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Building on the recent advances in next-generation sequencing, the integration of genomics, proteomics, metabolomics, and other approaches hold tremendous promise for precision medicine. The approval and adoption of these rapidly advancing technologies and methods presents several regulatory science considerations that need to be addressed. To better understand and address these regulatory science issues, a Clinical and Translational Science Award Working Group convened the Regulatory Science to Advance Precision Medicine Forum. The Forum identified an initial set of regulatory science gaps. The final set of key findings and recommendations provided here address issues related to the lack of standardization of complex tests, preclinical issues, establishing clinical validity and utility, pharmacogenomics considerations, and knowledge gaps.
Herbicide resistance is ‘wicked’ in nature; therefore, results of the many educational efforts to encourage diversification of weed control practices in the United States have been mixed. It is clear that we do not sufficiently understand the totality of the grassroots obstacles, concerns, challenges, and specific solutions needed for varied crop production systems. Weed management issues and solutions vary with such variables as management styles, regions, cropping systems, and available or affordable technologies. Therefore, to help the weed science community better understand the needs and ideas of those directly dealing with herbicide resistance, seven half-day regional listening sessions were held across the United States between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide resistance management. The major goals of the sessions were to gain an understanding of stakeholders and their goals and concerns related to herbicide resistance management, to become familiar with regional differences, and to identify decision maker needs to address herbicide resistance. The messages shared by listening-session participants could be summarized by six themes: we need new herbicides; there is no need for more regulation; there is a need for more education, especially for others who were not present; diversity is hard; the agricultural economy makes it difficult to make changes; and we are aware of herbicide resistance but are managing it. The authors concluded that more work is needed to bring a community-wide, interdisciplinary approach to understanding the complexity of managing weeds within the context of the whole farm operation and for communicating the need to address herbicide resistance.
Seven half-day regional listening sessions were held between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide-resistance management. The objective of the listening sessions was to connect with stakeholders and hear their challenges and recommendations for addressing herbicide resistance. The coordinating team hired Strategic Conservation Solutions, LLC, to facilitate all the sessions. They and the coordinating team used in-person meetings, teleconferences, and email to communicate and coordinate the activities leading up to each regional listening session. The agenda was the same across all sessions and included small-group discussions followed by reporting to the full group for discussion. The planning process was the same across all the sessions, although the selection of venue, time of day, and stakeholder participants differed to accommodate the differences among regions. The listening-session format required a great deal of work and flexibility on the part of the coordinating team and regional coordinators. Overall, the participant evaluations from the sessions were positive, with participants expressing appreciation that they were asked for their thoughts on the subject of herbicide resistance. This paper details the methods and processes used to conduct these regional listening sessions and provides an assessment of the strengths and limitations of those processes.
In the Central Kenyan Highlands, dairy cattle ownership is a crucial element in poverty alleviation. For example, in Kiambu district just north of Nairobi, out of the population of 744010, 48% of 189709 households stall feed dairy cattle. Farm sizes average 1.1 to 2.0 ha per household. Producing sufficient forage for dairy cattle is difficult and low dry matter intake constrains dairy production and there is a positive correlation between stover intake and milk yield.. Napier grass comprised 40% of the total dry matter fed to cattle and maize forage 24% according to the project’s Rapid Rural Appraisal, maize thinnings and stover being routinely fed to livestock. In another survey, dry maize stover accounted for nearly 65% of dry matter intake of dairy cattle during October.
While livestock sector is the back-bone of Ethiopian economy, production levels are low due to a variety of causes. It is characterized by low milk production, poor growth rates, extended calving or lambing intervals and a relatively late age at maturity. The major constrain for this is seasonality of feed quality and poor availability during the dry season, with nitrogen supply especially limiting. However legume forages such as cowpea offer the possibility to enhance dietary N levels and improve livestock production (Abule et al., 1995). With its quick growth, drought resistance and rapid ground cover cowpea has become an essential component of sustainable subsistence agriculture in marginal lands and drier regions of the tropics. This study was conducted to examine the ability of cowpea forages, offered as a supplement to low quality maize stover, to enhance intake and production performance in growing Ethiopian highland sheep.
In a previous study in Reading (altitude 66 m) (Mauricio et al., 1997) the lag phase was greater when cow faeces was used as a source of microorganisms in the in vitro gas production technique instead of rumen liquor when twelve temperate forages were fermented for 96 h. In the Reading study faeces and rumen liquor were obtained from a cow fed grass silage and concentrate (60:40). The present study was done in Piracicaba, Brazil-BR (altitude 780 m) which has a tropical climate. Using the same forages as in Mauricio et al. (1998), the study examined whether the same differences between faeces and rumen liquor would occur in a tropical environment. In addition, the opportunity was taken to develop an equation relating pressure and volume for the semi-automated pressure transducer technique and compare it with the equation developed in UK by Mauricio et al. (1998).
Professor Colomb resigned as President of the Commission because of pressing demands of work. The Organizing Committee appointed Stuart Bowyer (Vice President) as Acting President.
The Commission has proposed changing its name to “Bioastronomy: Search for Extrasolar Planets and Extraterrestial Life” to reflect our long-standing involvement in the search for extrasolar planets. The name change is pending approval of the IAU.
Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.
The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.
PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10−6). SLEs and CT were also associated with MDD status (p = 2.19 × 10−4 and p = 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.
CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.
On 1980 February 20 we conducted an 8-station intercontental VLBI experiment in order to study the nucleus and jet of M87 at 1666.6 MHz in right circular polarization. Our array was sensitive to structures from 0.001 to 0.1 arcsec. We made a hybrid map of the nucleus of M87, and also searched for compact structures within the knots of the jet. The map (Figure 1) shows that the nucleus of M87 contains a one-sided jet. This morphology is similar to that observed in many compact extragalactic sources. The position angle of the nuclear jet is 290.5 (±1) degrees, which precisely matches that of the 20 arcsec jet. No bending of the jet through an angle greater than about 2 degrees is observed. The nucleus also contains a large component (>0.1 arcsec) which is elongated along the same position angle as the jet and has a flux density of roughly 1 Jy. This component is fully resolved by the vast majority of our (u, v) points, and we could not map it with standard techniques.
We present a high resolution polarimetry and variability study of the M87 jet using VLA and HST data taken during 2002 to 2008. Both data-sets have an angular resolution as high as 0.06”, which is 2-3 times better than previous observations. New morphological details are revealed in both the optical and radio, which can help to reveal the energetic and magnetic field structure of the jet. By comparing the data with previously published HST and VLA observations, we show that the jet's morphology in total and polarized light is changing significantly on timescales of ~1 decade. We compare the evolution of the inner jet (particularly the nucleus and knot HST-1), when our observations overlap with the multi-wavelength monitoring campaigns conducted with HST and Chandra. We use these data to comment on particle acceleration and main emission processes.
Engineered remediation technologies such as denitrifying bioreactors target single contaminants along a nutrient transfer continuum. However, mixed contaminant discharges to a water body are more common from agricultural systems. Indeed, evidence presented herein indicates that pollution swapping within denitrifying bioreactor systems adds to such deleterious discharges. The present paper proposes a more holistic approach to contaminant remediation on farms, moving from the use of ‘denitrifying bioreactors’ to the concept of a ‘permeable reactive interceptor’ (PRI). Besides management changes, a PRI should contain additional remediation cells for specific contaminants in the form of solutes, particles or gases. Balance equations and case studies representing different geographic areas are presented and used to create weighting factors. Results showed that national legislation with respect to water and gaseous emissions will inform the eventual PRI design. As it will be expensive to monitor a system continuously in a holistic manner, it is suggested that developments in the field of molecular microbial ecology are essential to provide further insight in terms of element dynamics and the environmental controls on biotransformation and retention processes within PRIs. In turn, microbial and molecular fingerprinting could be used as an in-situ cost-effective tool to assess nutrient and gas balances during the operational phases of a PRI.
Nitrification inhibitors are used in agriculture for the purpose of decreasing nitrogen (N) losses, by limiting the microbially mediated oxidation of ammonium (NH4+) to nitrate (NO3−). Successful inhibition of nitrification has been shown in numerous studies, but the extent to which inhibitors affect other N transformations in soil is largely unknown. In the present study, cattle slurry was applied to microcosms of three different grassland soils, with or without the nitrification inhibitor dicyandiamide (DCD). A solution containing NH4+ and NO3−, labelled with 15N either on the NH4+ or the NO3− part, was mixed with the slurry before application. Gross N transformation rates were estimated using a 15N tracing model. In all three soils, DCD significantly inhibited gross autotrophic nitrification, by 79–90%. Gross mineralization of recalcitrant organic N increased significantly with DCD addition in two soils, whereas gross heterotrophic nitrification from the same pool decreased with DCD addition in two soils. Fungal to bacterial ratios were not significantly affected by DCD addition. Total gross mineralization and immobilization increased significantly across the three soils when DCD was used, which suggests that DCD can cause non-target effects on soil N mineralization–immobilization turnover.
A considerable expansion of biogas production in Germany, paralleled by a strong increase in maize acreage, has caused growing concern that greenhouse gas (GHG) emissions during crop substrate production might counteract the GHG emission saving potential. Based on a 2-year field trial, a GHG balance was conducted to evaluate the mitigation potential of regionally adapted cropping systems (continuous maize, maize-wheat-Italian ryegrass, perennial ryegrass ley), depending on nitrogen (N) level and N type. Considering the whole production chain, all cropping systems investigated contributed to the mitigation of GHG emissions (6·7–13·3 t CO2 eq/ha), with continuous maize revealing a carbon dioxide (CO2) saving potential of 55–61% compared with a fossil energy mix reference system. The current sustainability thresholds in terms of CO2 savings set by the EU Renewable Energy Directive could be met by all cropping systems (48–76%). Emissions from crop production had the largest impact on the mitigation effect (⩾50%) unless the biogas residue storage was not covered. The comparison of N fertilizer types showed less pronounced differences in GHG mitigation potential, whereas considerable site effects were observed.
Oral administration of the nitrification inhibitor dicyandiamide (DCD) to ruminants for excretion in urine represents a targeted mitigation strategy to reduce nitrogen (N) losses from grazed pasture. A farmlet grazing study was undertaken to examine the environmental benefits of administering DCD in trough water to non-lactating Friesian dairy cows that consecutively grazed 12 replicated plots (each 627 m2 with a grazing intensity of up to 319 cows/ha/day) during two grazing rotations in the winter of 2007 in the Waikato region, New Zealand. Nitrate-N (NO3−-N) leaching losses were measured using ceramic cup samplers (600 mm soil depth) and gaseous emissions of nitrous oxide (N2O) were quantified using a static chamber technique in the DCD and control treatments. Administration of DCD in trough water had no effect on daily water intake by dairy cows, which averaged 15 and 18 l/cow/day for the June and August grazing rotations, respectively. This resulted in a mean daily DCD intake of 46 and 110 g/cow/day, respectively. The DCD farmlet had significantly lower NO3−-N concentrations in leachate at the last three samplings, which reduced total NO3−-N leaching losses by 40% (from 32·0 to 19·2 kg N/ha). The DCD treatment reduced N2O emission rates compared to the control treatment following the August grazing, resulting in a 45% reduction in total N2O emissions relative to the control treatment (from 0·49 to 0·27 kg N2O-N/ha). This preliminary study highlights the potential for administering ruminants with DCD as an effective mitigation option for reducing N losses from agricultural systems.
Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies.
We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings.
A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This ‘heritability’ was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10−8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R2 = 0.08 in SLEs (p = 0.03).
These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.
Uptake of oestrogens into breast tissue and their subsequent metabolism can be studied by infusing radio-labelled steroids into volunteer patients. Such studies show that oestradiol is preferentially accumulated in breast tumours, oestradiol concentrations exceeding those of oestrone. This contrasts with plasma, in which oestrone concentrations in postmenopausal women are greater than those of the oestradiol. This observation suggests that tissue factors can modulate local oestrogen metabolism, and thus local steroid concentrations.
We have studied the local production of oestrogens from androgen, and also the interconversion of the major oestrogens, oestrone and oestradiol. Using isotopic techniques, it is possible to calculate the proportion of endogenous oestrogen produced from androgen, as opposed to uptake from the circulation. These studies suggest that a very variable proportion of tissue oestrogen derives from endogenous synthesis. After administration of aromatase inhibitors, aromatase activity is substantially inhibited, both in vivo and in vitro.
Relative oestrogen concentrations are determined in part by the activity of oestradiol dehydrogenase. In breast tissue, dehydrogenase activity is present and this is modified by various factors, including androgens. In addition, we have demonstrated that normal, benign and malignant breast tissues produce factors which can modulate both growth and dehydrogenase activity of cancer cells in vitro.
We conclude that breast tissue is a site of synthesis of oestrogens, and that a number of factors can affect their local concentration. Tumour cells produce growth factors which can influence steroid metabolism, and may thus be able to enhance favourably their own endocrine environment.
Elevated striatal dopamine synthesis capacity is thought to be fundamental to the pathophysiology of schizophrenia and has also been reported in people at risk of psychosis. It is therefore unclear if striatal hyperdopaminergia is a vulnerability marker for schizophrenia, or a state feature related to the psychosis itself. Relatives of patients with schizophrenia are themselves at increased risk of developing the condition. In this study we examined striatal dopamine synthesis capacity in both members of twin pairs discordant for schizophrenia.
In vivo striatal dopamine synthesis capacity was examined using fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scans in seven twin pairs discordant for schizophrenia and in a control sample of 10 healthy control twin pairs.
Striatal 18F-DOPA uptake was not elevated in the unaffected co-twins of patients with schizophrenia (p=0.65) or indeed in the twins with schizophrenia (p=0.89) compared to the control group. Levels of psychotic symptoms were low in the patients with schizophrenia who were in general stable [mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total=56.8 (25.5)] whereas the unaffected co-twins were largely asymptomatic.
Striatal dopamine synthesis capacity is not elevated in symptom-free individuals at genetic risk of schizophrenia, or in well-treated stable patients with chronic schizophrenia. These findings suggest that striatal hyperdopaminergia is not a vulnerability marker for schizophrenia.
The amorphous silicon memory device shows promise as an analogue weight element in neural networks. The device resistance can be programmed to within 5% of any specific value between lkΩ and lMΩ using 10ns to 1μ voltage pulses in the range 1–5V. In this paper we describe the physical structure of the element and its electrical characteristics. Finally, a simple example is discussed of a small neural network implementing the EXOR function using amorphous silicon memory elements as a resistive array of weights and external op-amps as the current summing nodes.
Polycapillary optics, shaped arrays consisting of hundreds of thousands of hollow glass capillary tubes, are used to redirect, collimate, or focus x-ray beams from conventional laboratory-based sources. Focused spot sizes as small as 20μm have been measured, with flux densities two orders of magnitude larger than that produced by pinhole or crossed slit collimation. Such flux increases have made possible faster and more sensitive x-ray fluorescence (XRF) and diffraction measurements to the extent that in situ measurements become possible. XRF data taken with a 12 W source were comparable to data taken with a 1.5 kW source. Ex situ diffraction and texture measurements on thin multilayered films and single crystal silicon demonstrate the tremendous experimental and analytical improvements made possible by polycapillary optics.
With 0.5° and 2° focusing polycapillary x-ray optics, diffraction intensity gains of more than two orders of magnitude were measured on small Lysozyme protein crystals with exposure times an order of magnitude less than required by traditional measurement techniques
In addition, the optics greatly reduce the background high energy Bremsstrahlung, permitting more accurate analysis of thin complex multilayer diffraction peaks. Rapid measurement times resulting from the application of these polycapillary optics, indicate tremendous possibilities for in situ process monitoring