Reduced Translocation Is Associated with Tolerance of Common Lambsquarters (\u3ci\u3eChenopodium album\u3c/i\u3e) to Glyphosate

Common lambsquarters tolerance to glyphosate is problematic because of the species’ widespread distribution, competitive ability with many crop species, the widespread use of glyphosate in agriculture, and the weed’s potential to develop decreased sensitivity to multiple herbicide sites of action. The mechanism that confers common lambsquarters tolerance to glyphosate is not known. Therefore, we conducted experiments to determine the mechanism of tolerance to glyphosate in an accession of common lambsquarters from Indiana relative to a sensitive accession from Wisconsin. The ED50 (the effective dose that reduced shoot mass 50% relative to nontreated plants) value for the tolerant accession (1.6 kg ae ha-1 ± 0.4 standard error of the mean [SEM]) was eightfold greater than the ED50 for the sensitive accession (0.2 kg ae ha-1 ± 0.2 SEM) 28 d after treatment. The glyphosate target-site (EPSPS) DNA sequence at proline 106, shikimate accumulation as an estimate of EPSPS sensitivity, and EPSPS protein abundance did not differ between accessions. Absorption of 14Cglyphosate was slightly greater in the tolerant accession than it was in the sensitive accession at 48 and 72 h after treatment (HAT). However, the tolerant accession translocated a smaller percentage of absorbed 14C-glyphosate to the tissue above the treated leaf, which included the shoot apical meristem, at 24, 48, and 72 HAT (P ≤ 0.05, 0.01, and 0.10, respectively). These results suggest an important role of reduced translocation in conferring tolerance of common lambsquarters to glyphosate

Inheritance of Evolved Glyphosate Resistance in a North Carolina Palmer Amaranth ( Amaranthus palmeri

Inheritance of glyphosate resistance in a Palmer amaranth biotype from North Carolina was studied. Glyphosate rates for 50% survival of glyphosate-resistant (GR) and glyphosate-susceptible (GS) biotypes were 1288 and 58 g ha−1, respectively. These values for F1 progenies obtained from reciprocal crosses (GR×GS and GS×GR were 794 and 501 g ha−1, respectively. Dose response of F1 progenies indicated that resistance was not fully dominant over susceptibility. Lack of significant differences between dose responses for reciprocal F1 families suggested that genetic control of glyphosate resistance was governed by nuclear genome. Analysis of F1 backcross (BC1F1) families showed that 10 and 8 BC1F1 families out of 15 fitted monogenic inheritance at 2000 and 3000 g ha−1 glyphosate, respectively. These results indicate that inheritance of glyphosate resistance in this biotype is incompletely dominant, nuclear inherited, and might not be consistent with a single gene mechanism of inheritance. Relative 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) copy number varied from 22 to 63 across 10 individuals from resistant biotype. This suggested that variable EPSPS copy number in the parents might be influential in determining if inheritance of glyphosate resistance is monogenic or polygenic in this biotype

Metabolism of 2,4-dichlorophenoxyacetic acid contributes to resistance in a common waterhemp (\u3ci\u3eAmaranthus tuberculatus\u3c/i\u3e) population

BACKGROUND: Synthetic auxins such as 2,4-D have been widely used for selective control of broadleaf weeds since the mid-1940s. In 2009, an Amaranthus tuberculatus (common waterhemp) population with 10-fold resistance to 2,4-D was found in Nebraska, USA. The 2,4-D resistance mechanism was examined by conducting [14C] 2,4-D absorption, translocation and metabolism experiments. RESULTS: No differences were found in 2,4-D absorption or translocation between the resistant and susceptible A. tuberculatus. Resistant plants metabolized [14C] 2,4-D more rapidly than did susceptible plants. The half-life of [14C] 2,4-D in susceptible plants was 105 h, compared to 22 h in resistant plants. Pre-treatment with the cytochrome P450 inhibitor malathion inhibited [14C] 2,4-D metabolism in resistant plants and reduced the 2,4-D dose required for 50% growth inhibition (GR50) of resistant plants by 7-fold to 27 g ha-1, similar to the GR50 for susceptible plants in the absence of malathion. CONCLUSIONS: Our results demonstrate that rapid 2,4-D metabolism is a contributing factor to resistance in A. tuberculatus, potentially mediated by cytochrome P450. Metabolism-based resistance to 2,4-D could pose a serious challenge for A. tuberculatus control due to the potential for cross-resistance to other herbicides

Stability of corn (\u3ci\u3eZea mays\u3c/i\u3e)- foxtail (\u3ci\u3eSetaria\u3c/i\u3e spp.) interference relationships

Variation in interference relationships have been shown for a number of crop-weed associations and may have an important effect on the implementation of decision support systems for weed management. Multiyear field experiments were conducted at eight locations to determine the stability of corn-foxtail interference relationships across years and locations. Two coefficients (I and A) of a rectangular hyperbola equation were estimated for each data set using nonlinear regression procedures. The I and A coefficients represent percent corn yield loss as foxtail density approaches zero and maximum percent corn yield loss, respectively. The coefficient I was stable across years at two locations and varied across years at four locations. Maximum yield loss (A) varied between years at one location. Both coefficients varied among locations. Although 3 to 4 foxtail plants m-1 row was a conservative estimate of the single-year economic threshold (Te) of foxtail density, variation in I and A resulted in a large variation in Te. Therefore, the utility of using common coefficient estimates to predict future crop yield loss from foxtail interference between years or among locations within a region is limited

Stability of corn (\u3ci\u3eZea mays\u3c/i\u3e)- foxtail (\u3ci\u3eSetaria\u3c/i\u3e spp.) interference relationships

Variation in interference relationships have been shown for a number of crop-weed associations and may have an important effect on the implementation of decision support systems for weed management. Multiyear field experiments were conducted at eight locations to determine the stability of corn-foxtail interference relationships across years and locations. Two coefficients (I and A) of a rectangular hyperbola equation were estimated for each data set using nonlinear regression procedures. The I and A coefficients represent percent corn yield loss as foxtail density approaches zero and maximum percent corn yield loss, respectively. The coefficient I was stable across years at two locations and varied across years at four locations. Maximum yield loss (A) varied between years at one location. Both coefficients varied among locations. Although 3 to 4 foxtail plants m-1 row was a conservative estimate of the single-year economic threshold (Te) of foxtail density, variation in I and A resulted in a large variation in Te. Therefore, the utility of using common coefficient estimates to predict future crop yield loss from foxtail interference between years or among locations within a region is limited

Folate receptor-β imaging using 99mTc-folate to explore distribution of polarized macrophage populations in human atherosclerotic plaque

UNLABELLED: In atherosclerotic plaques, the risk of rupture is increased at sites of macrophage accumulation. Activated macrophages express folate receptor-β (FR-β), which can be targeted by folate coupled to radioactive ligands to visualize vulnerability. The aim of this study was to explore the presence of activated macrophages in human atherosclerotic plaques by (99m)Tc-folate imaging and to evaluate whether this technique can discriminate between an M1-like and M2-like macrophage phenotype. METHODS: Carotid endarterectomy specimens of 20 patients were incubated with (99m)Tc-folate, imaged using micro-SPECT, and divided into 3-mm slices. The mean accumulation was calculated per slice, and the distribution of M1-like and M2-like macrophages per slice was quantified by immunohistochemical staining for CD86 as well as inducible nitric oxide synthase (iNOS) for M1 and CD163 and FR-β for M2 macrophages. Monocytes from healthy donors were differentiated toward M1-like or M2-like phenotype by in vitro culturing. Messenger RNA levels of specific M1 and M2 markers were measured by reverse-transcription polymerase chain reaction and expression of FR-β, CD86, and CD163 by flow cytometry. RESULTS: There was a heterogeneous accumulation of (99m)Tc-folate in plaques (median, 2.45 [0.77-6.40] MBq/g). Slices with the highest (99m)Tc-folate accumulation of each plaque showed significantly more expression of FR-β and CD163, compared with slices with the lowest (99m)Tc-folate accumulation, which showed significantly more expression of iNOS. In in vitro polarized macrophages, messenger RNA expression of FR-β, mannose receptor, IL-10, and matrix metalloproteinase-9 was significantly increased in M2-like macrophages, compared with M1-like macrophages. On a receptor level, CD86 was shown to be overexpressed on M1-like macrophages whereas FR-β and CD163 were overexpressed on M2-like macrophages measured by flow cytometry. CONCLUSION: Higher numbers of M2-like macrophages were present in areas of high (99m)Tc-folate accumulation than areas with low accumulation. It is anticipated that (99m)Tc-folate imaging using SPECT as a marker for M2-like macrophages in atherosclerosis might be a good indicator for plaque vulnerability

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Phage Encoded H-NS: A Potential Achilles Heel in the Bacterial Defence System

The relationship between phage and their microbial hosts is difficult to elucidate in complex natural ecosystems. Engineered systems performing enhanced biological phosphorus removal (EBPR), offer stable, lower complexity communities for studying phage-host interactions. Here, metagenomic data from an EBPR reactor dominated by Candidatus Accumulibacter phosphatis (CAP), led to the recovery of three complete and six partial phage genomes. Heat-stable nucleoid structuring (H-NS) protein, a global transcriptional repressor in bacteria, was identified in one of the complete phage genomes (EPV1), and was most similar to a homolog in CAP. We infer that EPV1 is a CAP-specific phage and has the potential to repress up to 6% of host genes based on the presence of putative H-NS binding sites in the CAP genome. These genes include CRISPR associated proteins and a Type III restriction-modification system, which are key host defense mechanisms against phage infection. Further, EPV1 was the only member of the phage community found in an EBPR microbial metagenome collected seven months prior. We propose that EPV1 laterally acquired H-NS from CAP providing it with a means to reduce bacterial defenses, a selective advantage over other phage in the EBPR system. Phage encoded H-NS could constitute a previously unrecognized weapon in the phage-host arms race

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE