Background: Microglia and macrophages (MMs) are the largest component of the inflammatory infiltrate in glioblastoma (GBM). However, whether there are immunophenotypic differences in isocitrate dehydrogenase (IDH)-mutated and -wildtype GBMs is unknown. Studies on specimens of untreated IDH-mutant GBMs are rare given they comprise 10% of all GBMs and often receive treatment at lower grades that can drastically alter MM phenotypes. Methods: We obtained large samples of untreated IDH-mutant and -wildtype GBMs. Using immunofluorescence techniques with single-cell automated segmentation, and comparison between single-cell RNA-sequencing (scRNA-seq) databases of human GBM, we discerned dissimilarities between GBM-associated MMs (GAMMs). Results: There are significantly fewer but more pro-inflammatory GAMMs in IDH-mutant GBMs, suggesting this contributes to the better prognosis of these tumors. Our pro-inflammatory score which combines the expression of inflammatory markers (CD68/HLA-A, -B, -C/TNF/CD163/IL10/TGFB2), Iba1 intensity, and GAMM surface area also indicates more pro-inflammatory GAMMs are associated with longer overall survival independent of IDH status. scRNA-seq analysis demonstrates microglia in IDH-mutants are mainly pro-inflammatory, while anti-inflammatory macrophages that upregulate genes such as FCER1G and TYROBP predominate in IDH-wildtype GBM. Conclusions: Taken together, these observations are the first head-to-head comparison of GAMMs in treatment-naïve IDH-mutant versus -wildtype GBMs that highlight biological disparities that can be exploited for therapeutic purposes.

Zn plays an important role in maintaining the anti-oxidant status within the heart and helps to counter the acute redox stress that occurs during myocardial ischaemia and reperfusion. Individuals with low Zn levels are at greater risk of developing an acute myocardial infarction; however, the impact of this on the extent of myocardial injury is unknown. The present study aimed to compare the effects of dietary Zn depletion with in vitro removal of Zn (N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN)) on the outcome of acute myocardial infarction and vascular function. Male Sprague–Dawley rats were fed either a Zn-adequate (35 mg Zn/kg diet) or Zn-deficient (<1 mg Zn/kg diet) diet for 2 weeks before heart isolation. Perfused hearts were subjected to a 30 min ischaemia/2 h reperfusion (I/R) protocol, during which time ventricular arrhythmias were recorded and after which infarct size was measured, along with markers of anti-oxidant status. In separate experiments, hearts were challenged with the Zn chelator TPEN (10 µm) before ischaemia onset. Both dietary and TPEN-induced Zn depletion significantly extended infarct size; dietary Zn depletion was associated with reduced total cardiac glutathione (GSH) levels, while TPEN decreased cardiac superoxide dismutase 1 levels. TPEN, but not dietary Zn depletion, also suppressed ventricular arrhythmias and depressed vascular responses to nitric oxide. These findings demonstrate that both modes of Zn depletion worsen the outcome from I/R but through different mechanisms. Dietary Zn deficiency, resulting in reduced cardiac GSH, is the most appropriate model for determining the role of endogenous Zn in I/R injury.

Synchrotron radiation was used to obtain a high-resolution powder diffraction pattern of the high-density form of BeH2, a material whose unit-cell dimensions have not previously been determined. The observed d-spacing values were presented to three different computer indexing programs. All three programs returned as best solution a body-centered orthorhombic unit cell with a = 9.082, b = 4.160, c = 7.707 Å and V = 292 Å3. Interpretation of the three-dimensional Patterson led to 12 BeH2 molecules per unit cell; thus, the theoretical density is 0.755 g/cm3. The molecular structure is based on a network of corner-sharing BeH4 tetrahedra rather than flat, infinite chains with hydrogen bridges previously assumed.

X-ray microscopy is a field that has developed rapidly in recent years. Two different approaches have been used. Zone plates have been employed to produce focussed beams with sizes as low as 0.07 pm for x-ray energies below 1 keV. Images of biological materials and elemental maps for major and minor low Z have been produced using above and below absorption edge differences. At higher energies collimators and focussing mirrors have been used to make small diameter beams for excitation of characteristic K— or L-x rays of all elements in the periodic table.

It is well established that dicamba can cause severe injury to soybean that is not resistant to dicamba. Dicamba-resistant (DR) cotton became available in 2015, followed by DR soybean in 2016; in late 2016 came the release of new dicamba formulations approved for topical use in cotton and soybeans. Until this approval, use of dicamba was limited to primarily corn, small grains, range and pasture, and eco-fallow acres. Hence, studies were conducted in 2015 and 2016 to examine off-target movement of two dicamba formulations using non-DR soybean as a bio-indicator. Diglycolamine (DGA) and N,N-Bis(3-aminopropyl)methylamine (BAPMA) dicamba were applied simultaneously at 560 g ae ha–1 in the center of two side-by-side 8-ha fields to vegetative glufosinate-resistant soybean. On the same day, a rate response experiment was established encompassing nine different dicamba rates of each formulation. Results from the rate response experiment indicate that soybean is equally sensitive to DGA and BAPMA dicamba. In 2015, a rain event occurring 6 to 8 h after application of the large drift trial probably limited off-target movement by incorporating some of the herbicide into the soil. As a result, secondary drift was less in 2015 than in 2016. However, minimal secondary injury (<5%) occurred 12 m farther into DGA dicamba plots in 2015. In 2016, secondary movement was decreased by 72 m when BAPMA dicamba was used compared to DGA dicamba. Appreciable secondary movement of both DGA and BAPMA dicamba is possible following in-crop applications of either formulated product to soybean in early to mid-summer. Additionally, the risk for secondary movement of BAPMA dicamba is slightly less than for DGA dicamba.

In the occurrence of dicamba drift, it is not well understood what measurements from soybean plants would correlate with damage to soybean offspring; therefore, possible relationships are of great interest. Sixteen drift trials were established in 2014 and 2015 at the Northeast Research and Extension Center in Keiser, AR. A single 8-m-wide by 30- or 60-m-long pass with a high-clearance sprayer was made in each soybean field, resulting in a dicamba drift event. Seeds were collected from plants in each drift trial and planted in the field in 2015 and 2016. Data were subjected to correlation analysis to determine pairwise associations among parent and offspring observations. Auxin-like symptomology in offspring consistent with dicamba, primarily as leaf cupping, appeared in plots at the unifoliate and first trifoliate stages. Auxin-like symptoms were more prevalent in offspring collected from plants from later reproductive stages as opposed to early reproductive stages. The highest correlation coefficients occurred when parent plants were treated at the R5 growth stage. Parent mature pod malformation was correlated with offspring emergence (r=−0.37, P=0.0082), vigor (r=−0.57, P ≤ 0.0001), injury (r=0.93, P ≤ 0.0001), and percent of plants injured (r=0.92, P ≤ 0.0001). This research documents that soybean damaged from dicamba drift during the R1 to R6 growth stages can negatively affect offspring and that occurrence of pod malformation after dicamba drift at the R5 growth stage may be indicative of injury to the offspring.

Soybean with resistance to dicamba (DR soybean) and glyphosate and cotton with resistance to glyphosate, glufosinate, and dicamba were recently commercialized in the United States and have been readily adopted. To evaluate results of over-the-top application of dicamba in DR crops, field studies were designed to examine off-target movement using proposed sprayer setup recommendations. Association analysis and nonlinear regression techniques were used to examine the effects of 26 field-scale drift trials conducted in 2014 and 2015 during soybean reproductive development (R1 through R6). The greatest predictors (injury, height reduction) of soybean yield reduction generally occurred and had steeper relationships after drift events at the R1 growth stage than at later stages. Using non-DR soybean as an indicator, dicamba was documented to move as much as 152 m from the application area (distance to 5% injury). Instances of height reduction (5%) differed among growth stages, with the greatest distance occurring at R1 (83.4 m). Soybean yield reduction was erratic, with the greatest distance to 5% loss in yield occurring at 42.8 m after an R1 drift event. Overall, the data suggest flowering-stage soybean is more sensitive than later reproductive soybean to injury, height reductions, and yield loss. Average and maximum wind speeds did not account for the injury documented from dicamba, and it is hypothesized that other meteorological variables also play a notable role in dicamba off-target movement as well as growing conditions following exposure. With concerns surrounding off-target movement of dicamba, proper stewardship of this new technology will be key to its longevity.

Polyphenol oxidase (PPO) in red clover (RC) has been shown to reduce both lipolysis and proteolysis in silo and implicated (in vitro) in the rumen. However, all in vivo comparisons have compared RC with other forages, typically with lower levels of PPO, which brings in other confounding factors as to the cause for the greater protection of dietary nitrogen (N) and C18 polyunsaturated fatty acids (PUFA) on RC silage. This study compared two RC silages which when ensiled had contrasting PPO activities (RC+ and RC−) against a control of perennial ryegrass silage (PRG) to ascertain the effect of PPO activity on dietary N digestibility and PUFA biohydrogenation. Two studies were performed the first to investigate rumen and duodenal flow with six Hereford×Friesian steers, prepared with rumen and duodenal cannulae, and the second investigating whole tract N balance using six Holstein-Friesian non-lactating dairy cows. All diets were offered at a restricted level based on animal live weight with each experiment consisting of two 3×3 Latin squares using big bale silages ensiled in 2010 and 2011, respectively. For the first experiment digesta flow at the duodenum was estimated using a dual-phase marker system with ytterbium acetate and chromium ethylenediaminetetraacetic acid as particulate and liquid phase markers, respectively. Total N intake was higher on the RC silages in both experiments and higher on RC− than RC+. Rumen ammonia-N reflected intake with ammonia-N per unit of N intake lower on RC+ than RC−. Microbial N duodenal flow was comparable across all silage diets with non-microbial N higher on RC than the PRG with no difference between RC+ and RC−, even when reported on a N intake basis. C18 PUFA biohydrogenation was lower on RC silage diets than PRG but with no difference between RC+ and RC−. The N balance trial showed a greater retention of N on RC+ over RC−; however, this response is likely related to the difference in N intake over any PPO driven protection. The lack of difference between RC silages, despite contrasting levels of PPO, may reflect a similar level of protein-bound-phenol complexing determined in each RC silage. Previously this complexing has been associated with PPOs protection mechanism; however, this study has shown that protection is not related to total PPO activity.

It is well established that soybean that does not contain the dicamba-resistant (DR) trait is highly sensitive to off-target exposure to dicamba. However, there is limited information on the effect of low doses of dicamba plus glyphosate mixtures on dicamba-sensitive soybean—a mixture likely to be used on a vast acreage of dicamba/glyphosate-resistant soybean. The objective of this research was to examine leaf and pod malformation, along with height and yield effects, when dicamba, glyphosate, or a mixture of the two was applied to soybean sensitive to both dicamba and glyphosate at sublethal doses. Field applications were made at three growth stages (R1, R3, and R5) at multiple locations. Two glyphosate rates (1/64 and 1/256 of the labeled rate of 870 g ae ha−1) and two dicamba rates (1/64 and 1/256 of the labeled rate of 560 g ae ha−1) were used. Adding glyphosate to dicamba increased leaf malformation by 6% more than dicamba alone when applied at the R1 soybean growth stage. After R3 applications, pod malformation was 10% greater in treatments containing dicamba and glyphosate than dicamba alone. Applications at R5 showed minimal leaf and pod malformation. Seed from field trials was planted in the greenhouse to evaluate the offspring. The number of offspring plants showing dicamba-like symptomology was not increased with the addition of glyphosate to dicamba. Overall, injury to offspring was similar in dicamba alone and dicamba plus glyphosate treatments; however, the number of plants injured increased when parent plants were exposed to sublethal doses of dicamba at R3 and R5 compared with R1 growth-stage exposure. Vigor was reduced in dicamba-containing treatments, but not glyphosate-alone treatments. Glyphosate addition to dicamba had no effect on vigor of soybean offspring. Although there is increased injury to parent plants when glyphosate is added to dicamba, this research demonstrates that glyphosate does not contribute to the negative effects of dicamba on soybean offspring.

Shapiro and Warga (2) have proved in an elementary way that all large integers are expressible as the sum of at most 20 primes. In so doing, they proved that

as x —> ∞, where u is a positive square-free integer,

Evidence from animal models indicates that exposure to an obesogenic or hyperglycemic intrauterine environment adversely impacts offspring kidney development and renal function. However, evidence from human studies has not been evaluated systematically. Therefore, the aim of this systematic review was to synthesize current research in humans that has examined the relationship between gestational obesity and/or diabetes and offspring kidney structure and function. Systematic electronic database searches were conducted of five relevant databases (CINAHL, Cochrane, EMBASE, MEDLINE and Scopus). Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed, and articles screened by two independent reviewers generated nine eligible papers for inclusion. Six studies were assessed as being of ‘neutral’ quality, two of ‘negative’ and one ‘positive’ quality. Observational studies suggest that offspring exposed to a hyperglycemic intrauterine environment are more likely to display markers of renal dysfunction and are at higher risk of end-stage renal disease. There was limited and inconsistent evidence for a link between exposure to an obesogenic intrauterine environment and offspring renal outcomes. Offspring renal outcome measures across studies were diverse, with a large variation in offspring age at follow-up, limiting comparability across studies. The collective current body of evidence suggests that intrauterine exposure to maternal obesity and/or diabetes adversely impacts renal programming in offspring, with an increased risk of kidney disease in adulthood. Further high-quality, longitudinal, prospective cohort studies that measure indicators of offspring renal development and function, including fetal kidney volume and albuminuria, at standardized follow-up time points, are warranted.

The thermal state at the bed of a large ice sheet is a critical boundary condition governing its future evolution. Radar surveys provide an opportunity for direct but remote observation of the ice-sheet bed, and therefore offer a means of constraining numerical ice-sheet models at the ice–bed interface. Here we have processed results of radar surveys of the Greenland Ice Sheet undertaken by the Program for Arctic Regional Climate Assessment (PARCA) between 1999 and 2003, to explore this opportunity. We consider the robustness of the measurements in the context of uncertain dielectric losses in the ice sheet, concluding that the observed radar signal characteristics reflect the character of the bed itself rather than that of uncertain englacial absorption. However, the identification of thaw is restricted to areas where subglacial water has sufficient depth to influence the radar reflection. We derive a map of inferred areas of subglacial thaw, and compare our results with other studies predicting regions with temperate bed. We show that in many areas the radar inferences of ponded water lie within areas predicted to be thawed by modelling and radiostratigraphy. There is clear disagreement in certain areas, suggesting the presence of high geothermal flux anomalies.

Inefficiencies in the national clinical research infrastructure have been apparent for decades. The National Center for Advancing Translational Science—sponsored Clinical and Translational Science Award (CTSA) program is able to address such inefficiencies. The Trial Innovation Network (TIN) is a collaborative initiative with the CTSA program and other National Institutes of Health (NIH) Institutes and Centers that addresses critical roadblocks to accelerate the translation of novel interventions to clinical practice. The TIN’s mission is to execute high-quality trials in a quick, cost-efficient manner. The TIN awardees are composed of 3 Trial Innovation Centers, the Recruitment Innovation Center, and the individual CTSA institutions that have identified TIN Liaison units. The TIN has launched a national scale single (central) Institutional Review Board system, master contracting agreements, quality-by-design approaches, novel recruitment support methods, and applies evidence-based strategies to recruitment and patient engagement. The TIN has received 113 submissions from 39 different CTSA institutions and 8 non-CTSA Institutions, with projects associated with 12 different NIH Institutes and Centers across a wide range of clinical/disease areas. Already more than 150 unique health systems/organizations are involved as sites in TIN-related multisite studies. The TIN will begin to capture data and metrics that quantify increased efficiency and quality improvement during operations.

Background: Central neuropathic pain syndromes are a result of central nervous system injury, most commonly related to stroke, traumatic spinal cord injury, or multiple sclerosis. These syndromes are distinctly less common than peripheral neuropathic pain, and less is known regarding the underlying pathophysiology, appropriate pharmacotherapy, and long-term outcomes. The objective of this study was to determine the long-term clinical effectiveness of the management of central neuropathic pain relative to peripheral neuropathic pain at tertiary pain centers. Methods: Patients diagnosed with central (n=79) and peripheral (n=710) neuropathic pain were identified for analysis from a prospective observational cohort study of patients with chronic neuropathic pain recruited from seven Canadian tertiary pain centers. Data regarding patient characteristics, analgesic use, and patient-reported outcomes were collected at baseline and 12-month follow-up. The primary outcome measure was the composite of a reduction in average pain intensity and pain interference. Secondary outcome measures included assessments of function, mood, quality of life, catastrophizing, and patient satisfaction. Results: At 12-month follow-up, 13.5% (95% confidence interval [CI], 5.6-25.8) of patients with central neuropathic pain and complete data sets (n=52) achieved a ≥30% reduction in pain, whereas 38.5% (95% CI, 25.3-53.0) achieved a reduction of at least 1 point on the Pain Interference Scale. The proportion of patients with central neuropathic pain achieving both these measures, and thus the primary outcome, was 9.6% (95% CI, 3.2-21.0). Patients with peripheral neuropathic pain and complete data sets (n=463) were more likely to achieve this primary outcome at 12 months (25.3% of patients; 95% CI, 21.4-29.5) (p=0.012). Conclusion: Patients with central neuropathic pain syndromes managed in tertiary care centers were less likely to achieve a meaningful improvement in pain and function compared with patients with peripheral neuropathic pain at 12-month follow-up.

After describing a newly assembled dataset consisting of almost 9,000 local appropriations made by the U.S. Congress between 1789 and 1882, we test competing accounts of the politics surrounding them before offering a more nuanced, historically contingent view of the emergence of the pork barrel. We demonstrate that for most of this historical period—despite contemporary accusations of crass electoral motives—the pattern of appropriations is largely inconsistent with accounts of distributive politics grounded in a logic of legislative credit-claiming. Instead, support for appropriations in the House mapped cleanly onto the partisan/ideological structure of Congress for most of this period, and only in the 1870s produced the universalistic coalitions commonly associated with pork-barrel spending. We trace this shift to two historical factors: the emergence of a solid Democratic South, and growth in the fraction of appropriations funding recurrent expenditures on extant projects rather than new starts.

Technologies emerging from current bioengineering research areas may have a substantial impact on society and raise many ethical issues. Consequentially, there is a significant interest amongst public and private organisations to identify ethical issues, improve stakeholder participation, and develop frameworks and assessment procedures to aid decision-makers evaluate these complex issues. This paper explores a form of bioethical analysis that has been developed to aid decision-makers in the agricultural and food sectors. Two agricultural technologies will be used as case studies to examine the application of this form of bioethical analysis in technology assessment, viz automatic milking systems (AMS) and bovine somatotrophin (bST). The bioethical framework applied, the Ethical Matrix developed by Mepham (e.g. 1996; 2000), is based on a principled approach drawn from the concept of the ‘common morality’ where the ‘impacts’ of a technology are assessed in terms of respect for three ethical principles (wellbeing, autonomy and justice) as they apply to various interest groups.

To explore stakeholder issues raised by the technologies, two workshops and separate postal surveys of farmers, consumers and retailers were conducted to examine the attitudes to the two technologies. Each survey included matched questions, so that attitudes could be cross-compared, with the Ethical Matrix used as a guiding framework. The three surveys highlighted specific attitudes of consumers, farmers and retailers to bST and AMS (response rates were 19.3%, 27.3% and 69% respectively), as well as identifying general trends in attitudes to technological development. Consumers distinguished clearly between what they considered to be more acceptable (AMS was largely acceptable with some caveats) and less acceptable technologies (bST). bST use in the UK was unacceptable to the majority of UK farmers whereas AMS was accepted with caution. Retailers, overall, had a cautious but considered approach to the technologies, applying a precautionary approach in their policies.

Applying the Ethical Matrix aided the clarification of ethical issues which underlie differences in opinion on the acceptability and required legal control of the two technologies. In summary, bST supporters placed a greater emphasis on productivity and prosperity, whereas sceptics focused on perceived risks, and on producers' and consumers' lack of autonomy. Potential positive impacts of AMS were identified as improvements in dairy production efficiency and enhancement of dairy farmer and cow welfare, while concerns included impacts on rural employment, milk quality and the increasingly instrumental use of animals.

The incorporation of bioethical analysis into technology assessment, specifically in the form of the Ethical Matrix, was generally regarded as providing a useful and valuable tool, helping to clarifying issues and encourage dialogue. Individuals with contrasting worldviews can use it effectively, allowing any conflicts and consistencies of the arguments to be cross-compared. This is particularly important for policy makers who need to be explicit and transparent and to justify their decisions by reference to widely accepted ethical norms. At a simplistic level, this method may act merely as a comprehensive check-list, but when applied more comprehensively it can encourage stakeholder dialogue and clarify the interactions of scientific and ethical aspects of a particular issue.

The rapid development and application of biosensors is likely to have considerable impact on livestock management. Biosensors are considered to be analytical devices incorporating a biological material, or a biologically derived material intimately associated with or integrated within a physicochemical transducer or transducing microsystem. For livestock production it is useful to consider where sensors may be used effectively. These may include monitoring of the living environment to ensure that adequate hygiene and animal welfare are maintained, waste management, monitoring of the metabolic state of the livestock so that adequate intake of nutrients is maintained, detection of oestrus or other conditions, monitoring for bacterial or viral infections, both in live animals, and during the processing of animal products. For animal welfare, biosensors are needed to measure biological effects e.g. genotoxicity, immunotoxicity, biotoxins and endocrine effects. The concentrations of specific analytes that are difficult to detect are important contaminants of water, waste, soil or air (e.g. surfactants, chlorinated hydrocarbons, sulphophenyl carboxylates, sulphonated dyes, fluorescent whitening agents, napthalensulphonates, carboxylic acids, dioxins, pesticide metabolites etc). The development of practical biosensing systems capable of operation under realistic conditions is discussed.