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We aimed to develop and test a relatively objective method for rapidly and accurately assessing the priority for research of interventions tendered as potential solutions to a prevailing problem in agriculture. In this test, our method aimed to direct research of evidenced-based strategies to ameliorate consistently high rates of foetal and calf loss experienced in northern Australia’s beef herd. Detailed reviews of factors affecting foetal and calf loss and potential solutions were conducted. A simple economic analysis, based on rating management interventions for their impact on earnings before interest and tax, was then developed to enable rapid simultaneous business-impact comparison of multiple options. If the outcome value for an option is negative, it suggests that the option is less profitable than is prevailing practice, if approximately zero, it suggests that the option is very marginal, and more positive values suggest a higher potential benefit. The values obtained were further analysed by rating for incidence and researchability to derive research priority. This sequence of activities was conducted by peers representing a broad spectrum of beef business (managing an estimated 0.4 million cattle), science and agribusiness representatives from across northern Australia. A sensitivity analysis demonstrated that the method was robust in ranking both business impact and research priority. Ten foetal and calf-loss minimisation interventions were rated by producer and agribusiness representatives and the project team as a high priority for business. Four of these were excluded because of low incidence or low researchability, leaving six rated as having highest priority for research. Informal feedback from many participants indicated high satisfaction with the proposed method. The conclusion was that this method, with suggested variations, successfully discriminated priority for a large range of potential interventions for calf loss research, development and extension (RD&E). The method described could readily supplant commonly used more subjective methods and be used to assess priority for RD&E of other issues for multiple agricultural commodities, as well as simply for rapid assessment of management options within a production enterprise.

Peatlands are important players in climate change-biosphere feedbacks via long-term net carbon (C) accumulation in soil organic matter and as potential net C sources including the potent greenhouse gas methane (CH4). Interactions of climate, site-hydrology, plant community, and groundwater chemical factors influence peatland development and functioning, including C dioxide (CO2) and CH4 fluxes, but the role of microbial community composition is not well understood. To assess microbial functional and taxonomic dissimilarities, we used high throughput sequencing of the small subunit ribosomal DNA (SSU rDNA) to determine bacterial and archaeal community composition in soils from twenty North American peatlands. Targeted DNA metabarcoding showed that although Proteobacteria, Acidobacteria, and Actinobacteria were the dominant phyla on average, intermediate and rich fens hosted greater diversity and taxonomic richness, as well as an array of candidate phyla when compared with acidic and nutrient-poor poor fens and bogs. Moreover, pH was revealed to be the strongest predictor of microbial community structure across sites. Predictive metagenome content (PICRUSt) showed increases in specific genes, such as purine/pyrimidine and amino-acid metabolism in mid-latitude peatlands from 38 to 45° N, suggesting a shift toward utilization of microbial biomass over utilization of initial plant biomass in these microbial communities. Overall, there appears to be noticeable differences in community structure between peatland classes, as well as differences in microbial metabolic activity between latitudes. These findings are in line with a predicted increase in the decomposition and accelerated C turnover, and suggest that peatlands north of 37° latitude may be particularly vulnerable to climate change.

Publisher Copyright: © 2022 This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Peatlands account for 15 to 30% of the world's soil carbon (C) stock and are important controls over global nitrogen (N) cycles. However, C and N concentrations are known to vary among peatlands contributing to the uncertainty of global C inventories, but there are few global studies that relate peatland classification to peat chemistry. We analyzed 436 peat cores sampled in 24 countries across six continents and measured C, N, and organic matter (OM) content at three depths down to 70 cm. Sites were distinguished between northern (387) and tropical (49) peatlands and assigned to one of six distinct broadly recognized peatland categories that vary primarily along a pH gradient. Peat C and N concentrations, OM content, and C:N ratios differed significantly among peatland categories, but few differences in chemistry with depth were found within each category. Across all peatlands C and N concentrations in the 10-20 cm layer, were 440 ± 85.1 g kg-1 and 13.9 ± 7.4 g kg-1, with an average C:N ratio of 30.1 ± 20.8. Among peatland categories, median C concentrations were highest in bogs, poor fens and tropical swamps (446-532 g kg-1) and lowest in intermediate and extremely rich fens (375-414 g kg-1). The C:OM ratio in peat was similar across most peatland categories, except in deeper samples from ombrotrophic tropical peat swamps that were higher than other peatlands categories. Peat N concentrations and C:N ratios varied approximately two-fold among peatland categories and N concentrations tended to be higher (and C:N lower) in intermediate fens compared with other peatland types. This study reports on a unique data set and demonstrates that differences in peat C and OM concentrations among broadly classified peatland categories are predictable, which can aid future studies that use land cover assessments to refine global peatland C and N stocks.

Peatlands both accumulate carbon and release methane, but their broad range in environmental conditions means that the diversity of microorganisms responsible for carbon cycling is still uncertain. Here we describe a community analysis of methanogenic archaea responsible for methane production in 17 peatlands from 36 to 53 N latitude across the eastern half of North America, including three metal-contaminated sites. Methanogenic community structure was analyzed through Illumina amplicon sequencing of the mcrA gene. Whether metal-contaminated sites were included or not, metal concentrations in peat were a primary driver of methanogenic community composition, particularly nickel, a trace element required in the F430 cofactor in methyl-coenzyme M reductase that is also toxic at high concentrations. Copper was also a strong predictor, likely due to inhibition at toxic levels and/or to cooccurrence with nickel, since copper enzymes are not known to be present in anaerobic archaea. The methanogenic groups Methanocellales and Methanosarcinales were prevalent in peatlands with low nickel concentrations, while Methanomicrobiales and Methanomassiliicoccales were abundant in peatlands with higher nickel concentrations. Results suggest that peat-associated trace metals are predictors of methanogenic communities in peatlands.

Operation of SiC MOSFETs beyond 300°C opens up opportunities for a wide range of CMOS based digital and analogue applications. However the majority of the literature focuses only on the optimization of a single type of MOS device (either PMOS or more commonly NMOS) and there is a lack of a comprehensive study describing the challenge of optimizing CMOS devices. This study reports on the impact of gate oxide performance in channel implanted SiC on the electrical stability for both NMOS and PMOS capacitors and transistors. Parameters including interface state density (Dit), flatband voltage (VFB), threshold voltage (VTH) and effective charge (NEFF) have been acquired from C-V characteristics to assess the effectiveness of the fabrication process in realising high quality gate dielectrics. The performance of SiC based CMOS transistors were analyzed by correlating the characteristics of the MOS interface properties, the MOSFET 1/f noise performance and transistor on-state stability at 300°C. The observed instability of PMOS devices is more significant than in equivalent NMOS devices. The results from MOS capacitors comprising interface state density (Dit), flatband voltage (VFB), threshold voltage (VTH) for both N and P MOS are in agreement with the expected characteristics of the respective transistors.

We present the influence of phosphorous auto-doping on the characteristics of the oxide interface in 4H-SiC following high temperature gate oxide annealing. IV characteristics show no evidence of direct tunnelling breakdown; however Fowler Nordheim (F-N) conduction is observed in high electric field with the oxides able to sustain >10MV/cm. Capacitance Voltage data show DIT 12 eV-1cm-2 close to the conduction band edge after POA, with undoped samples demonstrating DIT below 5x1011 eV-1cm-2. Photo CV data indicates smaller flat band voltage shifts of 0.6V at midpoint for the undoped samples, in comparison to 0.9V for the phosphorous doped devices. Temperature and bias stress tests at 200°C showed marginal hysteresis (0.3V) in both wafers. Reliability of time-dependent constant current and constant voltage characteristics revealed higher TDDB lifetimes in the undoped wafer. We conclude that the unintentional incorporation of phosphorous into the gate stack as a result of high temperature POA of the doped field oxide leads to a variation in flat band shift, higher DIT, and lower dielectric reliability.

The potential to thermally grow SiO2 on silicon carbide has resulted in it becoming the technology of choice to realise high temperature CMOS circuits. The challenge to achieve a high quality gate stack relies on engineering the metal-insulator-semiconductor interfaces to enable reliable high temperature functionality. Here we describe the effect of different process conditions for the formation of the dielectric layer on the characteristics of the resulting devices. The operating characteristics at elevated temperatures depend critically on the quality of the gate stack. Therefore a systematic evaluation of the intrinsic properties of the gate stack and data from reliability tests are needed.

Low frequency noise in 4H-SiC lateral p-channel metal oxide semiconductor field effect transistors (PMOSFETs) in the frequency range from 1 Hz to 100 kHz has been used to investigate the relationship between gate dielectric fabrication techniques and the resulting density of interface traps at the semiconductor-dielectric interface in order to examine the impact on device performance. The results show that the low frequency noise characteristics in p-channel 4H-SiC MOSFETs in weak inversion are in agreement with the McWhorter model and are dominated by the interaction of channel carriers with interface traps at the gate dielectric/semiconductor interface.

The purpose of this study was to examine biomechanical differences between genders during a prolonged fatiguing asymmetric lifting task. Thirty-seven participants performed an asymmetrical lifting task over a period of 75 minutes at a rate of six lifts per minute. The lift envelope started from the floor directly in front of the participant to a shelf 60 degrees to the right of the sagittal plane at a normalized height to the participant’s anterior superior iliac spine (ASIS). A handled box weighing 10% of the participants’ predetermined maximum lifting capacity was used as the lifting object. Electromagnetic tracking sensors were used to provide kinetic and kinematic data. Eleven sensors were affixed bilaterally to the participant’s hands, arms, and trunk. Strong indicators for fatigue were found after the lifting task. Ratings of Perceived Exertion (RPE) increased over time and maximal voluntary exertion in back and shoulder extension decreased post lifting. Kinematic changes were altered over time, more markedly in females than males, suggesting that biomechanical differences exist during similar tasks due to factors associated with gender. Males and females differ in their response to a fatigued state during the same asymmetric lifting task. Given that current ergonomic practice is based on gender neutralized or androcentric design, the difference in response between males and females to the same stimuli suggests that current workplace interventions may not be equally effective for both sexes.

Silicon Carbide devices are capable of operating as a semiconductor at high temperatures and this capability is being exploited today in discrete power components, bringing system advantages such as reduced cooling requirements [1]. Therefore there is an emerging need for control ICs mounted on the same modules and being capable of operating at the same temperatures. In addition, several application areas are pushing electronics to higher temperatures, particularly sensors and interface devices required for aero engines and in deep hydrocarbon and geothermal drilling. This paper discusses a developing CMOS manufacturing process using a 4H SiC substrate, which has been used to fabricate a range of simple logic and analogue circuits and is intended for power control and mixed signal sensor interface applications [2]. Test circuits have been found to operate at up to 400°C. The introduction of a floating capacitor structure to the process allows the use of switched capacitor techniques in mixed signal circuits operating over an extended temperature range.

The development of silicon carbide complimentary metal-oxide-semiconductor (CMOS) is a key-enabling step in the realisation of low power circuitry for high-temperature applications. This paper describes investigations using the charge pumping technique into the properties of the gate dielectric interface as part of the development of the technology to realise monolithic fabrication of both n and p channel devices. A comparison of the charge pumping technique and the Hill-Coleman and Terman methods is also carried out to explore the feasibility of the technique.

Despite the magnitude of the obesity epidemic, the mechanisms that contribute to increases in fat mass and to differences in fat depots are still poorly understood. Prostanoids have been proposed as potent adipogenic hormones, e.g. metabolites of prostaglandin J2 (PGJ2) bind and activate PPARgamma. We hypothesize that an altered expression of enzymes in PGJ2 synthesis may represent a novel pathogenic mechanism in human obesity. We characterized adipose depot-specific expression of enzymes in PGJ2 synthesis, prostaglandin transporter and PPARgamma isoforms. Paired omental and subcutaneous adipose tissue samples were obtained from 26 women undergoing elective abdominal surgery and gene expression examined in whole tissue and cultured preadipocytes using an Affymetrix cDNA microarray technique and validated with quantitative real-time PCR. All enzymes involved in prostaglandin synthesis were expressed in both adipose tissues. Expression of prostaglandin synthase-1 (PGHS1), prostaglandin D synthase (PTGDS), human prostaglandin transporter (hPGT) and PPARgamma2 was higher in OM adipose tissue compared to SC, whereas 17beta-hydroxysteroid dehydrogenase 5 (AKR1C3) showed predominance in SC adipose tissue. In SC adipose tissue, PGHS1 mRNA expression increased with BMI. The differential, depot-specific expression of key enzymes involved in transport, synthesis and metabolism of prostaglandins may have an important impact upon fat cell biology and may help to explain some of the observed depot-specific differences. In addition, the positive correlation between PGHS1 and BMI offers the novel hypothesis that the regulation of PG synthesis may have a role in determining fat distribution in human obesity.

The recent development of silicon carbide complimentary metal-oxide-semiconductor (CMOS) is a key enabling step in the realisation of low power circuitry for high temperature applications, such as aerospace and well logging. This paper describes investigations into the properties of the gate dielectric as part of the development of the technology to realize monolithic fabrication of both n and p channel devices. A comparison of the oxide quality of the silicon carbide CMOS transistors is performed to examine the feasibility of this technology for high temperature circuitry.

A need for high temperature integrated circuits is emerging in a number of application areas. As Silicon Carbide power discrete devices become more widely available, there is a growing need for control ICs capable of operating at the same temperatures and mounted on the same modules. Also, the use of high temperature sensors, in, for example, aero engines and in deep hydrocarbon and geothermal drilling applications results in a demand for high temperature sensor interface ICs. This paper presents new results on a range of simple logic and analogue circuits fabricated on a developing Silicon Carbide CMOS process which is intended for mixed signal integrated circuit applications such as those above. A small family of logic circuits, pin compatible with the 74xx series TTL logic parts, has been designed, fabricated and tested and includes, for example, a Quad Nand gate and a Dual D-type flip-flop. These have been found to be functional from room temperature up to 400°C. Analogue blocks have been investigated with a view to using switched capacitor or autozero techniques to compensate for temperature and time induced drifts, allowing very high temperature operation.

Impact craters on planetary bodies transition with increasing size from simple, to complex, to peak-ring basins and finally to multi-ring basins. Important to understanding the relationship between complex craters with central peaks and multi-ring basins is the analysis of protobasins (exhibiting a rim crest and interior ring plus a central peak) and peak-ring basins (exhibiting a rim crest and an interior ring). New data have permitted improved portrayal and classification of these transitional features on the Moon. We used new 128 pixel/degree gridded topographic data from the Lunar Orbiter Laser Altimeter (LOLA) instrument onboard the Lunar Reconnaissance Orbiter, combined with image mosaics, to conduct a survey of craters >50 km in diameter on the Moon and to update the existing catalogs of lunar peak-ring basins and protobasins. Our updated catalog includes 17 peak-ring basins (rim-crest diameters range from 207 km to 582 km, geometric mean = 343 km) and 3 protobasins (137-170 km, geometric mean = 157 km). Several basins inferred to be multi-ring basins in prior studies (Apollo, Moscoviense, Grimaldi, Freundlich-Sharonov, Coulomb-Sarton, and Korolev) are now classified as peak-ring basins due to their similarities with lunar peak-ring basin morphologies and absence of definitive topographic ring structures greater than two in number. We also include in our catalog 23 craters exhibiting small ring-like clusters of peaks (50-205 km, geometric mean = 81 km); one (Humboldt) exhibits a rim-crest diameter and an interior morphology that may be uniquely transitional to the process of forming peak rings. Comparisons of the predictions of models for the formation of peak-ring basins with the characteristics of the new basin catalog for the Moon suggest that formation and modification of an interior melt cavity and nonlinear scaling of impact melt volume with crater diameter provide important controls on the development of peak rings. In particular, a power-law model of growth of an interior melt cavity with increasing crater diameter is consistent with power-law fits to the peak-ring basin data for the Moon and Mercury. We suggest that the relationship between the depth of melting and depth of the transient cavity offers a plausible control on the onset diameter and subsequent development of peak-ring basins and also multi-ring basins, which is consistent with both planetary gravitational acceleration and mean impact velocity being important in determining the onset of basin morphological forms on the terrestrial planets.

The wide band-gap of Silicon Carbide (SiC) makes it a material suitable for high temperature integrated circuits [1], potentially operating up to and beyond 450°C. This paper describes the development of a 15V SiC CMOS technology developed to operate at high temperatures, n and p-channel transistor and preliminary circuit performance over temperature achieved in this technology.

The wide band-gap of Silicon Carbide makes it a material suitable for IC's [1] operating up to 450°C. The maximum operating temperature achieved will depend on the transistor technology selected, interconnect metallisation and device packaging. This paper describes transistor and circuit results achieved in SiC CMOS technology, where the major issue addressed is the gate dielectric performance. N and p-channel MOSFET structures have been demonstrated operating at temperatures up to 400°C Test circuits including simple logic cells, ring oscillators, operational amplifiers and gate drive circuits have been fabricated and the characteristics of ring oscillators are presented here. Floating capacitor structures have also been fabricated for use in future analogue and mixed signal circuits. This technology will be initially applied in applications including signal conditioning for sensors and control of SiC based power switching devices, where the high temperature capability will match that of the SiC power devices which are now becoming commercially available.

We report on a direct epitaxial growth approach for the heterogeneous integration of high-speed III–V devices with Si CMOS logic on a common Si substrate. InP-based heterojunction bipolar transistor (HBT) structures were successfully grown on Si-on-lattice-engineered- substrate (SOLES) and Ge-on-insulator-on-Si (GeOI/Si) substrates using molecular beam epitaxy. Structurally, the epiwafers exhibit sharp interfaces and a threading dislocation density of 3.5×10 7 cm −2 as measured by plan-view transmission electron microscopy. HBT devices fabricated on GeOI/Si substrates have current gain of 55–60 at a base sheet resistance of 650–700 Ω/sq, and f t and f max of around 220 GHz. HBT structures with DC and RF performance similar to those grown on lattice-matched InP were also achieved on patterned SOLES substrates with growth windows as small as 15×15 μm 2 . These results demonstrate a promising path of heterogeneous integration and selective placement of III–V devices at arbitrary locations on Si CMOS wafers.

Over the last decade, the introduction of microarray technology has had a profound impact on gene expression research. The publication of studies with dissimilar or altogether contradictory results, obtained using different microarray platforms to analyze identical RNA samples, has raised concerns about the reliability of this technology. The MicroArray Quality Control (MAQC) project was initiated to address these concerns, as well as other performance and data analysis issues. Expression data on four titration pools from two distinct reference RNA samples were generated at multiple test sites using a variety of microarray-based and alternative technology platforms. Here we describe the experimental design and probe mapping efforts behind the MAQC project. We show intraplatform consistency across test sites as well as a high level of interplatform concordance in terms of genes identified as differentially expressed. This study provides a resource that represents an important first step toward establishing a framework for the use of microarrays in clinical and regulatory settings.

Glycan binding proteins (GBPs) possess the unique ability to regulate a wide variety of biological processes through interactions with highly modifiable cell surface glycans. While many studies demonstrate the impact of glycan modification on GBP recognition and activity, the relative contribution of subtle changes in glycan structure on GBP binding can be difficult to define. To overcome limitations in the analysis of GBP-glycan interactions, recent studies utilized glycan microarray platforms containing hundreds of structurally defined glycans. These studies not only provided important information regarding GBP-glycan interactions, but have also resulted in significant insight into the binding specificity and biological activity of the galectin family. We will describe the methods used when employing glycan microarray platforms to examine galectin-glycan binding specificity and function.

An avian-like H3N2 influenza A virus (IAV) has recently caused sporadic canine influenza outbreaks in China and Korea, but the molecular mechanisms involved in the interspecies transmission of H3N2 IAV from avian to canine species are not well understood. Sequence analysis showed that residue 222 in haemagglutinin (HA) is predominantly tryptophan (W) in the closely related avian H3N2 IAV, but was leucine (L) in canine H3N2 IAV. In this study, reassortant viruses rH3N2-222L (canine-like) and rH3N2-222W (avian-like) with HA mutation L222W were generated using reverse genetics to evaluate the significance of the L222W mutation on receptor binding and host tropism of H3N2 IAV. Compared with rH3N2-222W, rH3N2-222L grew more rapidly in MDCK cells and had significantly higher infectivity in primary canine tracheal epithelial cells. Tissue-binding assays demonstrated that rH3N2-222L had a preference for canine tracheal tissues rather avian tracheal tissues, whereas rH3N2-222W favoured slightly avian rather canine tracheal tissues. Glycan microarray analysis suggested both rH3N2-222L and rH3N2-222W bound preferentially to α2,3-linked sialic acids. However, the rH3N2-222W had more than twofold less binding affinity than rH3N2-222L to a set of glycans with Neu5Aca2–3Galb1–4(Fuca-)-like or Neu5Aca2–3Galb1–3(Fuca-)-like structures. These data suggest the W to L mutation at position 222 of the HA could facilitate infection of H3N2 IAV in dogs, possibly by increasing the binding affinities of the HA to specific receptors with Neu5Aca2–3Galb1–4(Fuca-) or Neu5Aca2–3Galb1–3(Fuca-)-like structures that are present in dogs.

Studies of the fine-scale spatial epidemiology of malaria consistently identify malaria hotspots, comprising clusters of homesteads at high transmission intensity. These hotspots sustain transmission, and may be targeted by malaria-control programmes. Here we describe the spatial relationship between the location of Anopheles larval sites and human malaria infection in a cohort study of 642 children, aged 1–10-years-old. Our data suggest that proximity to larval sites predict human malaria infection, when homesteads are upwind of larval sites, but not when homesteads are downwind of larval sites. We conclude that following oviposition, female Anophelines fly upwind in search for human hosts and, thus, malaria transmission may be disrupted by targeting vector larval sites in close proximity, and downwind to malaria hotspots., Spatial epidemiology studies identify malaria hotspots, which sustain transmission and so could be targeted by control programmes. This study uses spatial data on larval sites and malaria episodes to show that transmission can be disrupted by targeting vector breeding sites close to and downwind of malaria hotspots.

We present recent results on the direct heterogeneous integration of InP HBTs and Si CMOS on a silicon template wafer or SOLES (Silicon On Lattice Engineered Substrate). InP HBTs whose performance are comparable to HBTs on the native InP substrates have been repeatedly achieved. 100% heterogeneous interconnect yield has been achieved on daisy chain test structures with CMOS-InP HBT spacing (interconnect length) as small as 2.5um. In DARPA COSMOS Phase 1 we designed and fabricated a differential amplifier that met the program Go/NoGo metrics with first pass design success. As the COSMOS Phase 2 demonstration vehicle we designed and fabricated a low power dissipation, high resolution, 500MHz bandwidth digital-to-analog converter (DAC).

There are many similarities between flying commercial aircraft and surgery, particularly in relation to minimising risk, and managing potentially fatal or catastrophic complications, or both. Since 1979, the development of Crew Resource Management (CRM) has improved air safety significantly by reducing human factors that are responsible for error. Similar developments in the operating theatre have, to a certain extent, lagged behind aviation, and it is well recognised that we can learn much from the industry. An increasing number of publications on aviation factors relate to surgery but to our knowledge there is a lack of research in our own specialty. We discuss how aviation principles related to human factors can be translated to the operating theatre to improve teamwork and safety for patients. Clinical research is clearly needed to develop this fascinating area more fully.

We present results on the direct monolithic integration of III–V devices and Si CMOS on a silicon substrate. InP HBTs (0.5 × 5 um2 emitter) with ft and fmax ≫ 200GHz were grown directly in windows adjacent to CMOS transistors on silicon template wafers or SOLES (Silicon on Lattices Engineered Substrates). A BCB based multilayer interconnect process was used to interconnect the InP HBT and Si CMOS to create a differential amplifier demonstration circuit. The heterogeneously integrated differential amplifier serves as the building block for high speed, low power dissipation mixed signal circuits such as ADCs and DACs.

We present results on the direct monolithic integration of III–V devices and Si CMOS on a silicon substrate. Through optimization of device fabrication and material growth processes III–V devices with electrical performance comparable to devices grown on native III–V substrates were grown directly in windows adjacent to CMOS transistors on silicon template wafers or SOLES (Silicon on Lattices Engineered Substrates). While the results presented here are for InP HBTs, our direct heterogeneously integration approach is equally applicable to other III–V electronic (FETs, HEMTs) and opto-electronic (photodiodes, VSCLS) devices and opens the door to a new class of highly integrated, high performance, mixed signal circuits.

Background The efficient allocation of financial resources for malaria control using appropriate combinations of interventions requires accurate information on the geographic distribution of malaria risk. An evidence-based description of the global range of Plasmodium falciparum malaria and its endemicity has not been assembled in almost 40 y. This paper aims to define the global geographic distribution of P. falciparum malaria in 2007 and to provide a preliminary description of its transmission intensity within this range. Methods and Findings The global spatial distribution of P. falciparum malaria was generated using nationally reported case-incidence data, medical intelligence, and biological rules of transmission exclusion, using temperature and aridity limits informed by the bionomics of dominant Anopheles vector species. A total of 4,278 spatially unique cross-sectional survey estimates of P. falciparum parasite rates were assembled. Extractions from a population surface showed that 2.37 billion people lived in areas at any risk of P. falciparum transmission in 2007. Globally, almost 1 billion people lived under unstable, or extremely low, malaria risk. Almost all P. falciparum parasite rates above 50% were reported in Africa in a latitude band consistent with the distribution of Anopheles gambiae s.s. Conditions of low parasite prevalence were also common in Africa, however. Outside of Africa, P. falciparum malaria prevalence is largely hypoendemic (less than 10%), with the median below 5% in the areas surveyed. Conclusions This new map is a plausible representation of the current extent of P. falciparum risk and the most contemporary summary of the population at risk of P. falciparum malaria within these limits. For 1 billion people at risk of unstable malaria transmission, elimination is epidemiologically feasible, and large areas of Africa are more amenable to control than appreciated previously. The release of this information in the public domain will help focus future resources for P. falciparum malaria control and elimination., Combining extensive surveillance and climate data, as well as biological characteristics of Anopheles mosquitoes, Robert Snow and colleagues create a global map of risk for P. falciparum malaria., Editors' Summary Background. Malaria is a parasitic disease that occurs in tropical and subtropical regions of the world. 500 million cases of malaria occur every year, and one million people, mostly children living in sub-Saharan Africa, die as a result. The parasite mainly responsible for these deaths—Plasmodium falciparum—is transmitted to people through the bites of infected mosquitoes. These insects inject a life stage of the parasite called sporozoites, which invade and reproduce in human liver cells. After a few days, the liver cells release merozoites (another life stage of the parasite), which invade red blood cells. Here, they multiply before bursting out and infecting more red blood cells, causing fever and damaging vital organs. Infected red blood cells also release gametocytes, which infect mosquitoes when they take a human blood meal. In the mosquito, the gametocytes multiply and develop into sporozoites, thus completing the parasite's life cycle. Malaria can be treated with antimalarial drugs and can be prevented by controlling the mosquitoes that spread the parasite (for example, by using insecticides) and by avoiding mosquito bites (for example, by sleeping under a insecticide-treated bednet). Why Was This Study Done? Because malaria poses such a large global public-health burden, many national and international agencies give countries where malaria is endemic (always present) financial resources for malaria control and, where feasible, elimination. The efficient allocation of these resources requires accurate information on the geographical distribution of malaria risk, but it has been 40 years since a map of malaria risk was assembled. In this study, which is part of the Malaria Atlas Project, the researchers have generated a new global map to show where the risk of P. falciparum transmission is moderate or high (stable transmission areas where malaria is endemic) and areas where the risk of transmission is low (unstable transmission areas where sporadic outbreaks of malaria occur). What Did the Researchers Do and Find? To construct their map of P. falciparum risk, the researchers collected nationally reported data on malaria cases each year and on the number of people infected in sampled communities. They also collected information about climatic conditions that affect the parasite's life cycle and consequently the likelihood of active transmission. For example, below a certain temperature, infected mosquitoes reach the end of their natural life span before the parasite has had time to turn into infectious sporozoites, which means that malaria transmission does not occur. By combining these different pieces of information with global population data, the researchers calculated that 2.37 billion people (about 35% of the world's population) live in areas where there is some risk of P. falciparum transmission, and that about 1 billion of these people live where there is a low but still present risk of malaria transmission. Furthermore, nearly all the regions where more than half of children carry P. falciparum parasites (a P. falciparum prevalence of more than 50%) are in Africa, although there are some African regions where few people are infected with P. falciparum. Outside Africa, the P. falciparum prevalence is generally below 5%. What Do These Findings Mean? The accuracy of this new map of the spatial distribution of P. falciparum malaria risk depends on the assumptions made in its assembly and the accuracy of the data fed into it. Nevertheless, by providing a contemporary indication of global patterns of P. falciparum malaria risk, this new map should be a valuable resource for agencies that are trying to control and eliminate malaria. (A similar map for the more common but less deadly P. vivax malaria would also be useful, but has not yet been constructed because less information is available and its biology is more complex.) Importantly, the map provides an estimate of the number of people who are living in areas where malaria transmission is low, areas where it should, in princple, be possible to use existing interventions to eliminate the parasite. In addition, it identifies large regions of Africa where the parasite might be more amenable to control and, ultimately, elimination than previously thought. Finally, with regular updates, this map will make it possible to monitor the progress of malaria control and elimination efforts. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050038. The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish) Information is available from the World Health Organization on malaria (in English, Spanish, French, Russian, Arabic, and Chinese) The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish) Information is available from the Roll Back Malaria Partnership on its approach to the global control of malaria More information is available on global mapping of malaria risk from the Malaria Atlas Project

A program of stringently-regulated gene expression is thought to be a fundamental component of the circadian clock. Although recent work has implicated a role for E-box-dependent transcription in circadian rhythmicity, the contribution of other enhancer elements has yet to be assessed. Here, we report that cells of the suprachiasmatic nuclei (SCN) exhibit a prominent circadian oscillation in cAMP response element (CRE)-mediated gene expression. Maximal reporter gene expression occurred from late-subjective night to mid-subjective day. Cycling of CRE-dependent transcription was not observed in other brain regions, including the supraoptic nucleus and piriform cortex. Levels of the phospho-active form of the transcription factor CREB (P-CREB) varied as a function of circadian time. Peak P-CREB levels occurred during the mid- to late-subjective night. Furthermore, photic stimulation during the subjective night, but not during the subjective day, triggered a marked increase in CRE-mediated gene expression in the SCN. Reporter gene experiments showed that activation of the p44/42 mitogen-activated protein kinase signaling cascade is required for Ca2+-dependent stimulation of CRE-mediated transcription in the SCN. These findings reveal the CREB/CRE transcriptional pathway to be circadian-regulated within the SCN, and raise the possibility that this pathway provides signaling information essential for normal clock function.

Recent studies suggest that the CREB-CRE transcriptional pathway is pivotal in the formation of some types of long-term memory. However, it has not been demonstrated that stimuli that induce learning and memory activate CRE-mediated gene expression. To address this issue, we used a mouse strain transgenic for a CRE-lac Z reporter to examine the effects of hippocampus-dependent learning on CRE-mediated gene expression in the brain. Training for contextual conditioning or passive avoidance led to significant increases in CRE-dependent gene expression in areas CA1 and CA3 of the hippocampus. Auditory cue fear-conditioning, which is amygdala dependent, was associated with increased CRE-mediated gene expression in the amygdala, but not the hippocampus. These data demonstrate that learning in response to behavioral conditioning activates the CRE transcriptional pathway in specific areas of brain.

Catalytic subunits of mammalian adenylyl cyclases have been proposed to contain 12 transmembrane domains, a property shared with some voltage-sensitive ion channels. Here we report that adenylyl cyclase activity in cerebellar neurons is synergistically stimulated by depolarizing agents and beta-adrenergic receptor activation. This phenomenon is Ca(2+)-independent and not attributable to Ca(2+)-stimulated adenylyl cyclase activity. Cholera toxin and forskolin also synergistically stimulate adenylyl cyclase activity in combination with depolarizing agents. We hypothesize that conformational changes in the catalytic subunit of the enzymes caused by changes in the membrane potential may enhance stimulation of adenylyl cyclases by the guanylyl nucleotide stimulatory protein. This novel mechanism for regulation of adenylyl cyclases generates robust cAMP signals that may contribute to various neuromodulatory events including some forms of neuroplasticity.

The Along-Track Scanning Radiometer-2 (ATSR-2) is equipped with visible and near-infrared channels at 1.6, 0.87, 0.66, and 0.56 microm. An in-flight visible calibration (VISCAL) system used to convert the raw signal to top-of-the-atmosphere reflectances is described. To monitor the long-term stability of the VISCAL, a number of large-area stable terrestrial sites have been employed. We describe the methods used to determine the long-term drifts in the ATSR-2 onboard calibration device and evaluate the suitability of the sites for calibration monitoring.

Major bleeding is a common complication after percutaneous coronary intervention (PCI), although little is known about how bleeding rates have changed over time and what has driven this. We analyzed all patients who underwent PCI in England and Wales from 2006 to 2013. Multivariate analyses using logistic regression models were performed to identify predictors of bleeding to identify potential factors influencing bleeding trends over time. 545,604 participants who had PCI in England and Wales between 2006 and 2013 were included in the analyses. Overall bleeding rates decreased from 7.0 (CI 6.2 to 7.8) per 1,000 procedures in 2006 to 5.5 (CI 4.7 to 6.2) per 1,000 in 2013. Increasing age, female sex, GPIIb/IIIa inhibitors use, and circulatory support were independently associated with increased risk of bleeding complications whereas radial access and vascular closure device use were independently associated with decreases in risk. Decreases in bleeding rates over time were associated with radial access site, and changes in pharmacology, but this was offset by greater proportion of ACS cases and the adverse patient clinical demographics. In conclusion, major bleeding complications after PCI have decreased due to changes in access site practice and decreased usage of GPIIb/IIIa inhibitors, but this is offset by the increase of patients with higher propensity to bleed. Changes in access site practice nationally have the potential to significantly reduce major bleeding after PCI.