uptake (Uvol) of NH+4NH4+ , NO−3NO3− , and SRP did not significantly differ among watersheds and we did not find any longitudinal patterns for Uvol. Uptake velocity (vf) of NH+4NH4+ increased with stream size, whereas NO−3NO3− and SRP vf did not differ with stream size or among watersheds. Both Uvol and vf were related to water column metabolism and material suspended in the water column, but specific relationships differed among solutes and uptake metrics. Median water column vf across 15 sites was 4, 9, and 19 % of median whole-stream NH+4NH4+ , NO−3NO3− , and SRP vf based upon a previous meta-analysis. Thus, although we could not demonstrate a generalized longitudinal pattern in water column nutrient uptake, water column processes can be important. An improved mechanistic understanding of the controls on uptake and the ultimate fate of nutrients will facilitate effective management and restoration for mitigating downstream nutrient export.

Since 2008, the central banks of advanced countries have borrowed trillions of dollars from their commercial banks in the form of interest-paying reserves and invested the proceeds in portfolios of risky assets. We investigate how this new style of central banking affects central banks' solvency. A central bank is insolvent if its requirement to pay dividends to its government exceeds its income by enough to cause an unending upward drift in its debts to commercial banks. We consider three sources of risk to central banks: interest-rate risk (the Federal Reserve), default risk (the European Central Bank), and exchange-rate risk (central banks of small open economies). We find that a central bank that pays dividends equal to a standard concept of net income will always be solvent—its reserve obligations will not explode. In some circumstances, the dividend will be negative, meaning that the government is making a payment to the bank. If the charter does not provide for payments in that direction, then reserves will tend to grow more in crises than they shrink in normal times. To prevent this buildup, the charter needs to provide for makeup reductions in payments from the bank to the government. We compute measures of the financial strength of central banks, and discuss how different institutions interact with quantitative easing policies to put these banks in less or more danger of instability. We conclude that the risks to financial stability are real in theory, but remote in practice today.

Matching efficiency is the productivity of the process for matching jobseekers to available jobs. Job-finding is the output; vacant jobs and active jobseekers are the inputs. Measurement of matching efficiency follows the same principles as measuring an index of productivity of production. We develop a framework for measuring matching productivity when the population of jobseekers is heterogeneous. The efficiency index for each type of jobseeker is the monthly job finding rate for the type adjusted for the overall tightness of the labor market. We find that overall matching efficiency declined smoothly over the period from 2001 through 2013. Measures of matching efficiency that neglect heterogeneity among the unemployed and also neglect jobseekers other than the unemployed suggest a 23 percent decline in efficiency between 2007 and 2009. We demonstrate that essentially all of this apparent decline results from changes in the composition of jobseekers rather than any true movement in efficiency. We also develop a new approach to measuring matching rates that avoids counting short-duration jobs as job-seeking successes.

We use a rich new body of data on the experiences of unemployed job-seekers to determine the sources of wage dispersion and to create a search model consistent with the acceptance decisions the job-seekers made. From the data and the model, we identify the distributions of four key variables: offered wages, offered non-wage job values, the value of the job-seeker's non-work alternative, and the job-seeker's personal productivity. We find that, conditional on personal productivity, the dispersion of offered wages is moderate, accounting for 21 percent of the total variation in observed offered wages, whereas the dispersion of the non-wage component of offered job values is substantially larger. We relate our findings to an influential recent paper by Hornstein, Krusell, and Violante who called attention to the tension between the fairly high dispersion of the values job-seekers assign to their job offers – which suggest a high value to sampling from multiple offers – and the fact that the job-seekers often accept the first offer they receive.

En la reseña bibliográfica sobre el libro de Adela Cortina: "Las fronteras de la persona. El valor de los animales, la dignidad de los humanos" (Taurus, Madrid, 2009), el Profesor Robert Hall, Facultad de Filosofía de la Universidad Autónoma de Querétaro y de la West Virginia State University, esboza los argumentos que Adela Cortina hace con referencia a la relación entre los humanos y los animales. Publicado originalmente en Dianoia, el resumen proporciona una visión interna de las fortalezas y de las debilidades de los argumentos de la autora. De acuerdo con Hall, Cortina presenta tres posturas con respecto a la consideración ética de los animales: 1) Aceptar a los animales no humanos en el núcleo de la ética en pie de igualdad con los seres humanos; 2) Incluir a los animales en la ética pero introduciendo una gradación en la relevancia moral; y 3) Dejar las cosas como están debido a la falta de evidencia para cambiar la clasificación actual. Hall puntualiza que el argumento en favor de la segunda postura que realiza Cortina, (incluir a los animales dentro de los argumentos éticos) lo hace prácticamente a través de la negación de las otras dos posturas en vez de estructurar un argumento concreto en favor de la segunda postura. Cortina argumenta que los rasgos únicos e inalienables de los humanos los coloca en una condición dentro de la ética por encima de los animales no humanos. Como consecuencia, Cortina argumenta que los animales tienen valores pero no derechos, una posición en la cual Hall argumenta, deja a los animales no humanos, intencionadamente o no intencionadamente, al capricho de los derechos humanos. In his review of Adele Cortina's Las fronteras de la persona. El valor de los animales, la dignidad de los humanos (Taurus, Madrid, 2009), Professor Robert Hall from the Faculty of Philosophy of the University of West Virginia and Universidad Autónoma de Querétaro, sketches the arguments Cortina makes with regards to the relationship between humans and animals. Originally published in Dianoia, the summary provides an insightful take on the strengths and weaknesses of the author's arguments. According to Hall, Cortina presents three options for considering animals in the ethical system: first to accept non-human animals on the same terms as humans; second to include animals into the ethical argument, though with a certain moral gradation; and third to leave the situation as it is due to lack of evidence to change the current classification. Hall notes that while Cortina argues in favor of including animals into ethical arguments, she does so mostly via negation of the other two options rather than by structuring an argument in favor of the second. Cortina argues that inalienable and unique human traits put them on an ethical footing above non-human animals. As a result, Cortina argues that animals have values, but not rights, a position which, Hall argues, leaves them, whether intentionally or unintentionally, at the whims of human rights.