Formation of the Acyl Chain within the Alkamides

poster abstractEchinacea, a coneflower species that is native to North America, are the most consumed medicinal plants in the United States and Europe. Their medicinal usage focuses on the treatment and prevention of colds, influenza, and other upper respiratory tract infections. In part, the traditional medicinal uses of Echinacea are attributed to their alkamide content. Structurally alkamides consist of an amine moiety acylated with a variety of fatty acids. To better describe the biosynthetic process leading to the formation of acyl chains within alkamides of Echinacea purpurea, stable isotope labeling experiments with analysis via LC/MS and NMR was undertaken. As previously reported from our lab, the acyl chains of alkamides are synthesized from fatty acid synthesis via HSQC NMR analysis of a tetraenoic isobutyl amide alkamide. As part of our continuing efforts to probe the acyl chain biosynthesis within E. purpurea, we herein report the HSQC NMR analysis of a proposed dienoic isobutyl amide alkamide that was labeled with a 70/30 [U-12C6]/[U-13C6]glucose mixture. The magnitude of 13C-13C one-bond coupling observed by NMR will allow for incorporation patterns to be determined and will help to elucidate the structure and biogenesis of this dienoic isobutyl amide alkamide

Human epidermal growth factor receptor bispecific ligand trap RB200: abrogation of collagen-induced arthritis in combination with tumour necrosis factor blockade

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic disease associated with inflammation and destruction of bone and cartilage. Although inhibition of TNFα is widely used to treat RA, a significant number of patients do not respond to TNFα blockade, and therefore there is a compelling need to continue to identify alternative therapeutic strategies for treating chronic inflammatory diseases such as RA. The anti-epidermal growth factor (anti-EGF) receptor antibody trastuzumab has revolutionised the treatment of patients with EGF receptor-positive breast cancer. Expression of EGF ligands and receptors (known as HER) has also been documented in RA. The highly unique compound RB200 is a bispecific ligand trap that is composed of full-length extracellular domains of HER1 and HER3 EGF receptors. Because of its pan-HER specificity, RB200 inhibits responses mediated by HER1, HER2 and HER3 in vitro and in vivo. The objective of this study was to assess the effect of RB200 combined with TNF blockade in a murine collagen-induced arthritis (CIA) model of RA. METHODS: Arthritic mice were treated with RB200 alone or in combination with the TNF receptor fusion protein etanercept. We performed immunohistochemistry to assess CD31 and in vivo fluorescent imaging using anti-E-selectin antibody labelled with fluorescent dye to elucidate the effect of RB200 on the vasculature in CIA. RESULTS: RB200 significantly abrogated CIA by reducing paw swelling and clinical scores. Importantly, low-dose RB200 combined with a suboptimal dose of etanercept led to complete abrogation of arthritis. Moreover, the combination of RB200 with etanercept abrogated the intensity of the E-selectin-targeted signal to the level seen in control animals not immunised to CIA. CONCLUSIONS: The human pan-EGF receptor bispecific ligand trap RB200, when combined with low-dose etanercept, abrogates CIA, suggesting that inhibition of events downstream of EGF receptor activation, in combination with TNFα inhibitors, may hold promise as a future therapy for patients with RA

Sensitivity Analysis of Cirrus Cloud Properties from High-Resolution Infrared Spectra. Part I: Methodology and Synthetic Cirrus

A set of simulated high-resolution infrared (IR) emission spectra of synthetic cirrus clouds is used to perform a sensitivity analysis of top-of-atmosphere (TOA) radiance to cloud parameters. Principal component analysis (PCA) is applied to assess the variability of radiance across the spectrum with respect to microphysical and bulk cloud quantities. These quantities include particle shape, effective radius (reff), ice water path (IWP), cloud height Zcld and thickness ΔZcld, and vertical profiles of temperature T(z) and water vapor mixing ratio w(z). It is shown that IWP variations in simulated cloud cover dominate TOA radiance variability. Cloud height and thickness, as well as T(z) variations, also contribute to considerable TOA radiance variability. The empirical orthogonal functions (EOFs) of radiance variability show both similarities and differences in spectral shape and magnitude of variability when one physical quantity or another is being modified. In certain cases, it is possible to identify the EOF that represents variability with respect to one or more physical quantities. In other instances, similar EOFs result from different sets of physical quantities, emphasizing the need for multiple, independent data sources to retrieve cloud parameters. When analyzing a set of simulated spectra that include joint variations of IWP, reff, and w(z) across a realistic range of values, the first two EOFs capture approximately 92%–97% and 2%–6% of the total variance, respectively; they reflect the combined effect of IWP and reff. The third EOF accounts for only 1%–2% of the variance and resembles the EOF from analysis of spectra where only w(z) changes. Sensitivity with respect to particle size increases significantly for reff several tens of microns or less. For small-particle reff, the sensitivity with respect to the joint variation of IWP, reff, and w(z) is well approximated by the sum of the sensitivities with respect to variations in each of three quantities separately

Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis

INTRODUCTION: Despite the advent of biological therapies for the treatment of rheumatoid arthritis, there is a compelling need to develop alternative therapeutic targets for nonresponders to existing treatments. Soluble receptors occur naturally in vivo, such as the splice variant of the cell surface receptor for vascular endothelial growth factor (VEGF)--a key regulator of angiogenesis in rheumatoid arthritis. Bioinformatics analyses predict that the majority of human genes undergo alternative splicing, generating proteins--many of which may have regulatory functions. The objective of the present study was to identify alternative splice variants (ASV) from cell surface receptor genes, and to determine whether the novel proteins encoded exert therapeutic activity in an in vivo model of arthritis. METHODS: To identify novel splice variants, we performed RT-PCR using an mRNA pool representing major human tissue types and tumors. Novel ASV were identified by alignment of each cloned sequence to its respective genomic sequence in comparison with full-length transcripts. To test whether these ASV have biologic activity, we characterized a subset of them for ligand binding, and for efficacy in an animal model of arthritis. The in vivo study was accomplished using adenoviruses expressing secreted ASV. RESULTS: We cloned 60 novel human ASV from 21 genes, encoding cell surface receptors--many of which are known to be important in the regulation of angiogenesis. The ASV were characterized by exon extension, intron retention and alternative exon utilization. Efficient expression and secretion of selected ASV--corresponding to VEGF receptor type 1, VEGF receptor type 2, VEGF receptor type 3, angiopoietin receptor Tie1, Met (receptor for hepatocyte growth factor), colony-stimulating factor 1 receptor, platelet-derived growth factor receptor beta, fibroblast growth factor receptor 1, Kit, and RAGE--was demonstrated, together with binding to their cognate ligands. Importantly, ASV derived from VEGF receptor type 1 and Tie1, and to a lesser extent from VEGF receptor type 2 and fibroblast growth factor receptor 1, reduced clinical signs of arthritis in vivo. The reduction was paralleled by decreased joint inflammation and destruction. CONCLUSION: The present study shows that unique ASV derived from receptors that play key roles in angiogenesis--namely, VEGF receptor type 1 and, for the first time, Tie1--can markedly reduce arthritis severity. More broadly, our results demonstrate that ASV are a source of novel proteins with therapeutic potential in diseases in which angiogenesis and cellular hyperplasia play a central role, such as rheumatoid arthritis

Rapidly Changing Range Limits in a Warming World: Critical Data Limitations and Knowledge Gaps for Advancing Understanding of Mangrove Range Dynamics in the Southeastern USA

Climate change is altering species’ range limits and transforming ecosystems. For example, warming temperatures are leading to the range expansion of tropical, cold-sensitive species at the expense of their cold-tolerant counterparts. In some temperate and subtropical coastal wetlands, warming winters are enabling mangrove forest encroachment into salt marsh, which is a major regime shift that has significant ecological and societal ramifications. Here, we synthesized existing data and expert knowledge to assess the distribution of mangroves near rapidly changing range limits in the southeastern USA. We used expert elicitation to identify data limitations and highlight knowledge gaps for advancing understanding of past, current, and future range dynamics. Mangroves near poleward range limits are often shorter, wider, and more shrublike compared to their tropical counterparts that grow as tall forests in freeze-free, resource-rich environments. The northern range limits of mangroves in the southeastern USA are particularly dynamic and climate sensitive due to abundance of suitable coastal wetland habitat and the exposure of mangroves to winter temperature extremes that are much colder than comparable range limits on other continents. Thus, there is need for methodological refinements and improved spatiotemporal data regarding changes in mangrove structure and abundance near northern range limits in the southeastern USA. Advancing understanding of rapidly changing range limits is critical for foundation plant species such as mangroves, as it provides a basis for anticipating and preparing for the cascading effects of climate-induced species redistribution on ecosystems and the human communities that depend on their ecosystem services

Detection of the spotted wing drosophila, Drosophila suzukii, in continental sub-Saharan Africa

The spotted wing drosophila, Drosophila suzukii Matsumura, is an insect pest of soft-skinned fruit, native to Eastern Asia. Since 2008, a world-wide dispersal of D. suzukii is seen, characterized by the establishment of the pest in many Asian, American and European countries. While the potential for invasion of continental Africa by D. suzukii has been predicted, its presence has only been shown for Morocco in Northern Africa. Knowledge about a possible establishment in other parts of the continent is needed as a basis for pest management. In 2019, we carried out a first survey in three counties in Kenya to monitor for the presence of D. suzukii using traps baited with a blend of apple cider vinegar and red wine. A total of 389 D. suzukii flies were captured in a fruit farm at Nakuru county, with more female flies being trapped than males. We confirmed the morphological identification of D. suzukii using DNA barcoding. In 2020, we performed a follow-up survey at 14 locations in six counties to delimit the distribution of D. suzukii in the main berry growing zones in Kenya. The survey indicated that so far D. suzukii is restricted to Nakuru county where it was initially detected. This is the first study to provide empirical evidence of D. suzukii in continental sub-Saharan Africa, confirming that the pest is expanding its geographic range intercontinentally. Given the high dispersal potential of D. suzukii, a concerted effort to develop management strategies is a necessity for containment of the pest

Leaf processing behaviour in Atta leafcutter ants: 90% of leaf cutting takes place inside the nest, and ants select pieces that require less cutting

Leafcutter ants cut trimmings from plants, carry them to their underground nests and cut them into smaller pieces before inoculating them with a fungus that serves as a primary food source for the colony. Cutting is energetically costly, so the amount of cutting is important in understanding foraging energetics. Estimates of the cutting density, metres of cutting per square metre of leaf, were made from samples of transported leaf cuttings and of fungal substrate from field colonies of Atta cephalotes and Atta colombica. To investigate cutting inside the nest, we made leaf-processing observations of our laboratory colony, A. cephalotes. We did not observe the commonly reported reduction of the leaf fragments into a pulp, which would greatly increase the energy cost of processing. Video clips of processing behaviours, including behaviours that have not previously been described, are linked. An estimated 2.9 (±0.3) km of cutting with mandibles was required to reduce a square metre of leaf to fungal substrate. Only about 12% (±1%) of this cutting took place outside of the nest. The cutting density and energy cost is lower for leaf material with higher ratios of perimeter to area, so we tested for, and found that the laboratory ants had a preference for leaves that were pre-cut into smaller pieces. Estimates suggest that the energy required to transport and cut up the leaf material is comparable to the metabolic energy available from the fungus grown on the leaves, and so conservation of energy is likely to be a particularly strong selective pressure for leafcutter ants.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by The Royal Society. The published article can be found at: http://rsos.royalsocietypublishing.org/Keywords: foraging, leaf processing, energetics, metabolic energy, Atta, leafcutter ant

Rapidly Changing Range Limits in a Warming World: Critical Data Limitations and Knowledge Gaps for Advancing Understanding of Mangrove Range Dynamics in the Southeastern USA

Climate change is altering species’ range limits and transforming ecosystems. For example, warming temperatures are leading to the range expansion of tropical, cold-sensitive species at the expense of their cold-tolerant counterparts. In some temperate and subtropical coastal wetlands, warming winters are enabling mangrove forest encroachment into salt marsh, which is a major regime shift that has significant ecological and societal ramifications. Here, we synthesized existing data and expert knowledge to assess the distribution of mangroves near rapidly changing range limits in the southeastern USA. We used expert elicitation to identify data limitations and highlight knowledge gaps for advancing understanding of past, current, and future range dynamics. Mangroves near poleward range limits are often shorter, wider, and more shrublike compared to their tropical counterparts that grow as tall forests in freeze-free, resource-rich environments. The northern range limits of mangroves in the southeastern USA are particularly dynamic and climate sensitive due to abundance of suitable coastal wetland habitat and the exposure of mangroves to winter temperature extremes that are much colder than comparable range limits on other continents. Thus, there is need for methodological refinements and improved spatiotemporal data regarding changes in mangrove structure and abundance near northern range limits in the southeastern USA. Advancing understanding of rapidly changing range limits is critical for foundation plant species such as mangroves, as it provides a basis for anticipating and preparing for the cascading effects of climate-induced species redistribution on ecosystems and the human communities that depend on their ecosystem services

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500