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We study the integral of the Frobenius norm as a measure of the discrepancy between two multivariate spectra. Such a measure can be used to fit time series models, and ensures proximity between model and process at all frequencies of the spectral density—this is more demanding than Kullback–Leibler discrepancy, which is instead related to one-step ahead forecasting performance. We develop new asymptotic results for linear and quadratic functionals of the periodogram, and make two applications of the integrated Frobenius norm: (i) fitting time series models, and (ii) testing whether model residuals are white noise. Model fitting results are further specialized to the case of structural time series models, wherein co-integration rank testing is formally developed. Both applications are studied through simulation studies, as well as illustrations on inflation and construction data. The numerical results show that the proposed estimator can fit moderate- to large-dimensional structural time series in real time, an option that is lacking in current literature.

There is an ongoing debate on whether residual seasonality is present in the estimates of real Gross Domestic Product (GDP) in U.S. national accounts and whether it explains the slower quarter-one GDP growth rate in the recent years. This article aims to bring clarity to this topic by (1) summarizing the techniques and methodologies used in these studies; (2) arguing for a sound methodological framework for evaluating claims of residual seasonality; and (3) proposing three diagnostic tests for detecting residual seasonality, applying them to different vintages and different sample spans of data on real GDP and its major components from the U.S. national accounts and making comparisons with results from the previous studies.

Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a trace amine-associated receptor 1–Orai1–Ca 2+ –calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the monocarboxylase transporter 2–calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halt lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a unique function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.

Octopamine is a well-established invertebrate neurotransmitter involved in fight-or-flight responses. In mammals, its function was replaced by norepinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a TAAR1-Orai1-Ca2+-calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the MCT2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halts lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a novel function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.

The Transportation Services Index (TSI) lags two months from its release date due to source data availability, and it is desirable to publish a preliminary TSI that is advanced two months ahead We model and forecast TSI with a co-integrated Vector Autoregression, also considering two explanatory series that do not have publication delay Thus we are able to produce forecasts and nowcasts of the index, and we demonstrate that – during normal economic conditions – out-of-sample performance is within the scope expected by the forecast confidence intervals We also examine the performance of the models at the onset of the COVID-19 pandemic, and the large forecast errors at this regime change are beyond the bounds indicated by our model The practical ramifications of this methodology is discussed [ABSTRACT FROM AUTHOR] Copyright of Statistical Journal of the IAOS is the property of IOS Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

The mitochondrial electron transport chain (ETC) is necessary for tumour growth1–6 and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies7–9. Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria10,11. However, it is unclear why a functional ETC is necessary for tumour growth in vivo. ETC function is coupled to the generation of ATP—that is, oxidative phosphorylation and the production of metabolites by the tricarboxylic acid (TCA) cycle. Mitochondrial complexes I and II donate electrons to ubiquinone, resulting in the generation of ubiquinol and the regeneration of the NAD+ and FAD cofactors, and complex III oxidizes ubiquinol back to ubiquinone, which also serves as an electron acceptor for dihydroorotate dehydrogenase (DHODH)—an enzyme necessary for de novo pyrimidine synthesis. Here we show impaired tumour growth in cancer cells that lack mitochondrial complex III. This phenotype was rescued by ectopic expression of Ciona intestinalis alternative oxidase (AOX)12, which also oxidizes ubiquinol to ubiquinone. Loss of mitochondrial complex I, II or DHODH diminished the tumour growth of AOX-expressing cancer cells deficient in mitochondrial complex III, which highlights the necessity of ubiquinone as an electron acceptor for tumour growth. Cancer cells that lack mitochondrial complex III but can regenerate NAD+ by expression of the NADH oxidase from Lactobacillus brevis (LbNOX)13 targeted to the mitochondria or cytosol were still unable to grow tumours. This suggests that regeneration of NAD+ is not sufficient to drive tumour growth in vivo. Collectively, our findings indicate that tumour growth requires the ETC to oxidize ubiquinol, which is essential to drive the oxidative TCA cycle and DHODH activity. Oxidation of ubiquinol by the mitochondrial electron transfer chain drives tumour growth by maintaining the function of the oxidative Krebs cycle and de novo pyrimidine synthesis.

DiGeorge Syndrome, or 22q11.2 deletion syndrome (22q11.2 DS), is a genetic disorder caused by microdeletions in chromosome 22, impairing the function of endothelial cells (EC) and/or mural cells and leading to deficits in blood vessel development such as abnormal aortic arch morphology, tortuous retinal vessels, and tetralogy of Fallot. The mechanism by which dysfunctional endothelial cells and pericytes contribute to the vasculopathy, however, remains unknown. In this study, we used human blood vessel organoids (VOs) generated from iPSC of 22q11.2 DS patients to model the vascular malformations and genetic dysfunctions. We combined high-resolution lightsheet imaging and single-cell transcriptome analysis to link the genetic profile and vascular phenotype at the single-cell level. We developed a comprehensive analytical methodology by integrating deep learning-mediated blood vessel segmentation, network graph construction, and tessellation analysis for automated morphology characterization. We report that 22q11.2DS VOs demonstrate a smaller size with increased angiogenesis/sprouting, suggesting a less stable vascular network. Overall, clinical presentations of smaller vascular diameter, less connected vasculature, and increased branch points were recapitulated in 22q11.2DS VOs. Single-cell transcriptome profiling showed heterogeneity in both 22q11.2DS and control VOs, but the former demonstrated alterations in endothelial characteristics that are organ-specific and suggest a perturbation in the vascular developmental process. Intercellular communication analysis indicated that the vascular dysfunctions in 22q11.2 deletion were due to a lower cell-cell contact and upregulated extracellular matrix organization involving collagen and fibronectin. Voronoi diagram-based tessellation analysis also indicated that the colocalization of endothelial tubes and mural cells was different between control and 22q11.2 VOs, indicating that alterations in EC and mural interactions might contribute to the deficits in vascular network formation. This study illustrates the utility of VO in revealing the pathogenesis of 22q11.2DS vasculopathy.

The metabolic syndrome (MetS), defined as the co-occurrence of disorders including obesity, dyslipidemia, insulin resistance, and hepatic steatosis, has become increasingly prevalent in the world over recent decades. Dietary and other environmental factors interacting with genetic predisposition are likely contributors to this epidemic. Among the involved dietary factors, excessive fructose consumption may be a key contributor. When fructose is consumed in large amounts, it can quickly produce many of the features of MetS both in humans and mice. The mechanisms by which fructose contributes to metabolic disease and its potential interactions with genetic factors in these processes remain uncertain. Here, we generated a small F2 genetic cohort of male mice derived from crossing fructose-sensitive and -resistant mouse strains to investigate the interrelationships between fructose-induced metabolic phenotypes and to identify hepatic transcriptional pathways that associate with these phenotypes. Our analysis indicates that the hepatic transcriptional pathways associated with fructose-induced hypertriglyceridemia and hyperinsulinemia are distinct from those that associate with fructose-mediated changes in body weight and liver triglyceride. These results suggest that multiple independent mechanisms and pathways may contribute to different aspects of fructose-induced metabolic disease.

Hunt et al. show that mitochondrial stress in Drosophila neurons activates ATF4 expression, resulting in increased L-2-hydroxyglutarate (L-2-HG) levels. Reducing L-2-HG levels improves neuronal activity, demonstrating that increased L-2-HG contributes to neuronal dysfunction., Mitochondrial stress contributes to a range of neurological diseases. Mitonuclear signaling pathways triggered by mitochondrial stress remodel cellular physiology and metabolism. How these signaling mechanisms contribute to neuronal dysfunction and disease is poorly understood. We find that mitochondrial stress in neurons activates the transcription factor ATF4 as part of the endoplasmic reticulum unfolded protein response (UPR) in Drosophila. We show that ATF4 activation reprograms nuclear gene expression and contributes to neuronal dysfunction. Mitochondrial stress causes an ATF4-dependent increase in the level of the metabolite L-2-hydroxyglutarate (L-2-HG) in the Drosophila brain. Reducing L-2-HG levels directly, by overexpressing L-2-HG dehydrogenase, improves neurological function. Modulation of L-2-HG levels by mitochondrial stress signaling therefore regulates neuronal function.

Genome-wide association on winter survival was conducted using data from image-based phenotyping method. Nine QTL were observed and three of them with candidate gene identified. Winter survival is an essential trait of winter wheat (Triticum aestivum L.) grown in regions with high risk of winterkill. We characterized a diversity panel of 450 Canadian wheat varieties that included mostly winter-growth habit wheats to identify key genetic factors that contribute to higher winter survival under field conditions. To more accurately quantify winter survival differences among varieties, image-based phenotyping methods, captured by unmanned aerial vehicle (UAV) and on ground level, were used to estimate the winter survival of each varieties. Winter survival index was developed to correct for emergence when evaluating winter survival. Winter survival measurement estimated by visual estimation, UAV imagery and ground imagery showed strong correlation with each other and had comparable broad-sense heritability. Genome-wide association studies resulted in the identification of seven quantitative trait loci (QTL) for winter survival including Vrn-A1. By using the recently released annotated sequence of the wheat genome and the available RNA-Seq data, two putative candidate genes underlying the QTL for winter survival were identified. However, our study showed that certain QTL was unique to specific winter survival measurement. Collectively, our study demonstrated the feasibility of using UAV-based imagery for the identification of loci associated with winter survival in wheat. The complexity of in-field condition make our result a valuable complement to indoor frost-tolerance studies in the identification of genetic factors not directly linked to freezing tolerance.

Mitochondrial complex I inhibition in the presence of a mito-antioxidant induces reductive stress, ISR, and cancer cell death., Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR-Cas9 genetic screen and uncovered that loss of genes encoding subunits of mitochondrial complex I was deleterious in the presence of the mitochondria-targeted antioxidant mito-vitamin E (MVE). Genetic or pharmacologic inhibition of mitochondrial complex I in combination with the mitochondria-targeted antioxidants, MVE or MitoTEMPO, induced a robust integrated stress response (ISR) and markedly diminished cell survival and proliferation in vitro. This was not observed following inhibition of mitochondrial complex III. Administration of MitoTEMPO in combination with the mitochondrial complex I inhibitor phenformin decreased the leukemic burden in a mouse model of T cell acute lymphoblastic leukemia. Thus, mitochondrial complex I is a dominant metabolic determinant of mROS-dependent cellular fitness.

Purpose/Objective(s) Primary tumor failure is common in patients treated with chemoradiation (CRT) for unresectable LA-NSCLC. Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control in Stage I NSCLC. This trial tested an SBRT boost to the primary tumor prior to the start of CRT to improve primary tumor control (PTC). Materials/Methods Patients with LA-NSCLC with primary tumor ≤10 cm were enrolled on a prospective phase II trial testing an SBRT boost in 2 fractions (central 6 Gy x 2, peripheral 8 Gy x 2) immediately followed by standard concurrent CRT (60 Gy in 30 fractions). Patients were staged with PET-CT, brain MRI, and underwent 4D-CT simulation for radiation planning using a customized immobilization device that enabled radiation planning for the sequential delivery of the SBRT boost and conventionally-fractionated radiation from the same CT dataset. Chemotherapy was carboplatin/paclitaxel (C/P) or cisplatin/etoposide. For patients receiving C/P, consolidation C/P for 2 cycles was given at the discretion of the medical oncologist. The trial was later amended to allow for consolidation durvalumab. The primary objective was to estimate PTC rate at 1-year with a hypothesis that the 1-year PTC rate is ≥90%. Secondary objectives were to establish the safety, feasibility, objective response rate (ORR; RECISTv1.1), and rates of regional & distant control, disease-free survival (DFS), and overall survival (OS). Exploratory functional MRI (fMRI) scans before and within the first 30 hrs of the first SBRT fraction were performed in 11 patients. Results The study enrolled 21 patients (10 male, 11 female), with median age 62 years (range 52-78). 16 patients received 6 Gy x 2 SBRT boost, while 5 patients received 8 Gy x 2 SBRT boost. 18 patients received C/P chemotherapy, of whom 9 patients received consolidation C/P. Six patients received consolidation durvalumab. Median pre-treatment primary tumor size was 5.0 cm (range 1.0-8.3). Median and mean follow-up were17.9 and 20.2 months, respectively. The most common toxicities were fatigue, neutropenia, leukopenia, lymphopenia, anemia, pneumonitis, fibrosis, dyspnea and esophagitis. Five grade 4 toxicities related to treatment occurred [lymphopenia (3), neutropenia (1), and leukopenia (1)], but no grade 5 toxicities related to treatment occurred. ORR at 3 and 6 months was 72.7% and 80.0%. The PTC rate was 100% and 92.3% at 1 and 2 years, respectively. The 2-year regional and distant control were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 yrs were 46.1% and 50.3%, respectively. Median survival was 37.8 months. fMRI detected a mean relative decrease in BOLD signal of -87.1% (P = 0.05). Conclusion Dose escalation to the primary tumor utilizing upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably with the literature. Through the use of 1 CT simulation dataset, accurate calculation of the planned dose through the 2 sequentially-delivered plans is achievable.

There are numerous mechanisms by which mammals respond to hypoxia. These include acute changes in pulmonary arterial tone due to smooth muscle cell contraction, acute increases in respiration triggered by the carotid body chemosensory cells, and chronic changes such as induction of red blood cell proliferation and angiogenesis by hypoxia inducible factor targets erythropoietin and vascular endothelial growth factor, respectively. Mitochondria account for the majority of oxygen consumption in the cell and have recently been appreciated to serve as signaling organelles required for the initiation or propagation of numerous homeostatic mechanisms. Mitochondria can influence cell signaling by production of reactive oxygen species and metabolites. Here we review recent evidence that mitochondrial signals can imitate acute and chronic hypoxia responses.

Mitochondrial metabolism encompasses pathways that generate ATP to drive intracellular unfavorable energetic reactions and produce the building blocks necessary for macromolecule synthesis. In the past two decades, it has become clear that mitochondrial metabolism does not play a passive role as an underlying mechanism of biology, but instead plays a dynamic and influential role in dictating cell fate and function by controlling gene expression through release of reactive oxygen species and metabolites (1). The compartmentalization of mitochondrial enzymes and complexes is essential for the maintenance of important signaling pathways within the cell. For this reason, the identity and concentration of metabolites is substantially different between the mitochondrial matrix and the cytosol. To date, much of our understanding of the concentration of mitochondrial metabolites has been limited to in vitro settings (2). In PNAS, Bayraktar et al. (3) establish MITO-Tag Mice, a tool that will have a substantial impact on the understanding of in vivo mitochondrial metabolism by allowing rapid assessment of mitochondrial metabolites. MITO-Tag Mice take advantage of the mitochondrial localization sequences of the outer mitochondrial membrane protein OMP25 to target a fusion protein containing the HA epitope from influenza hemagglutinin and GFP to the mitochondria. This MITO-Tag was previously published for in vitro use (2, 4). This methodology allowed the rapid isolation of tagged mitochondria from cells cultured in vitro using antibodies specific to the HA epitope. Now, in PNAS, Bayraktar et al. (3) take the important next step by generating a mouse model that expresses the MITO-Tag in specific cell types in vivo, using Cre-Lox recombination technology (Fig. 1). Fig. 1. MITO-Tag Mice use Cre-Lox recombination to express a mitochondria-targeted epitope tag in specific cell types or tissues. This epitope tag allows the rapid and direct isolation of mitochondria from the cell … [↵][1]1To whom correspondence should be addressed. Email: nav{at}northwestern.edu. [1]: #xref-corresp-1-1

Mitochondrial complex I regenerates NAD+ and proton pumps for TCA cycle function and ATP production, respectively. Mitochondrial complex I dysfunction has been implicated in many brain pathologies including Leigh syndrome and Parkinson's disease. We sought to determine whether NAD+ regeneration or proton pumping, i.e., bioenergetics, is the dominant function of mitochondrial complex I in protection from brain pathology. We generated a mouse that conditionally expresses the yeast NADH dehydrogenase (NDI1), a single enzyme that can replace the NAD+ regeneration capability of the 45-subunit mammalian mitochondrial complex I without proton pumping. NDI1 expression was sufficient to dramatically prolong lifespan without significantly improving motor function in a mouse model of Leigh syndrome driven by the loss of NDUFS4, a subunit of mitochondrial complex I. Therefore, mitochondrial complex I activity in the brain supports organismal survival through its NAD+ regeneration capacity, while optimal motor control requires the bioenergetic function of mitochondrial complex I.

This paper addresses the topic of nonnested time series model comparisons. The main result is a central limit theorem for the likelihood ratio statistic when the models are nonnested and non-equivalent. The concepts of model equivalence and forecast equivalence, which are important for determining the parameter subset corresponding to the null hypothesis, are developed. The method is validated through a simulation study and illustrated on a retail time series.

Mitochondrial complex I regenerates NAD+ and proton pumps for TCA cycle function and ATP production, respectively. Mitochondrial complex I dysfunction has been implicated in many brain pathologies including Leigh Syndrome and Parkinson’s disease. We sought to determine whether NAD+ regeneration or proton pumping is the dominant function of mitochondrial complex I in protection from brain pathology. We generated a mouse that conditionally expresses the yeast NDI1 protein, a single enzyme that can replace the NAD+ regeneration capability of the 45-subunit mammalian mitochondrial complex I without proton pumping. NDI1 expression was sufficient to dramatically prolong lifespan without significantly improving motor function in a mouse model of Leigh Syndrome. Therefore, complex I activity in the brain supports organismal survival through its NAD+ regeneration capacity while optimal motor control requires the bioenergetic function of mitochondrial complex I.

The continuing horrors of military conflicts and terrorism often involve the use of chemical warfare agents (CWAs) and toxic industrial chemicals (TICs). Many CWA and TIC exposures are difficult to treat due to the danger they pose to first responders and their rapid onset that can produce death shortly after exposure. While the specific mechanism(s) of toxicity of these agents are diverse, many are associated either directly or indirectly with increased oxidative stress in affected tissues. This has led to the exploration of various antioxidants as potential medical countermeasures for CWA/TIC exposures. Studies have been performed across a wide array of agents, model organisms, exposure systems, and antioxidants, looking at an almost equally diverse set of endpoints. Attempts at treating CWAs/TICs with antioxidants have met with mixed results, ranging from no effect to nearly complete protection. The aim of this commentary is to summarize the literature in each category for evidence of oxidative stress and antioxidant efficacy against CWAs and TICs. While there is great disparity in the data concerning methods, models, and remedies, the outlook on antioxidants as medical countermeasures for CWA/TIC management appears promising.

Thiocyanate (SCN) is used by the innate immune system, but less is known about its impact on inflammation and oxidative stress. Granulocytes oxidize SCN to evolve the bactericidal hypothiocyanous acid, which we previously demonstrated is metabolized by mammalian, but not bacterial, thioredoxin reductase (TrxR). There is also evidence that SCN is dysregulated in cystic fibrosis (CF), a disease marked by chronic infection and airway inflammation. To investigate antiinflammatory effects of SCN, we administered nebulized SCN or saline to β epithelial sodium channel (βENaC) mice, a phenotypic CF model. SCN significantly decreased airway neutrophil infiltrate and restored the redox ratio of glutathione in lung tissue and airway epithelial lining fluid to levels comparable to wild type. Furthermore, in Pseudomonas aeruginosa–infected βENaC and wild-type mice, SCN decreased inflammation, proinflammatory cytokines, and bacterial load. SCN also decreased airway neutrophil chemokine keratinocyte chemoattractant (also known as C-X-C motif chemokine ligand 1) and glutathione sulfonamide, a biomarker of granulocyte oxidative activity, in uninfected βENaC mice. Lung tissue TrxR activity and expression increased in inflamed lung tissue, providing in vivo evidence for the link between hypothiocyanous acid metabolism by TrxR and the promotion of selective biocide of pathogens. SCN treatment both suppressed inflammation and improved host defense, suggesting that nebulized SCN may have important therapeutic utility in diseases of both chronic airway inflammation and persistent bacterial infection, such as CF.

Cacao (Theobroma cacao) is a globally important crop, and its yield is severely restricted by disease. Two of the most damaging diseases, witches’ broom disease (WBD) and frosty pod rot disease (FPRD), are caused by a pair of related fungi: Moniliophthora perniciosa and Moniliophthora roreri, respectively. Resistant cultivars are the most effective long-term strategy to address Moniliophthora diseases, but efficiently generating resistant and productive new cultivars will require robust methods for screening germplasm before field testing. Marker-assisted selection (MAS) and genomic selection (GS) provide two potential avenues for predicting the performance of new genotypes, potentially increasing the selection gain per unit time. To test the effectiveness of these two approaches, we performed a genome-wide association study (GWAS) and GS on three related populations of cacao in Ecuador genotyped with a 15K single nucleotide polymorphism (SNP) microarray for three measures of WBD infection (vegetative broom, cushion broom, and chirimoya pod), one of FPRD (monilia pod) and two productivity traits (total fresh weight of pods and % healthy pods produced). GWAS yielded several SNPs associated with disease resistance in each population, but none were significantly correlated with the same trait in other populations. Genomic selection, using one population as a training set to estimate the phenotypes of the remaining two (composed of different families), varied among traits, from a mean prediction accuracy of 0.46 (vegetative broom) to 0.15 (monilia pod), and varied between training populations. Simulations demonstrated that selecting seedlings using GWAS markers alone generates no improvement over selecting at random, but that GS improves the selection process significantly. Our results suggest that the GWAS markers discovered here are not sufficiently predictive across diverse germplasm to be useful for MAS, but that using all markers in a GS framework holds substantial promise in accelerating disease-resistance in cacao.

Carotenoids serve antioxidant functions in plant photosynthetic processes, as well as in actions of disease reduction in mammalian systems. Lutein and zeaxanthin are important dietary carotenoids in suppressing aging eye diseases. Age-related macular degeneration now affects more than 1.75 million individuals in the US. Sweet corn (Zea mays var. rugosa) is one of only a few vegetable sources high in zeaxanthin. Mesotrione herbicide is currently labeled for selective pre- and post-emergence weed control in sweet corn production. Mesotrione competitively inhibits phytoene desaturase, a critical enzyme in carotenoid biosynthesis, which results in bleaching of leaf tissues in susceptible species and eventual plant death. Sweet corn is tolerant to mesotrione applications; however, differing sensitivity exists among genotypes. What remains unclear is the impact of mesotrione on carotenoid concentrations in mature sweet corn kernels following post-emergent applications to young corn plants. Our research objective was to measure mature kernel carotenoid concentrations in response to post-emergence applications of mesotrione to genotypes of different sensitivities. Post-emergence treatments included mesotrione applied alone, or in mixtures with the photosystem II inhibitor atrazine applied to corn plants of either 5-10 or 15-20 cm in height. Kernels were harvested from mature plants and measured for carotenoid concentrations. Mesotrione applied alone, or in mixtures with atrazine acted to increase concentrations of kernel antheraxanthin, lutein, and zeaxanthin in several sweet corn genotypes. Mesotrione applications resulted in greater pools of kernel carotenoids once the sweet corn genotypes overcame initial herbicidal photo-oxidative stress. This is the first report of herbicides directly up regulating a key biochemical pathway linked to the nutritional quality of a vegetable crop.

Well-maintained lawns are comfortable and safe places for leisure activities and sports practice, and they also bring environmental benefits; for example, they reduce soil exposure to erosion and releases atmospheric CO2, thus reducing the greenhouse effect. However, regardless of the purpose of use or the choice of the plant species to form the lawn, the highest costs involve cutting that is needed to keep the turfgrass at its appropriate height. Successive lawn cutting operations are necessary basically because of the vegetative and reproductive growth of turfgrass which, in Brazil, occurs mainly from October to March. Expenditures with successive mechanical cuttings have fostered the search of alternative procedures to keep lawn plants at appropriate height, such as the use of plant growth inhibitors, an increasingly interesting procedure. Since the use of this technology in Brazil is still at its early stage, the aim of this literature review is to examine aspects associated with lawn management by using growth inhibitors. Another alternative is to increase the knowledge of the classification and rational application of the different compounds currently available in the market. Um gramado bem mantido proporciona local confortável e seguro para diversão e prática de esportes, reduz a exposição do solo à erosão, libera oxigênio e captura CO2 atmosférico, atenuando o efeito estufa. Contudo, independentemente da modalidade de uso ou da escolha da espécie, o principal fator do custo de manutenção dos gramados é o corte para manter a altura adequada. As sucessivas operações de corte estão basicamente relacionadas ao crescimento vegetativo e florescimento da grama, sobretudo nos meses de outubro a março. O dispêndio com os cortes sucessivos leva à procura de alternativas para o manejo mecânico, tendo como possibilidade o uso de inibidores de crescimento vegetal. Como o uso dessa tecnologia em gramados no Brasil ainda é muito incipiente, pretende-se neste texto de revisão abordar os aspectos relativos ao manejo de gramados pelo uso de substâncias inibidoras do desenvolvimento vegetal, bem como atualizar os conhecimentos quanto à classificação e aplicação racional dos diferentes compostos atualmente disponíveis.

Although RNA interference (RNAi) has become a ubiquitous laboratory tool since its discovery 12 years ago, in vivo delivery to selected cell types remains a major technical challenge. Here, we report the use of lentiviral vectors for long-term in vivo delivery of RNAi selectively to resident alveolar macrophages (AMs), key immune effector cells in the lung. We demonstrate the therapeutic potential of this approach by RNAi-based downregulation of p65 (RelA), a component of the pro-inflammatory transcriptional regulator, nuclear factor κB (NF-κB) and a key participant in lung disease pathogenesis. In vivo RNAi delivery results in decreased induction of NF-κB and downstream neutrophilic chemokines in transduced AMs as well as attenuated lung neutrophilia following stimulation with lipopolysaccharide (LPS). Through concurrent delivery of a novel lentiviral reporter vector (lenti-NF-κB-luc-GFP) we track in vivo expression of NF-κB target genes in real time, a critical step towards extending RNAi-based therapy to longstanding lung diseases. Application of this system reveals that resident AMs persist in the airspaces of mice following the resolution of LPS-induced inflammation, thus allowing these localized cells to be used as effective vehicles for prolonged RNAi delivery in disease settings.

International audience; AbstractNitrogen is the most limiting nutrient in most agro-ecosystems and thus critical for sustaining high yields. Conventional agricultural practices use synthetic fertilizers to ensure an adequate supply of nitrogen in soils, but fertilizers come at a significant monetary and environmental cost. A strategy to improve nitrogen supply in cropping systems is the inclusion of nitrogen-fixing legumes, which can provide nitrogen benefits to companion crops through belowground nitrogen transfer. However, a better understanding of the underlying mechanisms and factors that govern nitrogen transfer is important in order to determine potential areas for improving this association. Here, we review the mechanisms of belowground nitrogen transfer in managed herbaceous cropping systems, focusing on forage systems. We classify three major routes of nitrogen transfer from legumes to non-legumes: (1) decomposition of legume root tissues and uptake of mineralized nitrogen by neighboring plants, (2) exudation of soluble nitrogen compounds by legumes and uptake by non-legumes, and (3) transfer of nitrogen mediated by plant-associated mycorrhizae. Literature data shows that rates of nitrogen transfer range from 0 to 73 % from forage legumes to companion grasses in mixed stands, depending on the legume species and cultivar. We list the factors that affect nitrogen transfer including abiotic factors, e.g., water stress, temperature, light, soil available nitrogen, and application of nitrogen fertilizer, and biotic factors, e.g., root contact, plant density, growth stage, production year, defoliation, and root herbivores. While the rates of nitrogen transfer are often constrained by abiotic conditions, such as temperature and water availability, that are beyond the control of growers, agronomic practices, e.g., planting density and choice of species and cultivar, may help to increase nitrogen transfer. Ultimately, the selection of plant pairs with compatible traits offers the best path forward to improving nitrogen transfer in intercrops.

Sulfur mustard (bis 2-chloroethyl ethyl sulfide, SM) is a powerful bi-functional vesicating chemical warfare agent. SM tissue injury is partially mediated by the overproduction of reactive oxygen species resulting in oxidative stress. We hypothesized that using a catalytic antioxidant (AEOL 10150) to alleviate oxidative stress and secondary inflammation following exposure to SM would attenuate the toxic effects of SM inhalation. Adult male rats were intubated and exposed to SM (1.4 mg/kg), a dose that produces an LD50 at approximately 24 h. Rats were randomized and treated via subcutaneous injection with either sterile PBS or AEOL 10150 (5 mg/kg, sc, every 4 h) beginning 1 h post-SM exposure. Rats were euthanized between 6 and 48 h after exposure to SM and survival and markers of injury were determined. Catalytic antioxidant treatment improved survival after SM inhalation in a dose-dependent manner, up to 52% over SM PBS at 48 h post-exposure. This improvement was sustained for at least 72 h after SM exposure when treatments were stopped after 48 h. Non-invasive monitoring throughout the duration of the studies also revealed blood oxygen saturations were improved by 10% and clinical scores were reduced by 57% after SM exposure in the catalytic antioxidant treatment group. Tissue analysis showed catalytic antioxidant therapy was able to decrease airway cast formation by 69% at 48 h post-exposure. To investigate antioxidant induced changes at the peak of injury, several biomarkers of oxidative stress and inflammation were evaluated at 24 h post-exposure. AEOL 10150 attenuated SM-mediated lung lipid oxidation, nitrosative stress and many proinflammatory cytokines. The findings indicate that catalytic antioxidants may be useful medical countermeasure against inhaled SM exposure.

Background: Accelerated partial breast irradiation (APBI) delivers adjuvant radiation (RT) to the 1-2 cm of the breast at highest risk for recurrence surrounding the lumpectomy (L) cavity over 5-8 days and is an alternative to standard whole breast irradiation for hormone sensitive (HS) stage 1 (T1, N0) breast cancer (BC) based on 2 randomized controlled trials. External beam methods for APBI are common but have notable inherent drawbacks that include: inter-fraction inaccuracy due to patient setup based on anatomy, intra fraction error related to patient or respiratory motion, and inaccurate geometric targeting by relying on L cavity position instead of the tumor position. Postoperative RT has other limitations including delivery in the setting of disrupted blood or lymphatic supply that may be suboptimal for radio sensitivity and it eliminates observation of radiation-induced tumor response. MRI is an established tool for measuring BC extent and response from neoadjuvant systemic therapy. It's hypothesized that MRI directed pre-operative APBI using intensity modulated radiotherapy (IMRT) with image guidance (IGRT) will improve RT delivery, and that MRI features can be identified to correlate with pathologic radiation response. Trial Design: There are 2 cohorts to this single arm prospective trial. The first cohort is for establishing and verifying patient flow and image fusion between MRI, CT and RT planning. In the second cohort eligible patients will receive preoperative APBI 38.5 Gy in 10 fractions BID with IMRT, IGRT in the prone position using MRI defined targets fused to CT treatment planning. Eligibility: For cohort 1 it is HS Stage 1 BC that has completed CT in prone position for RT planning. Eligibility for cohort 2 requires: age > 50 yo, clinical stage 1 BC, HS, HER2 negative, intending L, clinically negative axilla verified by ultrasound, able to tolerate the prone position, and MRI with contrast. Specific aims: To determine the reproducibility of MRI directed preoperative APBI based on meeting 3 criteria: ability to define RT targets by MRI, quality of RT plans and completion of treatment (APBI and surgery). Additional aims include assessing toxicity, cosmetic outcome, local regional cancer control and collection of tissue for correlative studies. Statistical methods: The optimal two-stage design by Simon is used. Sample size for cohort 2 is based on the first endpoint. 19 eligible patients will be required in the first stage; if 3 or more treatments are scored unacceptable, then early stopping will be recommended. Otherwise, accrual will continue to a total accrual of 30. If > 4 of 30 treatments are scored unacceptable, the technique will be considered not reproducible, and a Phase II study will not be pursued. Under the null hypothesis of an 80% reproducibility rate, this two-stage design has an expected sample size of 24.4. Patient accrual to cohort 1 has completed the targeted accrual of 3. Patient accrual to Cohort 2 is 5/30. Contact information: Soyhun Mc Elroy (Sohyun.McElroy@osumc.edu) or Julia White (Julia.White@osumc.edu) Funding source: Susan G Komen Breast Cancer Foundation Grant # GRT00035216 Citation Format: White J, McElroy S, Sekhon A, Wei L, Bazan J, Yang X, DiCostanzo D, Kuhn K, Gupta N, Knopp M. Feasibility of assessing radiation response with MRI/CT directed preoperative accelerated partial breast irradiation in the prone position for hormone responsive early stage breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-03-04.

Papadopoulos, Y. A., McElroy, M. S., Fillmore, S. A. E., McRae, K. B., Duyinsveld, J. L. and Fredeen, A. H. 2012. Sward complexity and grass species composition affects the performance of grass-white clover pasture mixtures. Can. J. Plant Sci. 92: 1199–1205. The productivity of managed permanent pastures is closely associated with the species composition of seeded mixtures. Ecological theory suggests that increasing plant species' diversity will result in higher productivity, resilience, and resistance to invasive species. To better understand the relationship between sward species composition and pasture productivity, mixtures of four common pasture grass species, timothy (Phleum pratense L.), Kentucky bluegrass (Poa pratensis L.), reed canarygrass (Phalaris arundinacea L.), and meadow fescue (Festuca pratensis L.), were seeded in 2004 in binary (two-grass), tertiary (three-grass), and quaternary (four-grass) combinations with white clover (Trifolium repens L.). Plots were rotationally grazed for 5 yr, with yield determined in the first post-establishment year (2005) and in 3 subsequent production years (2007, 2008, and 2009). Mean dry matter yield (DMY) increased appreciably from post-establishment (3801 kg ha−1) to the production years (6613 kg ha−1). Contrasts revealed significantly higher DMY production in quaternary mixtures versus less complex plots in production years. Repeated measure analysis found significant quadratic trends in DMY for plots containing bluegrass and timothy, showing different patterns of growth between the respective mixtures. Principal component analysis (PCA) of averaged yields over the production years revealed a strong association between seeded grass growth and DMY. This relationship between DMY and seeded grass growth was strongest in swards containing a combination of timothy and bluegrass. In general, the growth of unseeded grasses and forbs increased in mixtures with large proportions of timothy and reed canarygrass. In spite of the fact that mixtures containing timothy and bluegrass were shown to produce high DMY, it appears the aggressiveness of bluegrass suppressed the yield potential of timothy. White clover yields and unseeded grasses/forbs were both significantly lower in mixtures containing bluegrass. Also, the PCA revealed a favourable compatibility between meadow fescue and white clover growth, while bluegrass appears to suppress meadow fescue growth. Results show that species complexity increases sward productivity over the long term, and that the presence of two grass species, in particular (timothy and bluegrass), has considerable influence on DMY.

Amicarbazone is a photosystem II (PSII)-inhibiting herbicide in the triazolinone family, which is similar in mode of action to the triazines. Annual bluegrass is a cool-season weed and has shown resistance to some PSII-inhibiting herbicides. The objective was to evaluate triazine-resistant and -susceptible annual bluegrass populations for potential cross-resistance to amicarbazone. Two triazine-resistant (MS-01, MS-02) and triazine-susceptible (AL-01, COM-01) annual bluegrass populations were treated with amicarbazone, atrazine, and simazine at 0.26, 1.7, and 1.7 kg ai ha−1, respectively. All herbicide treatments controlled the susceptible populations greater than 94% 2 wk after treatment (WAT). No visual injury of MS-01 and MS-02 was observed at any time following herbicide treatment. Quantum yield (ΦPSII) of annual bluegrass was measured 0 to 72 h after application (HAA) to determine the photochemical effects of amicarbazone compared to other PSII inhibitors. ΦPSIIof triazine-susceptible populations was reduced at all measurement times by all three herbicides. However, amicarbazone decreased ΦPSIIof susceptible populations faster and greater than atrazine and simazine at most measurement times. Amicarbazone did not reduce ΦPSIIof the MS-01 population. Amicarbazone significantly reduced ΦPSIIof the MS-02 population during several measurement timings; however, these reductions were short-lived compared to the susceptible populations and no trend in ΦPSIIreduction was observed. Sequencing of thepsbAgene revealed a Ser to Gly substitution at amino acid position 264 known to confer resistance to triazine herbicides. These data indicate amicarbazone efficiently inhibited PSII of susceptible annual bluegrass populations; however, triazine-resistant annual bluegrass populations with Ser264to Gly mutations are cross-resistant to amicarbazone.

Amicarbazone is a photosystem II (PSII) inhibiting herbicide of the triazolinone herbicide family. Greenhouse experiments were conducted to compare the effects of amicarbazone and atrazine on annual bluegrass control and quantum yield (ΦPSII) when applied at three treatment placements (soil-only, foliage-only, and foliage + soil). Herbicide rates for amicarbazone and atrazine were 0.53 and 2.25 kg ha−1, respectively. Amicarbazone applied soil-only and foliage + soil controlled annual bluegrass 57 and 59%, respectively, 1 wk after treatment (WAT). Atrazine applied to foliage + soil controlled annual bluegrass 48% at 1 WAT. All soil-only and foliage + soil treatments were similar 2 WAT. Foliage-only application of amicarbazone provided significantly less control than other amicarbazone treatments throughout the study. Amicarbazone applied soil-only and foliage + soil controlled annual bluegrass 100% at 3 WAT. Soil-only and foliage + soil applications of atrazine and amicarbazone had similar reductions in quantum yield (ΦPSII) at 1 to 3 WAT. Foliar-applied amicarbazone reduced ΦPSII 78, 84, and 86% at 1, 2, and 3 WAT, respectively. The rapid reduction in annual bluegrass ΦPSII and the increase in control resulting from soil contact of amicarbazone indicate root exposure of amicarbazone is beneficial for annual bluegrass control.

SUMMARYThe objective of this research was to assess current patterns of hospital antibiotic prescribing in Northern Ireland and to determine targets for improving the quality of antibiotic prescribing. A point prevalence survey was conducted in four acute teaching hospitals. The most commonly used antibiotics were combinations of penicillins including β-lactamase inhibitors (33·6%), metronidazole (9·1%), and macrolides (8·1%). The indication for treatment was recorded in 84·3% of the prescribing episodes. A small fraction (3·9%) of the surgical prophylactic antibiotic prescriptions was for >24 h. The results showed that overall 52·4% of the prescribed antibiotics were in compliance with the hospital antibiotic guidelines. The findings identified the following indicators as targets for quality improvement: indication recorded in patient notes, the duration of surgical prophylaxis and compliance with hospital antibiotic guidelines. The results strongly suggest that antibiotic use could be improved by taking steps to address the identified targets for quality improvement.