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Context: The authors hypothesized that in people with hip-related groin pain, less static ankle dorsiflexion could lead to compensatory hip adduction and contralateral pelvic drop during step-down. Ankle dorsiflexion may be a modifiable factor to improve ability in those with hip-related groin pain to decrease hip/pelvic motion during functional tasks and improve function., Objective: To determine whether smaller static ankle dorsiflexion angles were associated with altered ankle, hip, and pelvis kinematics during step-down in people with hip-related groin pain., Design: Cross-sectional Setting: Academic medical center., Patients: A total of 30 people with hip-related groin pain (12 males and 18 females; 28.7 [5.3] y) participated., Intervention: None., Main Outcome Measures: Weight-bearing static ankle dorsiflexion with knee flexed and knee extended were measured via digital inclinometer. Pelvis, hip, and ankle kinematics during forward step-down were measured via 3D motion capture. Static ankle dorsiflexion and kinematics were compared with bivariate correlations., Results: Smaller static ankle dorsiflexion angles were associated with smaller ankle dorsiflexion angles during the step-down for both the knee flexed and knee extended static measures. Among the total sample, smaller static ankle dorsiflexion angle with knee flexed was associated with greater anterior pelvic tilt and greater contralateral pelvic drop during the step-down. Among only those who did not require a lowered step for safety, smaller static ankle dorsiflexion angles with knee flexed and knee extended were associated with greater anterior pelvic tilt, greater contralateral pelvic drop, and greater hip flexion., Conclusions: Among those with hip-related groin pain, smaller static ankle dorsiflexion angles are associated with less ankle dorsiflexion motion and altered pelvis and hip kinematics during a step-down. Future research is needed to assess the effect of treating restricted ankle dorsiflexion on quality of motion and symptoms in patients with hip-related groin pain.

The fruit fly Drosophila is a prime model in circadian research, but still little is known about its circadian regulation of metabolism. Daily rhythmicity in levels of several metabolites has been found, but knowledge about hydrophobic metabolites is limited. We here compared metabolite levels including lipids between period 01 (per 01 ) clock mutants and Canton-S wildtype (WT CS ) flies in an isogenic and non-isogenic background using LC-MS. In the non-isogenic background, metabolites with differing levels comprised essential amino acids, kynurenines, pterinates, glycero(phospho)lipids, and fatty acid esters. Notably, detectable diacylglycerols (DAG) and acylcarnitines (AC), involved in lipid metabolism, showed lower levels in per 01 mutants. Most of these differences disappeared in the isogenic background, yet the level differences for AC as well as DAG were consistent for fly bodies. AC levels were dependent on the time of day in WT CS in phase with food consumption under LD conditions, while DAGs showed weak daily oscillations. Two short-chain ACs continued to cycle even in constant darkness. per 01 mutants in LD showed no or very weak diel AC oscillations out of phase with feeding activity. The low levels of DAGs and ACs in per 01 did not correlate with lower total food consumption, body mass or weight. Clock mutant flies showed higher sensitivity to starvation independent of their background-dependent activity level. Our results suggest that neither feeding, energy storage nor mobilisation is significantly affected in per 01 mutants, but point towards impaired mitochondrial activity, supported by upregulation of the mitochondrial stress marker 4EBP in the clock mutants.

The plant hormone jasmonoyl-isoleucine (JA-Ile) is an important regulator of plant growth and defense in response to various biotic and abiotic stress cues. Under our experimental conditions, JA-Ile levels increased approximately seven-fold in NaCl-treated Arabidopsis thaliana roots. Although these levels were around 1000-fold lower than in wounded leaves, genes of the JA-Ile signaling pathway were induced by a factor of 100 or more. Induction was severely compromised in plants lacking the JA-Ile receptor CORONATINE INSENSITIVE 1 or enzymes required for JA-Ile biosynthesis. To explain efficient gene expression at very low JA-Ile levels, we hypothesized that salt-induced expression of the JA/JA-Ile transporter JAT1/AtABCG16 would lead to increased nuclear levels of JA-Ile. However, mutant plants with different jat1 alleles were similar to wild-type ones with respect to salt-induced gene expression. The mechanism that allows COI1-dependent gene expression at very low JA-Ile levels remains to be elucidated.

The authors wish to make the following correction to this paper [...].

Mycotoxins in agriculturally used plants can cause intoxication in animals and can lead to severe financial losses for farmers. The endophytic fungus Epichloë festucae var. lolii living symbiotically within the cool season grass species Lolium perenne can produce vertebrate and invertebrate toxic alkaloids. Hence, an exact quantitation of alkaloid concentrations is essential to determine intoxication risk for animals. Many studies use different methods to detect alkaloid concentrations, which complicates the comparability. In this study, we showed that alkaloid concentrations of individual plants exceeded toxicity thresholds on real world grasslands in Germany, but not on the population level. Alkaloid concentrations on five German grasslands with high alkaloid levels peaked in summer but were also below toxicity thresholds on population level. Furthermore, we showed that alkaloid concentrations follow the same seasonal trend, regardless of whether plant fresh or dry weight was used, in the field and in a common garden study. However, alkaloid concentrations were around three times higher when detected with dry weight. Finally, we showed that alkaloid concentrations can additionally be biased to different alkaloid detection methods. We highlight that toxicity risks should be analyzed using plant dry weight, but concentration trends of fresh weight are reliable.

Introduction: Diabetes mellitus (DM) is associated with systemic musculoskeletal system impairments suggesting concurrent development of lower and upper extremity musculoskeletal problems. This study aims to examine relationships between lower and upper extremity function in people with DM., Methods: Sixty people with type 2 DM and peripheral neuropathy [mean (standard deviation); 67(6) years old, DM duration 14(10) yrs] completed the following measures: 1) Self-reports of function: Foot and Ankle Ability Measure (FAAM; higher = better function) and Shoulder Pain and Disability Index (SPADI; lower = better function), 2) Range of motion (goniometry): ankle dorsiflexion and shoulder flexion, and 3) Strength: unilateral heel rise power (UHR, 3D kinetics) and hand grip dynamometry. Pearson correlations examined associations between lower and upper extremity measures, p < .05., Results: Forty of 60 (67%) reported pain/disability in both the foot/ankle and shoulder and 95% of study participants had some limitation in foot or shoulder function. Significant between extremity correlations: FAAM and SPADI (r = -0.39), ankle dorsiflexion and shoulder flexion range of motion (r = 0.35), and UHR and hand grip strength (r = 0.40). Significant within extremity correlations: FAAM and UHR (r = .47) and SPADI with shoulder flexion (r = -0.44)., Conclusion: Upper and lower extremity inter- and intra-relationships indicate systemic musculoskeletal impairments in people with DM. Healthcare practitioners should consider the potential for concurrent and disabling musculoskeletal problems in people with DM., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The present study evaluates the chemical composition of Zinnia elegans and Gazania rigens based on their metabolomic profiles using liquid chromatography coupled with high-resolution mass spectrometry (LC-HR-MS), alongside with the anti-infective activities of their ethanol extracts, as well as, different fractions. A significant difference was observed between the LC-MS profiles of the two plants such as, coumarins, sesquiterpene lactones and phenylethanoids which were characteristic for Z. elegans , while amides and phenolic acid derivatives were characteristic for G. rigens . These results highlight the chemical potential of Z. elegans and G. rigens. Furthermore, the ethyl acetate fraction of Z. elegans showed a significant antimalarial activity with IC 50 values of 21.03 and 13.72 µg/mL against Plasmodium falciparum D 6 and P. falciparum W 2 , respectively.

In Brassicaceae, tissue damage triggers the mustard oil bomb i.e., activates the degradation of glucosinolates by myrosinases leading to a rapid accumulation of isothiocyanates at the site of damage. Isothiocyanates are reactive electrophilic species (RES) known to covalently bind to thiols in proteins and glutathione, a process that is not only toxic to herbivores and microbes but can also cause cell death of healthy plant tissues. Previously, it has been shown that subtoxic isothiocyanate concentrations can induce transcriptional reprogramming in intact plant cells. Glutathione depletion by RES leading to breakdown of the redox potential has been proposed as a central and common RES signal transduction mechanism. Using transcriptome analyses, we show that after exposure of Arabidopsis seedlings (grown in liquid culture) to subtoxic concentrations of sulforaphane hundreds of genes were regulated without depletion of the cellular glutathione pool. Heat shock genes were among the most highly up-regulated genes and this response was found to be dependent on the canonical heat shock factors A1 (HSFA1). HSFA1-deficient plants were more sensitive to isothiocyanates than wild type plants. Moreover, pretreatment of Arabidopsis seedlings with subtoxic concentrations of isothiocyanates increased resistance against exposure to toxic levels of isothiocyanates and, hence, may reduce the autotoxicity of the mustard oil bomb by inducing cell protection mechanisms., (Copyright © 2020 Ferber, Gerhards, Sauer, Krischke, Dittrich, Müller, Berger, Fekete and Mueller.)

Background: Hepatitis C virus (HCV) infection is a major cause of hepatic diseases all over the world. This necessitates the need to discover novel anti-HCV drugs to overcome emerging drug resistance and liver complications., Purpose: Total extract and petroleum ether fraction of the marine sponge ( Amphimedon spp.) were used for silver nanoparticle (SNP) synthesis to explore their HCV NS3 helicase- and protease-inhibitory potential., Methods: Characterization of the prepared SNPs was carried out with ultraviolet-visible spectroscopy, transmission electron microscopy, and Fourier-transform infrared spectroscopy. The metabolomic profile of different Amphimedon fractions was assessed using liquid chromatography coupled with high-resolution mass spectrometry. Fourteen known compounds were isolated and their HCV helicase and protease activities assessed using in silico modeling of their interaction with both HCV protease and helicase enzymes to reveal their anti-HCV mechanism of action. In vitro anti-HCV activity against HCV NS3 helicase and protease was then conducted to validate the computation results and compared to that of the SNPs., Results: Transmission electron-microscopy analysis of NPs prepared from Amphimedon total extract and petroleum ether revealed particle sizes of 8.22-14.30 nm and 8.22-9.97 nm, and absorption bands at λ max of 450 and 415 nm, respectively. Metabolomic profiling revealed the richness of Amphimedon spp. with different phytochemical classes. Bioassay-guided isolation resulted in the isolation of 14 known compounds with anti-HCV activity, initially revealed by docking studies. In vitro anti-HCV NS3 helicase and protease assays of both isolated compounds and NPs further confirmed the computational results., Conclusion: Our findings indicate that Amphimedon , total extract, petroleum ether fraction, and derived NPs are promising biosources for providing anti-HCV drug candidates, with nakinadine B and 3,4-dihydro-6-hydroxymanzamine A the most potent anti-HCV agents, possessing good oral bioavailability and penetration power., Competing Interests: Professor Dr Ronald J Quinn reports grants from the Australian Research Council during the conduct of the study. The authors declare that they have no other conflicts of interest., (© 2020 Shady et al.)

Objective: Describe the proportional occurrence of visually determined, lower extremity movement patterns (dynamic knee valgus [DKVal], neutral [NEU], dynamic knee varus [DKVar]) during a single leg squat (SLSquat) among patients with chronic hip joint pain (CHJP). Compare 3D hip and pelvic kinematics among the categories and determine whether within-session movement pattern changes are possible among those who demonstrate DKVal or DKVar. Design: Cross-sectional. Setting: Movement science laboratory. Participants: 36 patients with CHJP (18 to 40 years). Main Outcome Measures: Visually based classification of lower extremity movement and 3D kinematic angles of hip and pelvis during SLSquat, performed under usual (self-selected) and modified (therapist instruction) conditions. Results: Based on visual appraisal, 14 patients demonstrated DKVal, 22 demonstrated NEU and none demonstrated DKVar. Those with DKVal demonstrated greater hip adduction (23.5 + 5.7º vs. 16.0 + 5.7º, p  < 0.001) and internal rotation (7.4 + 7.1º vs. 1.6 + 7.0º, p  = 0.023) than those with NEU. Compared to the usual condition, the DKVal group demonstrated significant decrease in hip adduction (23.5 + 5.7° vs. 20.9 + 5.8°, p  = 0.001) and internal rotation (7.4 + 7.1° vs. 5.3 + 7.8°, p  = .050) in the modified condition. Conclusions: Patients with CHJP demonstrated 2 movement patterns, DKVal and NEU. Compared to NEU, those with DKVal demonstrated greater hip adduction and internal rotation motion and were able to make small modifications to their movement pattern with therapist instruction.

Objective: To compare 3-D hip kinematics during the single-leg squat and step-down in patients with hip-related groin pain to those in asymptomatic participants, and to assess relationships among hip kinematics, muscle strength, and bony morphology., Design: Controlled laboratory cross-sectional study., Methods: Forty patients with hip-related groin pain and 40 matched, asymptomatic participants between 18 and 40 years of age participated. A handheld dynamometer was used to assess hip abductor and external rotator strength. An 8-camera motion-analysis system was used to quantify 3-D kinematics during the single-leg squat and step-down. Magnetic resonance imaging was used to quantify bony morphology. The independent t test and Mann-Whitney U test were used to assess between-group differences. Pearson coefficient correlations were used to assess relationships., Results: Patients with hip-related groin pain had smaller peak hip flexion angles, smaller knee flexion angles, and lesser squat depth compared to asymptomatic participants during the single-leg squat. Among patients with hip-related groin pain, smaller hip flexion angles during the single-leg squat were associated with hip abductor weakness ( r = 0.47, P ≤.01). Among asymptomatic participants, smaller peak hip flexion angles during the single-leg squat were associated with less acetabular coverage ( r = 0.33, P = .04) and shallow squat depth ( r = 0.48, P ≤.01); a smaller hip internal rotation angle during the step-down was associated with larger femoral neck shaft angle ( r = -0.43, P <.01)., Conclusion: Compared to asymptomatic participants, patients with hip-related groin pain had smaller hip and knee flexion angles and shallower squat depth during the single-leg squat. Smaller hip flexion angles were associated with hip abductor weakness among those with hip-related groin pain. J Orthop Sports Phys Ther 2020;50(5):243-251. Epub 6 Jan 2020. doi:10.2519/jospt.2020.9150 .

The underlying factors contributing to metatarsophalangeal joint deformity, a known precursor to skin breakdown in individuals with diabetes mellitus (DM), is likely to involve multiple body systems. The purpose of this cross-sectional study was to identify multi-system factors associated with metatarsophalangeal joint deformity in individuals with type 2 DM and peripheral neuropathy ( n = 60). Metatarsophalangeal joint deformity was quantified with a computed tomography (CT) scan. System biomarkers included the musculoskeletal system (foot intrinsic muscle deterioration, tarsal/metatarsal bone mineral density, ankle dorsiflexion, metatarsophalangeal extension movement during a sit to stand task); the vascular system (ankle-brachial index); and the endocrine/immune systems (high sensitivity C-reactive protein, skin intrinsic fluorescence, and hemoglobin A1C). Muscle deterioration ( r = 0.27), bone density ( r = -0.35), metatarsophalangeal extension movement ( r = 0.50), maximum dorsiflexion ( r = -0.31), and ankle-brachial index ( r = 0.33) were related to metatarsophalangeal joint deformity ( p < 0.05). Bone mineral density and metatarsophalangeal extension movement were retained in a regression model relating to deformity ( R 2 = 0.34). All musculoskeletal system biomarkers and the ankle-brachial index demonstrated weak to moderate relationships to metatarsophalangeal joint deformity. Bone mineral density of the tarsal/metatarsal bones and extending the toes during a sit to stand task were the two strongest factors associated with metatarsophalangeal joint deformity. Evaluation and management of foot bone mineral density and toe extension movement pattern could reduce metatarsophalangeal joint deformity and the risk of skin breakdown and subsequent amputation.

Fungal endophytes of the genus Epichloë live symbiotically in cool season grass species and can produce alkaloids toxic to insects and vertebrates, yet reports of intoxication of grazing animals have been rare in Europe in contrast to overseas. However, due to the beneficial resistance traits observed in Epichloë infected grasses, the inclusion of Epichloë in seed mixtures might become increasingly advantageous. Despite the toxicity of fungal alkaloids, European seed mixtures are rarely tested for Epichloë infection and their infection status is unknown for consumers. In this study, we tested 24 commercially available seed mixtures for their infection rates with Epichloë endophytes and measured the concentrations of the alkaloids ergovaline, lolitrem B, paxilline, and peramine. We detected Epichloë infections in six seed mixtures, and four contained vertebrate and insect toxic alkaloids typical for Epichloë festucae var. lolii infecting Lolium perenne . As Epichloë infected seed mixtures can harm livestock, when infected grasses become dominant in the seeded grasslands, we recommend seed producers to test and communicate Epichloë infection status or avoiding Epichloë infected seed mixtures., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Study Design: Pilot, multicentre randomised clinical trial (RCT)., Objectives: Assess viability of performing a definitive RCT and compare preliminary effects of movement pattern training (MoveTrain) and strengthening/flexibility (Standard) to improve function in people with chronic hip-related groin pain (HRGP)., Background: To determine the best physical therapist-led intervention for patients with HRGP, we must understand treatment effects of different treatment modes., Methods: Forty-six patients (17M:29F; 29±5.3 years; body mass index 25.6±6.3 kg/m 2 ) with HRGP were randomised. MoveTrain included task-specific training to optimise biomechanics during daily tasks. Standard included strengthening/flexibility. Treatment included 10 visits/12 weeks and home exercise programme (HEP). Primary outcomes for feasibility were recruitment, retention, treatment adherence and treatment fidelity. Secondary outcomes were patient-reported function (Hip disability and Osteoarthritis Outcome Score (HOOS)), lower extremity kinematics and hip muscle strength., Results: We achieved target recruitment, and retention was excellent (91%). Patient session attendance was high (93%); however, reported HEP adherence (62%) was lower than expected. Physical therapists' adherence to treatment protocols was high (90%). Patients demonstrated high treatment receipt; 91% of exercises performed were rated independent. Both groups demonstrated clinically important improvements in function (HOOS) and muscle strength; however, there were no between-group differences (HOOS subscales, p≥0.13, strength, p≥0.34). Compared with Standard, MoveTrain demonstrated greater reductions in hip adduction (p=0.016) and pelvic drop (p=0.026) during a single leg squat. No adverse events were noted., Conclusion: Our experience in completing this RCT confirmed that a larger, multicentre RCT is feasible and highlighted modifications we will implement to optimise the future RCT., Trial Registration Number: NCT02913222., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The plant endophytic fungus Serendipita indica colonizes roots of a wide range of plant species and can enhance growth and stress resistance of these plants. Due to its ease of axenic cultivation and its broad host plant range including the model plant Arabidopsis thaliana and numerous crop plants, it is widely used as a model fungus to study beneficial fungus-root interactions. In addition, it was suggested to be utilized for commercial applications, e.g. to enhance yield in barley and other species. To produce inoculum, S. indica is mostly cultivated in a complex Hill-Käfer medium (CM medium), however, growth in this medium is slow, and yield of chlamydospores, which are often used for plant root inoculation, is relatively low., Results: We tested and optimized a simple vegetable juice-based medium for an enhanced yield of fungal inoculum. The described vegetable juice (VJ) medium is based on commercially available vegetable juice and is easy to prepare. VJ medium was superior to the currently used CM medium with respect to biomass production in liquid medium and hyphal growth on agar plates. Using solid VJ medium supplemented with sucrose (VJS), a high amount of chlamydospores developed already after 8 days of cultivation, producing significantly more spores than on CM medium. Use of VJ medium is not restricted to S. indica , as it also supported growth of two pathogenic fungi often used in plant pathology experiments: the ascomycete Fusarium graminearum , the causal agent of Fusarium head blight disease on wheat and barley, and Verticillium longisporum , the causal agent of verticillium wilt., Conclusions: The described VJ medium is recommended for streamlined and efficient production of inoculum for the plant endophytic fungus Serendipita indica and might prove superior for the propagation of other fungi for research purposes., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Clinicians and patients face a dilemma in understanding how best to resume walking after a healed diabetic neuropathic ulcer. The objectives of this brief review are to: provide context for the patient's health and mobility status; propose 5 suggestions to safely and effectively progress mobility following a healed foot ulcer; and to consider topics for future research to improve care in this area. Rates of ulcer recurrence and mortality are high, and activity is low following a diabetic foot wound. Medical and rehabilitation approaches have emphasized protection of the insensitive, fragile foot with the hope to prevent subsequent harm to the foot and person. In particular, the 1-2 months following wound unloading and "healing" have the greatest risk for ulcer recurrence. While early protection should be emphasized, a growing body of evidence suggests that over-protection of the foot and limited walking can be harmful, presumably because of the negative effects of prolonged immobility and stress protection. Multiple recent studies report the ability of exercise and walking to have a positive effect on various diabetic foot outcomes without additional harm. Much less is known about how an ulcerated foot can resume walking after the wound is healed. This review integrates available guidelines, evidence, and precautions to suggest advice on how best to resume and progress walking in this population at high risk for ulcer recurrence., (© 2019 John Wiley & Sons Ltd.)

The green synthesis of silver nanoparticles (SNPs) using plant extracts is an eco-friendly method. It is a single step and offers several advantages such as time reducing, cost-effective and environmental non-toxic. Silver nanoparticles are a type of Noble metal nanoparticles and it has tremendous applications in the field of diagnostics, therapeutics, antimicrobial activity, anticancer and neurodegenerative diseases. In the present work, the aqueous extracts of aerial parts of Lampranthus coccineus and Malephora lutea F. Aizoaceae were successfully used for the synthesis of silver nanoparticles. The formation of silver nanoparticles was early detected by a color change from pale yellow to reddish-brown color and was further confirmed by transmission electron microscope (TEM), UV-visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), and energy-dispersive X-ray diffraction (EDX). The TEM analysis of showed spherical nanoparticles with a mean size between 12.86 nm and 28.19 nm and the UV- visible spectroscopy showed λmax of 417 nm, which confirms the presence of nanoparticles. The neuroprotective potential of SNPs was evaluated by assessing the antioxidant and cholinesterase inhibitory activity. Metabolomic profiling was performed on methanolic extracts of L. coccineus and M. lutea and resulted in the identification of 12 compounds, then docking was performed to investigate the possible interaction between the identified compounds and human acetylcholinesterase, butyrylcholinesterase, and glutathione transferase receptor, which are associated with the progress of Alzheimer's disease. Overall our SNPs highlighted its promising potential in terms of anticholinesterase and antioxidant activity as plant-based anti-Alzheimer drug and against oxidative stress., Competing Interests: The authors have declared that no competing interests exist.

Symbiotic Epichloë species are fungal endophytes of cool-season grasses that can produce alkaloids with toxicity to vertebrates and/or invertebrates. Monitoring infections and presence of alkaloids in grasses infected with Epichloë species can provide an estimate of possible intoxication risks for livestock. We sampled 3,046 individuals of 13 different grass species in three regions on 150 study sites in Germany. We determined infection rates and used PCR to identify Epichloë species diversity based on the presence of different alkaloid biosynthesis genes, then confirmed the possible chemotypes with high-performance liquid chromatography (HPLC)/ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) measurements. Infections of Epichloë spp. were found in Festuca pratensis Huds. (81%), Festuca ovina L. aggregate (agg.) (73%), Lolium perenne L. (15%), Festuca rubra L. (15%) and Dactylis glomerata L. (8%). The other eight grass species did not appear to be infected. For the majority of Epichloë -infected L. perenne samples (98%), the alkaloids lolitrem B and peramine were present, but ergovaline was not detected, which was consistent with the genetic evaluation, as dmaW , the gene encoding the first step of the ergot alkaloid biosynthesis pathway, was absent. Epichloë uncinata in F. pratensis produced anti-insect loline compounds. The Epichloë spp. observed in the F. ovina agg. samples showed the greatest level of diversity, and different intermediates of the indole-diterpene pathway could be detected. Epichloë infection rates alone are insufficient to estimate intoxication risks for livestock, as other factors, like the ability of the endophyte to produce the alkaloids, also need to be assessed. IMPORTANCE Severe problems of livestock intoxication from Epichloë -infected forage grasses have been reported from New Zealand, Australia, and the United States, but much less frequently from Europe, and particularly not from Germany. Nevertheless, it is important to monitor infection rates and alkaloids of grasses with Epichloë fungi to estimate possible intoxication risks. Most studies focus on agricultural grass species like Lolium perenne and Festuca arundinacea , but other cool-season grass species can also be infected. We show that in Germany, infection rates and alkaloids differ between grass species and that some of the alkaloids can be toxic to livestock. Changes in grassland management due to changing climate, especially with a shift toward grasslands dominated with Epichloë -infected species such as Lolium perenne , may result in greater numbers of intoxicated livestock in the near future. We therefore suggest regular monitoring of grass species for infections and alkaloids and call for maintaining heterogenous grasslands for livestock., (Copyright © 2019 American Society for Microbiology.)

Background: Impaired foot perfusion is a primary contributor to foot ulcer formation. There is no existing device nor method that can be used to measure local foot perfusion during standardized foot muscle exercise in an MRI environment., Purpose: To develop a new MRI-compatible foot dynamometer and MRI methods to characterize local perfusion in diabetic feet with ulcers., Study Type: Prospective., Population/subjects: Seven participants without diabetes and 10 participants with diabetic foot ulcers., Field Strength/sequence: 3.0T, arterial spin labeling (ASL)., Assessments: Using a new MRI-compatible foot dynamometer, all participants underwent MRI ASL perfusion assessment at rest and during a standardized toe-flexion exercise. The participants without diabetes were scanned twice to assess the reproducibility of perfusion measurements. The absolute perfusion and perfusion reserve values were compared between two groups and between regions near ulcers (peri-ulcer) and away from ulcers (away-ulcer)., Statistical Tests: Bland-Altman methods for the calculation of coefficient of repeatability (CR) and two-sided and unpaired Student's t-test to compare multiple differences., Results: The perfusion reserves measured had the best reproducibility (CR in medial region: 1.6, lateral region: 0.9). The foot perfusion reserve was significantly lower in the participants with diabetes compared with the participants without diabetes (1.34 ± 0.32, 95% confidence interval [CI]: 1.1, 1.58 vs. 1.76 ± 0.31, 95% CI: 1.53, 1.98, P = 0.02). Both peri-ulcer exercise perfusion (8.7 ± 3.9 ml/min/100g) and perfusion reserve (1.07 ± 0.39, 95% CI: 0.78, 1.35) were significantly lower than away-ulcer exercise perfusion (12.7 ± 3.8 ml/min/100g, P = 0.02) and perfusion reserve (1.39 ± 0.37, 95% CI: 1.11, 1.66, P = 0.03), respectively., Data Conclusion: This study demonstrates intravenous contrast-free methods for local perfusion in feet with ulcers by standardized exercise-based MRI. Ischemia regions around foot ulcers can be quantitatively distinguished from normal perfused muscle regions., Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:474-480., (© 2018 International Society for Magnetic Resonance in Medicine.)

Long-chain bases (LCBs), also termed sphingobases, are building blocks of sphingolipids, which make up a significant proportion of the cellular membrane system. They are also bioactive molecules regulating intracellular processes. Elevated levels of LCBs like phytosphingosine and dihydrosphingosine can induce cell death in plants and correlate with programmed cell death (PCD) reactions after pathogen recognition. We investigated the previously hypothesized antagonism between phosphorylated and nonphosphorylated LCBs with respect to cell death in Arabidopsis thaliana. Using HPLC-MS/MS, we determined levels of phosphorylated and nonphosphorylated LCBs after cell death induction by LCB application or by Fumonisin B1 (FB1) treatment. We show that previously reported antagonistic effects of phosphorylated LCBs after simultaneous application with nonphosphorylated LCBs are linked to reduced uptake of nonphosphorylated LCBs into the tissue. Furthermore, phosphorylated LCBs did not antagonize PCD induced by avirulence protein recognition. In a functional approach, we used Arabidopsis lines with perturbed levels of phosphorylated LCBs. In these plants, the degree of FB1-induced cell death did not consistently correlate negatively with levels of phosphorylated LCBs, but positively with levels of major nonphosphorylated LCBs phytosphingosine and dihydrosphingosine. As treatment with phosphorylated LCBs did not antagonize cell death, and elevated in vivo levels of these LCB species did not reduce FB1-induced cell death, we conclude that the hypothesized general cell death-antagonizing effect of phosphorylated LCBs in plant cell death reactions should be rejected. Instead, our time-course analysis of LCB levels during cell death reactions showed a positive correlation between levels of nonphosphorylated LCBs and cell death., (� The Author(s) 2019. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Diffusion tensor imaging (DTI) has been used to characterize calf skeletal muscle architecture., Purpose: To assess the diffusional properties of the calf muscles of subjects with and without diabetes, at rest and during isometric plantarflexion exercise., Study Type: Prospective., Subjects: Twenty-six subjects in two groups: 13 healthy and 13 subjects with type 2 diabetes (DM); each group consisted of seven females and six males., Field Strength/sequence: 3T/2D single-shot spin echo planar imaging., Assessment: Fractional anisotropy (FA), mean diffusivity (MD), diffusion eigenvalues, and fiber tracking indices were obtained from the medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus (SOL) muscles of the calf at rest and during isometric plantarflexion exercise., Statistical Tests: We used a combination of nonparametric (Wilcoxon) and parametric (t-test) statistical assessments., Results: The medial gastrocnemius muscle had more indices with significant differences between the two groups (six indices with P < 0.05) than did the lateral gastrocnemius (three indices with P < 0.05) and soleus muscles (only one index with P < 0.05). While the healthy group showed elevated MD values from rest to exercise (MG = 5.83%, LG = 13.45%, and SOL = 11.68%), the diabetic MD showed higher increases (MG = 19.74%, LG = 29.31%, and SOL = 20.84%) that were different between groups (MG: P = 0.009, LG: P = 0.037, and SOL: P = 0.049)., Data Conclusion: Our results indicate considerable diffusional changes between healthy subjects and subjects with diabetes at rest and during isometric plantarflexion exercise in the calf muscles. The medial gastrocnemius muscle displayed the most diffusion sensitivity to diabetes-related microstructural changes., Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1285-1295., (© 2018 International Society for Magnetic Resonance in Medicine.)

Background: People with diabetes are at high risk for shoulder pain, limited joint mobility, and adhesive capsulitis., Objective: The objective of this study was to evaluate the effects of a shoulder movement intervention (ShoMo) compared to a wellness intervention on the primary outcomes of active shoulder flexion and reported Shoulder Pain and Disability Index (SPADI) measured after intervention and 9 months later., Design: The design was a prospective, randomized, controlled clinical trial., Setting: The setting was a research center at an academic medical center., Participants: Fifty-two participants with type 2 diabetes and shoulder pain or limited motion were randomized to a group receiving ShoMo (N = 27; mean age = 59.3; SD = 7.0) or a group receiving wellness activities (N = 25; mean age = 57.9; SD = 7.7)., Intervention: The ShoMo group received instruction in a progressive, active shoulder movement program. The wellness group received instruction in diabetes management., Measurements: Measurements were made at baseline, after 3 months of intervention, and at 6, 9, and 12 months after baseline., Results: After intervention, the ShoMo group had a 7.2-degree increase in active shoulder flexion compared with the wellness group (95% CI = 0.9-13.5°), but there was no difference at subsequent follow-ups. The ShoMo group showed a 12.7-point improvement in the SPADI score compared to the wellness group after intervention (95% CI = 1.1-24.3), which remained better than the wellness group 9 months later., Limitations: The number of participants and duration of follow-up were inadequate to determine if intervention can help to prevent future severe shoulder problems., Conclusions: A progressive shoulder movement program can have meaningful effects on active motion and symptoms in people with type 2 diabetes and mild-to-moderate shoulder symptoms, with symptom improvement lasting at least 9 months.

Malvaviscus arboreus Cav. is a medicinal plant belonging to family Malvaceae with both ethnomedical and culinary value; however, its phytochemical and biological profiles have been scarcely studied. Accordingly, this work was designed to explore the chemical composition and the hepatoprotective potential of M. arboreus against carbon tetrachloride (CCl4)-induced hepatotoxicity. The total extract of the aerial parts and its derived fractions (petroleum ether, dichloromethane, ethyl acetate, and aqueous) were orally administered to rats for six consecutive days, followed by injection of CCl4 (1:1 v/v, in olive oil, 1.5 ml/kg, i.p.) on the next day. Results showed that the ethyl acetate and dichloromethane fractions significantly alleviated liver injury in rats as indicated by the reduced levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TB), and malondialdehyde (MDA), along with enhancement of the total antioxidant capacities of their livers, with the maximum effects were recorded by the ethyl acetate fraction. Moreover, the protective actions of both fractions were comparable to those of silymarin (100 mg/kg), and have been also substantiated by histopathological evaluations. On the other hand, liquid chromatography-high resolution electrospray ionization mass spectrometry (LC‒HR‒ESI‒MS) metabolomic profiling of the crude extract of M. arboreus aerial parts showed the presence of a variety of phytochemicals, mostly phenolics, whereas the detailed chemical analysis of the most active fraction (i.e. ethyl acetate) resulted in the isolation and identification of six compounds for the first time in the genus, comprising four phenolic acids; β-resorcylic, caffeic, protocatechuic, and 4-hydroxyphenylacetic acids, in addition to two flavonoids; trifolin and astragalin. Such phenolic principles, together with their probable synergistic antioxidant and liver-protecting properties, seem to contribute to the observed hepatoprotective potential of M. arboreus., Competing Interests: The authors have declared that no competing interests exist.

Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance. In this study, we found that pro-survival protein Bcl-2 is upregulated in paclitaxel resistant cells, potentially contributing to chemotherapy resistance. To exploit the increase in Bcl-2 expression for targeting therapy resistance, we investigated the effects of a peptide derived from the nuclear receptor Nur77 that converts Bcl-2 from an anti-apoptotic protein to a pro-apoptotic protein. The Nur77 derived peptide preferentially induced apoptosis in paclitaxel-resistant cancer cells with high expression of Bcl-2. This peptide also induced apoptosis of multidrug resistant H69AR lung cancer cells that express Bcl-2 and inhibited their growth in 3D spheroids. The Nur77 peptide strongly suppressed the growth of paclitaxel-resistant lung cancer cells in a zebrafish xenograft tumor model. Taken together, our data supports a new strategy for treating lung cancers that acquire resistance to chemotherapy through overexpression of Bcl-2., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Reactive electrophile species (RES), including prostaglandins, phytoprostanes and 12-oxo phytodienoic acid (OPDA), activate detoxification responses in plants and animals. However, the pathways leading to the activation of defense reactions related to abiotic or biotic stress as a function of RES formation, accumulation or treatment are poorly understood in plants. Here, the thiol-modification of proteins, including the RES-activated basic region/leucine zipper transcription factor TGA2, was studied. TGA2 contains a single cysteine residue (Cys186) that was covalently modified by reactive cyclopentenones but not required for induction of detoxification genes in response to OPDA or prostaglandin A1. Activation of the glutathione-S-transferase 6 (GST6) promoter was responsive to cyclopentenones but not to unreactive cyclopentanones, including jasmonic acid suggesting that thiol reactivity of RES is important to activate the TGA2-dependent signaling pathway resulting in GST6 activation We show that RES modify thiols in numerous proteins in vivo, however, thiol reactivity alone appears not to be sufficient for biological activity as demonstrated by the failure of several membrane permeable thiol reactive reagents to activate the GST6 promoter.

Study Design Ancillary analysis, time-controlled randomized clinical trial. Background Movement-pattern training (MPT) has been shown to improve function among patients with chronic hip joint pain (CHJP). Objective To determine the association among treatment outcomes and mechanical factors associated with CHJP. Methods Twenty-eight patients with CHJP, 18 to 40 years of age, participated in MPT, either immediately after assessment or after a wait-list period. Movement-pattern training included task-specific training to reduce hip adduction motion during functional tasks and hip muscle strengthening. Hip-specific function was assessed using the Modified Harris Hip Score (MHHS) and Hip disability and Osteoarthritis Outcome Score (HOOS). Three-dimensional kinematic data were used to quantify hip adduction motion, dynamometry to quantify abductor strength, and magnetic resonance imaging to measure femoral head sphericity using the alpha angle. Paired t tests assessed change from pretreatment to posttreatment. Spearman correlations assessed associations. Results There was significant improvement in MHHS and HOOS scores (P≤.02), adduction motion (P = .045), and abductor strength (P = .01) from pretreatment to posttreatment. Reduction in hip adduction motion (r = -0.67, P<.01) and lower body mass index (r = -0.38, P = .049) correlated with MHHS improvement. Alpha angle and abductor strength change were not correlated with change in MHHS or HOOS scores. Conclusion After MPT, patients reported improvements in pain and function that were associated with their ability to reduce hip adduction motion during functional tasks. Level of Evidence Therapy, level 2b. J Orthop Sports Phys Ther 2018;48(4):316-324. doi:10.2519/jospt.2018.7810.

Study Design Secondary analysis, cross-sectional study. Background Chronic hip joint pain (CHJP) can lead to limitations in activity participation, but the musculoskeletal factors associated with the condition are relatively unknown. Understanding the factors associated with CHJP may help develop rehabilitation strategies to improve quality of life of individuals with long-term hip pain. Objectives To compare measures of hip abductor muscle volume and hip abductor muscle strength between women with CHJP and asymptomatic controls. Methods Thirty women, 15 with CHJP and 15 matched asymptomatic controls (age range, 18-40 years), participated in this study. Magnetic resonance imaging was used to determine the volume of the primary hip abductor muscles, consisting of the gluteus medius, gluteus minimus, a small portion of the gluteus maximus, and the tensor fascia latae, within a defined region of interest. Break tests were performed using a handheld dynamometer to assess hip abductor strength. During the strength test, the participant was positioned in sidelying with the involved hip in 15° of abduction. Independent-samples t tests were used to compare muscle volume and strength values between those with CHJP and asymptomatic controls. Results Compared to asymptomatic controls, women with CHJP demonstrated significantly increased gluteal muscle volume (228 ± 40 cm 3 versus 199 ± 29 cm 3 , P = .032), but decreased hip abductor strength (74.6 ± 16.8 Nm versus 93.6 ± 20.2 Nm, P = .009). There were no significant differences in tensor fascia lata muscle volume between the 2 groups (P = .640). Conclusion Women with CHJP appear to have larger gluteal muscle volume, but decreased hip abductor strength, compared to asymptomatic controls. J Orthop Sports Phys Ther 2017;47(12):923-930. Epub 9 Oct 2017. doi:10.2519/jospt.2017.7380.

We previously reported that raloxifene, an estrogen receptor modulator, is also a ligand for the aryl hydrocarbon receptor (AhR). Raloxifene induces apoptosis in estrogen receptor-negative human cancer cells through the AhR. We performed structure-activity studies with seven raloxifene analogs to better understand the structural requirements of raloxifene for induction of AhR-mediated transcriptional activity and apoptosis. We identified Y134 as a raloxifene analog that activates AhR-mediated transcriptional activity and induces apoptosis in MDA-MB-231 human triple negative breast cancer cells. Suppression of AhR expression strongly reduced apoptosis induced by Y134, indicating the requirement of AhR for Y134-induced apoptosis. Y134 also induced apoptosis in hepatoma cells without having an effect on cell cycle regulation. Toxicity testing on zebrafish embryos revealed that Y134 has a significantly better safety profile than raloxifene. Our studies also identified an analog of raloxifene that acts as a partial antagonist of the AhR, and is capable of inhibiting AhR agonist-induced transcriptional activity. We conclude that Y134 is a promising raloxifene analog for further optimization as an anti-cancer agent targeting the AhR., Competing Interests: The authors declare no conflict of interest.

The production of shiga toxin (Stx) is a critical step in the establishment and progress of enterohemorrhagic Escherichia coli (EHEC) infections. The possible release of Stx from dead and dying bacteria, and the risk of resistance development have restricted the usage of antibiotics against EHEC. The chlorinated quaternary ammonium compound, strepthonium A, was isolated from the culture of Streptomyces sp. SBT345 that was cultivated from the Mediterranean sponge Agelas oroides. The structure was elucidated and confirmed by spectroscopic analyses including 1D and 2D NMR, ESI-HRMS, as well as ESI-HRMS 2 . Strepthonium A follows Lipinski's rule of five with respect to its molecular weight, CLogP values and the number of hydrogen acceptors and donors. Verotoxin ELISA assay demonstrated that Strepthonium A reduced the Stx production in EHEC strain EDL933 at 80 μM concentration without growth inhibition. This study demonstrates the potential of strepthonium A in restraining the production of Stx in EHEC infections.

High temperatures rapidly induce a genetically programmed heat-shock response (HSR) that is essential to establish short-term acquired thermotolerance. In addition, an immediate HSR-independent metabolic response is triggered, resulting in an accumulation of unsaturated triacylglycerols (TAGs) in the cytosol. The metabolic processes involved in heat-induced TAG formation in plants and their physiological significance remain to be clarified. Lipidomic analyses of Arabidopsis ( Arabidopsis thaliana ) seedlings indicated that during heat stress, polyunsaturated fatty acids from thylakoid galactolipids are incorporated into cytosolic TAGs. In addition, rapid conversion of plastidic monogalactosyl diacylglycerols (MGDGs) into oligogalactolipids, acylated MGDGs, and diacylglycerols (DAGs), the direct precursor of TAGs, was observed. For TAG synthesis, DAG requires a fatty acid from the acyl-CoA pool or phosphatidylcholine. Since seedlings deficient in PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE1 (PDAT1) were unable to accumulate TAGs after heat stress, phosphatidylcholine appears to be the major fatty acid donor. Results suggest that rapid plastid lipid metabolism drives TAG accumulation during heat stress. PDAT1-mediated TAG accumulation was found to increase heat resistance, since nonacclimated pdat1 mutant seedlings were more sensitive to severe heat stress, as indicated by a more dramatic decline of the maximum efficiency of PSII and lower seedling survival compared to wild-type seedlings. In contrast, nonacclimated trigalactosyldiacylglycerol1 ( tgd1 ) mutants overaccumulating TAGs and oligogalactolipids were more resistant to heat stress. Hence, thylakoid lipid metabolism and TAG formation increases thermotolerance in addition to the genetically encoded HSR., (© 2017 American Society of Plant Biologists. All Rights Reserved.)

Approximately 53 million Americans live with a disability. For decades, the National Institutes of Health (NIH) has been conducting and supporting research to discover new ways to minimize disability and enhance the quality of life of people with disabilities. After the passage of the Americans With Disabilities Act, NIH established the National Center for Medical Rehabilitation Research, with the goal of developing and implementing a rehabilitation research agenda. Currently, 17 institutes and centers at NIH invest more than $500 million per year in rehabilitation research. Recently, the director of NIH, Francis Collins, appointed a Blue Ribbon Panel to evaluate the status of rehabilitation research across institutes and centers. As a follow-up to the work of that panel, NIH recently organized a conference, "Rehabilitation Research at NIH: Moving the Field Forward." This report is a summary of the discussions and proposals that will help guide rehabilitation research at NIH in the near future. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Aim: People with type 2 diabetes (T2DM) have a high incidence of musculoskeletal disorders thought to be influenced by high non-enzymatic advanced glycated end-products (AGEs). The goals of this study were to determine differences in shoulder activity level and AGEs in people with T2DM compared to matched controls, and to determine factors associated with shoulder pain and disability., Methods: Eighty-one participants, T2DM (n=52) and controls (n=29), were examined for magnitude and duration of shoulder activity (measured using accelerometers), skin intrinsic florescence (SIF) as a surrogate measure of AGE level, and the Shoulder Pain and Disability Index (SPADI) as a self-report of shoulder pain and disability., Results: Compared with controls, T2DM participants had 23% less shoulder activity (p=0.01), greater SIF level (3.6±1.7 vs 2.7±0.6AU, p=0.01), less shoulder strength (p<0.05), and the duration of their shoulder activity was moderately associated (r=0.40; p<0.01) with reported shoulder pain and disability. Shoulder pain and disability were not related to SIF level., Conclusions: Persons with T2DM have higher SIF levels and shoulder symptoms and disability indices than controls. Research is needed to determine if a shoulder mobility intervention to increase strength and mobility can help decrease shoulder pain and disability., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Storage of seeds is accompanied by loss of germination and oxidation of storage and membrane lipids. A lipidomic analysis revealed that during natural and artificial aging of Arabidopsis seeds, levels of several diacylglycerols and free fatty acids, such as linoleic acid and linolenic acid as well as free oxidized fatty acids and oxygenated triacylglycerols, increased. Lipids can be oxidized by enzymatic or non-enzymatic processes. In the enzymatic pathway, lipoxygenases (LOXs) catalyze the first oxygenation step of polyunsaturated fatty acids. Analysis of lipid levels in mutants with defects in the two 9-LOX genes revealed that the strong increase in free 9-hydroxy- and 9-keto-fatty acids is dependent on LOX1 but not LOX5. Fatty acid oxidation correlated with an aging-induced decrease of germination, raising the question of whether these oxylipins negatively regulate germination. However, seeds of the lox1 mutant were only slightly more tolerant to aging, indicating that 9-LOX products contribute to but are not the major cause of loss of germination during aging. In contrast to free oxidized fatty acids, accumulation of oxygenated triacylglycerols upon accelerated aging was mainly based on non-enzymatic oxidation of seed storage lipids., (© The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Purpose: Excess lower extremity intermuscular adipose tissue (IMAT), reduced strength, and functional limitations are common in obese individuals with and without diabetes (the former termed diabesity). Individuals with diabesity are particularly susceptible to accelerated sarcopenia, which may be underdiagnosed. The purpose of this study was to determine critical values for leg IMAT volume, plantar flexor (PF) muscle strength, and physical performance that help identify individuals with diabesity who have sarcopenia., Methods: Forty-three age- and sex-matched obese adults were studied: 12 with type 2 diabetes, 21 with diabetes and peripheral neuropathy, and 10 nondiabetic controls. Dual-energy x-ray absorptiometry-derived skeletal muscle index determined classification of sarcopenia. Leg fat (% IMAT), ankle (PF) peak torque, and power while ascending 10 steps, were used as explanators of sarcopenia. Receiver operating curves identified critical values for each explanator individually. Logistic regression models using all 3 explanators, and only PF torque and stair power, were also created. Receiver operating curve analyses identified the predicted probability that maximized each model's sensitivity and specificity. A leave-one-out cross validation was used to simulate the models' performance in an independent sample., Results and Discussion: Thirty-two participants were sarcopenic, and 11 were not. Critical values for individual explanators were 21% IMAT, 68 Nm PF torque, and 441 watts of stair power. Predicted probabilities of .76 and .67 were chosen as the optimal cutoff probabilities for the model combining all 3 explanators, and the model combining PF torque and stair power, respectively. The cross-validation analysis produced an accuracy of 82.4%, using the cutoff probability of .5, and an accuracy of 76.5% using the cutoff of 0.76. The area under the curve for the cross validation receiver operating curve analysis was 0.82. Critical values of leg % IMAT, PF torque, and stair power can classify individuals with diabesity as sarcopenic. The results of the cross validation give us confidence that the sample used in this study was representative of the target population, and suggests models created from this sample may perform well in externally derived data sets., Conclusion: Clinicians may be able to use these critical values to select interventions that specifically target sarcopenia. Measures of % IMAT, PF torque, and stair power may offer a customized alternative to traditional sarcopenic classification systems, which may not be optimally suited to the common impairments among individuals with diabesity.

Climate change leads to phenology shifts of many species. However, not all species shift in parallel, which can desynchronize interspecific interactions. Within trophic cascades, herbivores can be top-down controlled by predators or bottom-up controlled by host plant quality and host symbionts, such as plant-associated micro-organisms. Synchronization of trophic levels is required to prevent insect herbivore (pest) outbreaks. In a common garden experiment, we simulated an earlier arrival time (~2 weeks) of the aphid Rhopalosiphum padi on its host grass Lolium perenne by enhancing the aphid abundance during the colonization period. L. perenne was either uninfected or infected with the endophytic fungus Epichloë festucae var. lolii. The plant symbiotic fungus produces insect deterring alkaloids within the host grass. Throughout the season, we tested the effects of enhanced aphid abundance in spring on aphid predators (top-down) and grass-endophyte (bottom-up) responses. Higher aphid population sizes earlier in the season lead to overall higher aphid abundances, as predator occurrence was independent of aphid abundances on the pots. Nonetheless, after predator occurrence, aphids were controlled within 2 weeks on all pots. Possible bottom-up control of aphids by increased endophyte concentrations occurred time delayed after high herbivore abundances. Endophyte-derived alkaloid concentrations were not significantly affected by enhanced aphid abundance but increased throughout the season. We conclude that phenology shifts in an herbivorous species can desynchronize predator-prey and plant-microorganism interactions and might enhance the probability of pest outbreaks with climate change., Competing Interests: The authors declare that they have no conflict of interest. Data accessibility Data available from the Dryad Digital Repository: http://dx.doi.org/10.5061/dryad.9qt80.

Objective: Overfeeding with a high-fat and/or high-carbohydrate (CHO) diet is known to increase plasma concentrations of endotoxin (lipopolysaccharide [LPS]) that may lead to metabolic disturbances like insulin resistance. The impact of CHO quality (i.e., the glycemic index [GI]) independent of fat intake on metabolic endotoxemia remains unclear. In the present study, the effects of changes in energy balance and GI on plasma endotoxin were studied., Methods: Fifteen healthy young men overconsumed diets containing 65% CHO and 20% fat for 1 week (OF; +50% of energy requirement) followed by 3 weeks of caloric restriction (CR; -50% of energy requirement) and were then randomized to 2 weeks hypercaloric refeeding (RF, +50% of energy requirement) with either a low- or high-GI (40 vs 74) diet., Results: During OF, subjects gained 1.9 ± 0.7 kg body weight (+0.6 ± 0.8% fat mass) followed by a weight loss of 6.1 ± 0.8 kg (-2.0 ± 0.6% fat mass) and weight regain of 4.0 ± 0.6 kg (0.9 ± 0.8% fat mass). Fasting insulin and homeostasis model assessment-insulin resistance (HOMA IR ) increased with OF and RF and decreased with CR, Matsuda ISI decreased by 37% after RF (all p < 0.05). Endotoxin significantly increased by 30.8% with OF and by 24.7% with RF (both p < 0.05), whereas CR normalized endotoxin levels. No difference in endotoxin levels was observed between refeeding a hypercaloric high- or low-GI diet. Changes in endotoxin levels with RF were not related to changes in insulin sensitivity., Conclusion: A hypercaloric diet (OF and RF) increased plasma endotoxin irrespective of GI, whereas a negative energy balance did not reduce endotoxemia. Impaired insulin sensitivity with hypercaloric refeeding on a high-GI diet was not explained by metabolic endotoxemia.

Diabetic peripheral neuropathy (DPN) occurs in more than 50% of people with diabetes and is an important risk factor for skin breakdown, amputation, and reduced physical mobility (ie, walking and stair climbing). Although many beneficial effects of exercise for people with diabetes have been well established, few studies have examined whether exercise provides comparable benefits to people with DPN. Until recently, DPN was considered to be a contraindication for walking or any weight-bearing exercise because of concerns about injuring a person's insensitive feet. These guidelines were recently adjusted, however, after research demonstrated that weight-bearing activities do not increase the risk of foot ulcers in people who have DPN but do not have severe foot deformity. Emerging research has revealed positive adaptations in response to overload stress in these people, including evidence for peripheral neuroplasticity in animal models and early clinical trials. This perspective article reviews the evidence for peripheral neuroplasticity in animal models and early clinical trials, as well as adaptations of the integumentary system and the musculoskeletal system in response to overload stress. These positive adaptations are proposed to promote improved function in people with DPN and to foster the paradigm shift to including weight-bearing exercise for people with DPN. This perspective article also provides specific assessment and treatment recommendations for this important, high-risk group., (© 2017 American Physical Therapy Association.)

Abiotic and biotic stresses are often characterized by an induction of reactive electrophile species (RES) such as the jasmonate 12-oxo-phytodienoic acid (OPDA) or the structurally related phytoprostanes. Previously, RES oxylipins have been shown massively to induce heat-shock-response (HSR) genes including HSP101 chaperones. Moreover, jasmonates have been reported to play a role in basal thermotolerance. We show that representative HSR marker genes are strongly induced by RES oxylipins through the four master regulator transcription factors HSFA1a, b, d, and e essential for short-term adaptation to heat stress in Arabidopsis. When compared with Arabidopsis seedlings treated at the optimal acclimation temperature of 37 °C, the exogenous application of RES oxylipins at 20 °C induced a much weaker induction of HSP101 at both the gene and protein expression levels which, however, was not sufficient to confer short-term acquired thermotolerance. Moreover, jasmonate-deficient mutant lines displayed a wild-type-like HSR and were not compromised in acquiring thermotolerance. Hence, the OPDA- and RES oxylipin-induced HSR is not sufficient to protect seedlings from severe heat stress but may help plants to cope better with stresses associated with protein unfolding by inducing a battery of chaperones in the absence of heat., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Peroxiredoxins are ubiquitous thiol-dependent peroxidases for which chaperone and signaling roles have been reported in various types of organisms in recent years. In plants, the peroxidase function of the two typical plastidial 2-Cys peroxiredoxins (2-Cys PRX A and B) has been highlighted while the other functions, particularly in ROS-dependent signaling pathways, are still elusive notably due to the lack of knowledge of interacting partners. Using an ex vivo approach based on co-immunoprecipitation of leaf extracts from Arabidopsis thaliana wild-type and mutant plants lacking 2-Cys PRX expression followed by mass spectrometry-based proteomics, 158 proteins were found associated with 2-Cys PRXs. Already known partners like thioredoxin-related electron donors (Chloroplastic Drought-induced Stress Protein of 32kDa, Atypical Cysteine Histidine-rich Thioredoxin 2) and enzymes involved in chlorophyll synthesis (Protochlorophyllide OxidoReductase B) or carbon metabolism (Fructose-1,6-BisPhosphatase) were identified, validating the relevance of the approach. Bioinformatic and bibliographic analyses allowed the functional classification of the identified proteins and revealed that more than 40% are localized in plastids. The possible roles of plant 2-Cys PRXs in redox signaling pathways are discussed in relation with the functions of the potential partners notably those involved in redox homeostasis, carbon and amino acid metabolisms as well as chlorophyll biosynthesis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Mammalian phosphoglycolate phosphatase (PGP) is thought to target phosphoglycolate, a 2-deoxyribose fragment derived from the repair of oxidative DNA lesions. However, the physiological role of this activity and the biological function of the DNA damage product phosphoglycolate is unknown. We now show that knockin replacement of murine Pgp with its phosphatase-inactive Pgp D34N mutant is embryonically lethal due to intrauterine growth arrest and developmental delay in midgestation. PGP inactivation attenuated triosephosphate isomerase activity, increased triglyceride levels at the expense of the cellular phosphatidylcholine content, and inhibited cell proliferation. These effects were prevented under hypoxic conditions or by blocking phosphoglycolate release from damaged DNA. Thus, PGP is essential to sustain cell proliferation in the presence of oxygen. Collectively, our findings reveal a previously unknown mechanism coupling a DNA damage repair product to the control of intermediary metabolism and cell proliferation.

Purpose: To develop a noncontrast oximetric angiosome imaging approach to assess skeletal muscle oxygenation in diabetic feet., Materials and Methods: In four healthy and five subjects with diabetes, the feasibility of foot oximetry was examined using a 3T clinical magnetic resonance imaging (MRI) scanner. The subjects' feet were scanned at rest and during a toe-flexion isometric exercise. The oxygen extraction fraction of skeletal muscle was measured using a susceptibility-based MRI method. Our newly developed MR foot oximetric angiosome model was compared with the traditional angiosome model in the assessment of the distribution of oxygen extraction fraction., Results: Using the traditional angiosome during the toe-flexion exercise, the oxygen extraction fraction in the medial foot of healthy subjects increased (4.9 ± 3%) and decreased (-2.7 ± 4.4%) in subjects with diabetes (difference = 7.6%; 95% confidence interval = -13.7 ± 1.4; P = 0.02). Using the oximetric angiosome, the percent difference in the areas of oxygen extraction fraction within the 0.7-1.0 range (expected oxygen extraction fraction during exercise) between rest and exercise was higher in healthy subjects (8 ± 4%) than in subjects with diabetes (4 ± 4%; P = 0.02)., Conclusion: This study demonstrates the feasibility of measuring skeletal muscle oxygen extraction fraction in the foot muscle during a toe-flexion isometric exercise. Instead of assessing oxygen extraction fraction in a foot muscle region linked to a supplying artery (traditional angiosome), the foot oximetric angiosome model assesses oxygen extraction fraction by its different levels in all foot muscle regions and thus may be more appropriate for assessing local ischemia in ulcerated diabetic feet. J. Magn. Reson. Imaging 2016. J. MAGN. RESON. IMAGING 2016;44:940-946., (© 2016 International Society for Magnetic Resonance in Medicine.)

Community-acquired (CA) Staphylococcus aureus cause various diseases even in healthy individuals. Enhanced virulence of CA-strains is partly attributed to increased production of toxins such as phenol-soluble modulins (PSM). The pathogen is internalized efficiently by mammalian host cells and intracellular S. aureus has recently been shown to contribute to disease. Upon internalization, cytotoxic S. aureus strains can disrupt phagosomal membranes and kill host cells in a PSM-dependent manner. However, PSM are not sufficient for these processes. Here we screened for factors required for intracellular S. aureus virulence. We infected escape reporter host cells with strains from an established transposon mutant library and detected phagosomal escape rates using automated microscopy. We thereby, among other factors, identified a non-ribosomal peptide synthetase (NRPS) to be required for efficient phagosomal escape and intracellular survival of S. aureus as well as induction of host cell death. By genetic complementation as well as supplementation with the synthetic NRPS product, the cyclic dipeptide phevalin, wild-type phenotypes were restored. We further demonstrate that the NRPS is contributing to virulence in a mouse pneumonia model. Together, our data illustrate a hitherto unrecognized function of the S. aureus NRPS and its dipeptide product during S. aureus infection., Competing Interests: The authors have declared that no competing interests exist.

Background: Metatarsophalangeal joint (MTPJ) hyperextension deformity is common in people with diabetic neuropathy and a known risk factor for ulceration and amputation. An MTPJ hyperextension movement pattern may contribute to the development of this acquired deformity., Objective: The purpose of this study was to determine, in people with diabetes mellitus and peripheral neuropathy (DM+PN), the ankle and MTPJ ranges of motion that characterize an MTPJ hyperextension movement pattern and its relationship to MTPJ deformity severity. It was hypothesized that severity of MTPJ deformity would be related to limitations in maximum ankle dorsiflexion and increased MTPJ extension during active ankle dorsiflexion movement tasks., Design: A cross-sectional study design was used that included 34 people with DM+PN (mean age=59 years, SD=9)., Methods: Computed tomography and 3-dimensional motion capture analysis were used to measure resting MTPJ angle and intersegmental foot motion during the tasks of ankle dorsiflexion and plantar flexion with the knee extended and flexed to 90 degrees, walking, and sit-to/from-stand., Results: The MTPJ extension movement pattern during all tasks was directly correlated with severity of MTPJ deformity: maximum ankle dorsiflexion with knee extended (r=.35; 95% confidence interval [CI]=.02, .62), with knee flexed (r=.35; 95% CI=0.01, 0.61), during the swing phase of gait (r=.47; 95% CI=0.16, 0.70), during standing up (r=.48; 95% CI=0.17, 0.71), and during sitting down (r=.38; 95% CI=0.05, 0.64). All correlations were statistically significant., Limitations: This study was cross-sectional, and causal relationships cannot be made., Conclusions: A hyperextension MTPJ movement pattern associated with limited ankle dorsiflexion has been characterized in people with diabetic neuropathy. Increased MTPJ extension during movement and functional tasks was correlated with severity of resting MTPJ alignment. Repetition of this movement pattern could be an important factor in the etiology of MTPJ deformity and future risk of ulceration., (© 2016 American Physical Therapy Association.)

Study Design Feasibility randomized clinical trial. Background Rehabilitation may be an appropriate treatment strategy for patients with chronic hip joint pain; however, the evidence related to the effectiveness of rehabilitation is limited. Objectives To assess feasibility of performing a randomized clinical trial to investigate the effectiveness of movement-pattern training (MPT) to improve function in people with chronic hip joint pain. Methods Thirty-five patients with chronic hip joint pain were randomized into a treatment (MPT) group or a control (wait-list) group. The MPT program included 6 one-hour supervised sessions and incorporated (1) task-specific training for basic functional tasks and symptom-provoking tasks, and (2) strengthening of hip musculature. The wait-list group received no treatment. Primary outcomes for feasibility were patient retention and adherence. Secondary outcomes to assess treatment effects were patient-reported function (Hip disability and Osteoarthritis Outcome Score), lower extremity kinematics, and hip muscle strength. Results Retention rates did not differ between the MPT (89%) and wait-list groups (94%, P = 1.0). Sixteen of the 18 patients (89%) in the MPT group attended at least 80% of the treatment sessions. For the home exercise program, 89% of patients reported performing their home program at least once per day. Secondary outcomes support the rationale for conduct of a superiority randomized clinical trial. Conclusion Based on retention and adherence rates, a larger randomized clinical trial appears feasible and warranted to assess treatment effects more precisely. Data from this feasibility study will inform our future clinical trial. Level of Evidence Therapy, level 2b-. J Orthop Sports Phys Ther 2016;46(6):452-461. Epub 26 Apr 2016. doi:10.2519/jospt.2016.6279.

Background: Diabetic forefoot joint deformities are a known risk factor for skin breakdown and amputation, but the causes of deformity are not well understood. The purposes of this study were to determine the effects of intrinsic foot muscle deterioration and limited ankle joint mobility on the severity of metatarsophalangeal joint (MTPJ) deformity, and determine the relationships between these potential contributing factors and indicators of diabetic complications (peripheral neuropathy and advanced glycation end products)., Methods: A total of 34 participants with diabetic neuropathy (average age, 59 years; range 41-73) were studied. MTPJ angle and intrinsic foot muscle deterioration were measured with computed tomography and magnetic resonance imaging, respectively. Maximum ankle dorsiflexion was measured using kinematics. Skin intrinsic fluorescence served as a proxy measure for advanced glycation end product accumulation., Results: Total forefoot lean muscle volume (r = -0.52, P < .01) and maximum ankle dorsiflexion (r = -0.42, P < .05) were correlated with severity of MTPJ deformity. Together they explained 35% of the variance of MTPJ angle. Neuropathy was correlated with forefoot muscle deterioration (ρ = 0.53, P < .01). Skin intrinsic fluorescence was correlated to severity of neuropathy (r = 0.50, P < .01) but not maximum ankle dorsiflexion, or forefoot deterioration when controlling for neuropathy., Conclusion: These results suggest that the interplay of intrinsic foot muscle deterioration and limited ankle mobility may be the primary contributor to the development of MTPJ deformity. Identifying these muscle and ankle motion impairments as risk factors for MTPJ deformity supports the need for targeted interventions early in the disease process to slow, or possibly stop the progression of deformity over time and reduce the risk of amputation., Level of Evidence: Level IV, case series., (© The Author(s) 2015.)

13-Lipoxygenase-derived oxylipins, such as jasmonates act as potent signaling molecules in plants. Although experimental evidence supports the impact of oxylipins generated by the 9-Lipoxygenase (9-LOX) pathway in root development and pathogen defense, their signaling function in plants remains largely elusive. Based on the root growth inhibiting properties of the 9-LOX-oxylipin 9-HOT (9-hydroxy-10,12,15-octadecatrienoic acid), we established a screening approach aiming at identifying transcription factors (TFs) involved in signaling and/or metabolism of this oxylipin. Making use of the AtTORF-Ex (Arabidopsis thaliana Transcription Factor Open Reading Frame Expression) collection of plant lines overexpressing TF genes, we screened for those TFs which restore root growth on 9-HOT. Out of 6,000 lines, eight TFs were recovered at least three times and were therefore selected for detailed analysis. Overexpression of the basic leucine Zipper (bZIP) TF TGA5 and its target, the monoxygenase CYP81D11 reduced the effect of added 9-HOT, presumably due to activation of a detoxification pathway. The highly related ETHYLENE RESPONSE FACTORs ERF106 and ERF107 induce a broad detoxification response towards 9-LOX-oxylipins and xenobiotic compounds. From a set of 18 related group S-bZIP factors isolated in the screen, bZIP11 is known to participate in auxin-mediated root growth and may connect oxylipins to root meristem function. The TF candidates isolated in this screen provide starting points for further attempts to dissect putative signaling pathways involving 9-LOX-derived oxylipins.

Background: Diabetes mellitus related medial column foot deformity is a major contributor to ulceration and amputation. However, little is known about the relationship between medial column alignment and function and the integrity of the soft tissues that support and move the medial column. The purposes of this study were to determine the predictors of medial column alignment and function in people with diabetes and peripheral neuropathy., Methods: 23 participants with diabetes and neuropathy had radiographs, heel rise kinematics, magnetic resonance imaging and isokinetic muscle testing to measure: 1) medial column alignment (Meary's angle--the angle between the 1st metatarsal longitudinal axis and the talar head and neck), 2) medial column function (forefoot relative to hindfoot plantarflexion during heel rise), 3) intrinsic foot muscle and fat volume, ratio of posterior tibialis to flexor digitorum tendon volume, 4) plantar fascia function (Meary's angle change from toes flat to extended) and 5) plantarflexor peak torque. Predictors of medial column alignment and function were determined using simultaneous entry multiple regression., Findings: Posterior tibialis to flexor digitorum tendon volume ratio and intrinsic foot muscle volume were significant predictors of medial column alignment (P<.05), accounting for 44% of the variance. Intrinsic foot fat volume and plantarflexor peak torque were significant predictors of medial column function (P<.05), accounting for 37% of the variance., Interpretation: Deterioration of medial column supporting structures predicted alignment and function. Prospective research is required to monitor alignment, structure, and function over time to inform early intervention strategies to prevent deformity, ulceration, and amputation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)