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Nourhan Hisham Shady,1 Amira R Khattab,2 Safwat Ahmed,3 Miaomiao Liu,4 Ronald J Quinn,4 Mostafa A Fouad,5 Mohamed Salah Kamel,5 Abdullatif Bin Muhsinah,6 Markus Krischke,7 Martin J Mueller,7 Usama Ramadan Abdelmohsen1,5 1Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, Universities Zone, Minia 61111, Egypt; 2Department of Pharmacognosy, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria 1029, Egypt; 3Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt 41522; 4Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia; 5Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; 6Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia; 7Department of Pharmaceutical Biology, Julius-von-Sachs Institute for Biological Sciences, University of Würzburg, Würzburg 97082, GermanyCorrespondence: Martin J Mueller; Usama Ramadan Abdelmohsen Tel +49 9313186160; +20 86-2347759Fax +49 9313186182; +20 86-2369075Email martin.mueller@biozentrum.uni-wuerzburg.de; usama.ramadan@mu.edu.egBackground: 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 λmax 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.Keywords: Amphimedon, nanoparticles, marine sponge, natural products, HCV helicase, protease, molecular docking, metabolomics

Background: Hallux rigidus is a common problem characterized by localized osteoarthritis and limited range of motion of the hallux. First metatarsophalangeal joint arthrodesis has been the accepted procedure for the treatment of late-stage disease. Despite the success of arthrodesis, some patients object to the notion of eliminating motion at the metatarsophalangeal joint. For this reason, motion-sparing procedures such as the modified oblique Keller capsular interpositional arthroplasty have been developed.Methods: We compared a cohort of ten patients (ten toes) who had undergone the modified Keller arthroplasty with a group of twelve patients (twelve toes) who had undergone a first metatarsophalangeal joint arthrodesis at an average of sixty-three and sixty-eight months, respectively. Clinical outcomes were evaluated, and range of motion, great toe dynamometer strength, plantar pressures, and radiographs were assessed.Results: Clinical outcome differences existed between the groups, with the American Orthopaedic Foot and Ankle Society score being significantly higher for the arthroplasty group than for the arthrodesis group. The arthroplasty group had a mean of 54 degrees of passive and 30 degrees of active range of motion of the first metatarsophalangeal joint. The plantar pressure data revealed significantly higher pressures in the arthrodesis group under the great toe but not under the second metatarsal head.Conclusions: The modified oblique Keller capsular interpositional arthroplasty appears to be a motion-sparing procedure with clinical outcomes equivalent to those of arthrodesis, and it is associated with a more normal pattern of plantar pressures during walking.Level Of Evidence: Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Background: Weight-bearing exercise has been contraindicated among people with diabetic peripheral neuropathy (DM+PN). However, recent cohort studies have suggested that daily weight-bearing activity is associated with lower risk for foot ulceration.Objective: The objective of this study was to determine the effect of a lower-extremity exercise and walking intervention program on weight-bearing activity and foot ulcer incidence in people with DM+PN.Design: This was an observer-blinded, 12-month randomized controlled trial.Setting: The settings were physical therapy offices in part 1 of the intervention and the community in part 2 of the intervention.Participants: The participants were 79 individuals with DM+PN who were randomly assigned either to a control group (n=38) or an intervention group (n=41) group.Intervention: Intervention components included leg strengthening and balance exercises; a graduated, self-monitored walking program (part 1); and motivational telephone calls every 2 weeks (part 2). Both groups received diabetic foot care education, regular foot care, and 8 sessions with a physical therapist.Measurements: Total and exercise boutDSrelated daily steps at baseline and at 3, 6, and 12 months were measured by accelerometers. Foot lesions/ulcers were photographed and classified by an independent panel of dermatologists. Use of adequate footwear was monitored.Results: At 6 months, bout-related daily steps increased 14% from baseline in the intervention group and decreased 6% from baseline in the control group. Although the groups did not differ statistically in the change in total daily steps, at 12 months steps had decreased by 13% in the control group. Foot ulcer rates did not differ significantly between groups.Conclusion: Promoting weight-bearing activity did not lead to significant increases in foot ulcers. Weight-bearing activity can be considered following adequate assessment and counseling of patients with DM+PN. [ABSTRACT FROM AUTHOR]

Background: Limited ankle dorsiflexion has been implicated as a contributing factor to plantar ulceration of the forefoot in diabetes mellitus. The purpose of this study was to compare outcomes for patients with diabetes mellitus and a neuropathic plantar ulcer treated with a total-contact cast with and without an Achilles tendon lengthening. Our primary hypothesis was that the Achilles tendon lengthening would lead to a lower rate of ulcer recurrence.Methods: Sixty-four subjects were randomized into two treatment groups, immobilization in a total-contact cast alone or combined with percutaneous Achilles tendon lengthening, with measurements made before and after treatment, at the seven-month follow-up examination, and at the final follow-up evaluation (a mean [and standard deviation] of 2.1 +/- 0.7 years after initial healing). There were thirty-three subjects in the total-contact cast group and thirty-one subjects in the Achilles tendon lengthening group. There were no significant differences in age, body-mass index, or duration of diabetes between the groups. Outcome measures were time to healing of the ulcer, ulcer recurrence rate, range of dorsiflexion of the ankle, peak torque (strength) of the plantar flexor muscles, and peak plantar pressures on the forefoot.Results: Twenty-nine (88%) of thirty-three ulcers in the total-contact cast group and all thirty ulcers (100%) in the Achilles tendon lengthening group healed after a mean duration (and standard deviation) of 41 +/- 28 days and 58 +/- 47 days, respectively (p > 0.05). (One patient in the Achilles tendon lengthening group died before treatment was completed.) In the first seven months of follow-up, sixteen (59%) of the twenty-seven patients in the total-contact cast group who were available for follow-up and four (15%) of the twenty-seven patients in the Achilles tendon lengthening group who were available for follow-up had an ulcer recurrence (p = 0.001). At the time of the two-year follow-up, twenty-one (81%) of the twenty-six patients in the total-contact cast group and ten (38%) of the twenty-six patients in the Achilles tendon lengthening group had ulcer recurrence (p = 0.002). Compared with the group treated with the total-contact cast, the group treated with Achilles tendon lengthening had increased dorsiflexion and it remained increased at seven months (p < 0.001). Plantar flexor peak torque also decreased after Achilles tendon lengthening (p < 0.004), but it returned to baseline after seven months. Peak plantar pressures on the forefoot during barefoot walking were reduced (p < 0.0002) following Achilles tendon lengthening yet returned to baseline values within seven months after treatment.Conclusions: All ulcers healed in the Achilles tendon lengthening group, and the risk for ulcer recurrence was 75% less at seven months and 52% less at two years than that in the total-contact cast group. Achilles tendon lengthening should be considered an effective strategy to reduce recurrence of neuropathic ulceration of the plantar aspect of the forefoot in patients with diabetes mellitus and limited ankle dorsiflexion (

The purpose of this perspective is to present a general theory--the Physical Stress Theory (PST). The basic premise of the PST is that changes in the relative level of physical stress cause a predictable adaptive response in all biological tissue. Specific thresholds define the upper and lower stress levels for each characteristic tissue response. Qualitatively, the 5 tissue responses to physical stress are decreased stress tolerance (eg, atrophy), maintenance, increased stress tolerance (eg, hypertrophy), injury, and death. Fundamental principles of tissue adaptation to physical stress are described that, in the authors' opinion, can be used to help guide physical therapy practice, education, and research. The description of fundamental principles is followed by a review of selected literature describing adaptation to physical stress for each of the 4 main organ systems described in the Guide to Physical Therapist Practice (ie, cardiovascular/pulmonary, integumentary, musculoskeletal, neuromuscular). Limitations and implications of the PST for practice, research, and education are presented. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: Total contact casting is effective at healing neuropathic ulcers, but patients have a high rate (30%-57%) of ulcer recurrence when they resume walking without the cast. The purposes of this case report are to describe how data from plantar pressure measurement and spiral x-ray computed tomography (SXCT) were used to help manage a patient with recurrent plantar ulcers and to discuss potential future benefits of this technology. CASE DESCRIPTION: The patient was a 62-year-old man with type 1 diabetes mellitus (DM) of 34 years' duration, peripheral neuropathy, and a recurrent plantar ulcer. Although total contact casting or relieving weight bearing with crutches apparently allowed the ulcer to heal, the ulcer recurred 3 times in an 18-month period. Spiral x-ray computed tomography and simultaneous pressure measurement were conducted to better understand the mechanism of his ulceration. OUTCOMES: The patient had a severe bony deformity that coincided with the location of highest plantar pressures (886 kPa). The results of the SXCT and pressure measurement convinced the patient to wear his prescribed footwear always, even when getting up in the middle of the night. The ulcer healed in 6 weeks, and the patient resumed his work, which required standing and walking for 8 to 10 hours a day. DISCUSSION: Following intervention, the patient's recurrent ulcer healed and remained healed for several months. Future benefits of these methods may include the ability to define how structural changes of the foot relate to increased plantar pressures and to help design and fabricate optimal orthoses. [ABSTRACT FROM AUTHOR]

Background and Purpose: Limited ankle plantar-flexor moments and power during walking have been documented in several patient populations and are believed to contribute to gait deviations. The primary purpose of this study was to determine the relationship of plantar-flexor peak torque (PFPT) and dorsiflexion range of motion (ROM) to peak ankle moments and power during walking in a group of subjects without diabetes mellitus (DM) and in a group of subjects with DM and associated peripheral neuropathies. Subjects. Nineteen subjects, 9 with DM and associated peripheral neuropathies (mean age=58 years, SD=14, range=35-75 years) and 10 (without DM (mean age=57 years, SD=11, range=37-68 years), were evaluated. Methods: The following data were collected on all subjects: PFPT, dorsiflexion ROM, and ankle moments and power during walking (using a two-dimensional link-segment model). Hierarchical multiple regression was used for data analysis. Results: Plantar-flexor peak torque made substantial contributions to the ankle moment (40%) and ankle plantar-flexor power (53%) during walking. There also was a high correlation between PFPT and dorsiflexion ROM (r=.78) and between dorsiflexion ROM and ankle power (r=.72). Conclusion and Discussion: Plantar-flexor peak torque and dorsiflexion ROM are interrelated and appear to be important factors that contribute to ankle plantar-flexor moments and power during walking. This finding suggests that increasing PFPT and dorsiflexion ROM may help decrease gait deviations such as decreased step length and walking speed. When increasing PFPT is not possible, the natural occurrence of limited dorsiflexion ROM may help to maximize ankle moments during walking. Further research is needed to test whether these proposed treatment strategies can have a clinically useful effect. [ABSTRACT FROM AUTHOR]

Persons with diabetes mellitus (DM) and peripheral neuropathy are at high risk for skin breakdown due to unnoticed excessive pressures to the plantar foot during walking. We developed methods that combined spiral x-ray computed tomography (SXCT) imaging and plantar pressure analysis to quantify internal foot structure and external pressure during plantar loading. Methods were tested using a subject with DM who had a plantar ulcer, and a healthy control. SXCT measurements were within 2 mm of truth and SXCT plantar recordings were within 6.5% of walking trials. Hammer toe deformity (second toe), severe atrophy of the intrinsic muscles and less contact area during plantar loading, and a peak plantar pressure three times greater at the site of the ulcer were measured in the diabetic foot as compared with the healthy control. This preliminary investigation suggests that these methods are accurate for structural and pressure measurements of diabetic and healthy feet. [ABSTRACT FROM AUTHOR]

Early plant responses to different stress situations often encompass cytosolic Ca 2+ increases, plasma membrane depolarization and the generation of reactive oxygen species 1-3 . However, the mechanisms by which these signalling elements are translated into defined physiological outcomes are poorly understood. Here, to study the basis for encoding of specificity in plant signal processing, we used light-gated ion channels (channelrhodopsins). We developed a genetically engineered channelrhodopsin variant called XXM 2.0 with high Ca 2+ conductance that enabled triggering cytosolic Ca 2+ elevations in planta. Plant responses to light-induced Ca 2+ influx through XXM 2.0 were studied side by side with effects caused by an anion efflux through the light-gated anion channelrhodopsin ACR1 2.0 4 . Although both tools triggered membrane depolarizations, their activation led to distinct plant stress responses: XXM 2.0-induced Ca 2+ signals stimulated production of reactive oxygen species and defence mechanisms; ACR1 2.0-mediated anion efflux triggered drought stress responses. Our findings imply that discrete Ca 2+ signals and anion efflux serve as triggers for specific metabolic and transcriptional reprogramming enabling plants to adapt to particular stress situations. Our optogenetics approach unveiled that within plant leaves, distinct physiological responses are triggered by specific ion fluxes, which are accompanied by similar electrical signals., (© 2024. The Author(s).)

Background: Decreased muscle volume and increased muscle-associated adipose tissue (MAAT, sum of intra and inter-muscular adipose tissue) of the foot intrinsic muscle compartment are associated with deformity, decreased function, and increased risk of ulceration and amputation in those with diabetic peripheral neuropathy (DPN)., Research Question: What is the muscle quality (normal, abnormal muscle, and adipose volumes) of the DPN foot intrinsic compartment, how does it change over time, and is muscle quality related to gait and foot function?, Methods: Computed tomography was performed on the intrinsic foot muscle compartment of 45 subjects with DPN (mean age: 67.2 ± 6.4 years) at baseline and 3.6 years. Images were processed to obtain volumes of MAAT, highly abnormal, mildly abnormal, and normal muscle. For each category, annual rates of change were calculated. Paired t-tests compared baseline and follow-up. Foot function during gait was assessed using 3D motion analysis and the Foot and Ankle Ability Measure. Correlations between muscle compartment and foot function during gait were analyzed using Pearson's correlations., Results: Total muscle volume decreased, driven by a loss of normal muscle and mildly abnormal muscle (p<0.05). MAAT and the adipose-muscle ratio increased. At baseline, 51.5% of the compartment was abnormal muscle or MAAT, increasing to 55.0% at follow-up. Decreased total muscle volume correlated with greater midfoot collapse during gait (r = -0.40, p = 0.02). Greater volumes of highly abnormal muscle correlated with a lower FAAM score (r = -0.33, p = 0.03)., Significance: Muscle volume loss may progress in parallel with MAAT accumulation, impacting contractile performance in individuals with DPN. Only 48.5% of the DPN intrinsic foot muscle compartment consists of normal muscle and greater abnormal muscle is associated with worse foot function. These changes identify an important target for rehabilitative intervention to slow or prevent muscle deterioration and poor foot outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Plants tightly control growth of their lateral organs, which led to the concept of apical dominance. However, outgrowth of the dormant lateral primordia is sensitive to the plant's nutritional status, resulting in an immense plasticity in plant architecture. While the impact of hormonal regulation on apical dominance is well characterized, the prime importance of sugar signaling to unleash lateral organ formation has just recently emerged. Here, we aimed to identify transcriptional regulators, which control the trade-off between growth of apical versus lateral organs. Making use of locally inducible gain-of-function as well as single and higher-order loss-of-function approaches of the sugar-responsive S 1 -basic-leucine-zipper (S 1 -bZIP) transcription factors, we disclosed their largely redundant function in establishing apical growth dominance. Consistently, comprehensive phenotypical and analytical studies of S 1 -bZIP mutants show a clear shift of sugar and organic nitrogen (N) allocation from apical to lateral organs, coinciding with strong lateral organ outgrowth. Tissue-specific transcriptomics reveal specific clade III SWEET sugar transporters, crucial for long-distance sugar transport to apical sinks and the glutaminase GLUTAMINE AMIDO-TRANSFERASE 1&#95;2.1 , involved in N homeostasis, as direct S 1 -bZIP targets, linking the architectural and metabolic mutant phenotypes to downstream gene regulation. Based on these results, we propose that S 1 -bZIPs control carbohydrate (C) partitioning from source leaves to apical organs and tune systemic N supply to restrict lateral organ formation by C/N depletion. Knowledge of the underlying mechanisms controlling plant C/N partitioning is of pivotal importance for breeding strategies to generate plants with desired architectural and nutritional characteristics., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: There is growing scientific evidence for the therapeutic benefits of the Amazonian plant-based psychedelic "ayahuasca" for neuropsychiatric disorders such as depression and anxiety. However, there are certain challenges when incorporating botanical ayahuasca into biomedical research and clinical therapy environments. Formulations inspired by ayahuasca, which contain specific and standardized active components, are a potential remedy., Methods: We investigated subjective acute and persisting effects of a novel formulation containing the reversible monoamine oxidase inhibitor harmine (orodispersible tablet containing 100 mg MAO-I) and N,N-dimethyltryptamine (incremental intranasal dosing of up to 100 mg DMT), compared with two other conditions, namely harmine alone and placebo, in a crossover RCT in 31 healthy male subjects., Results: DMT + harmine, but not harmine alone, induced a psychedelic experience assessed with the 5D-ASC rating scale [global score: F (2,60) = 80.21, p  < 0.001] and acute experience sampling items over time, characterized by psychological insights [PIQ, F (2,58.5) = 28.514, p  < 0.001], emotional breakthroughs [EBI, F (2,60) = 26.509, p  < 0.001], and low scores on the challenging experience questionnaire [CEQ, F (2,60) = 12.84, p  < 0.001]. Participants attributed personal and spiritual significance to the experience (GSR) with mainly positive persisting effects (PEQ) at 1- and 4-months follow-up. Acute drug effects correlated positively with persisting effects. We found no changes in trait measures of personality, psychological flexibility, or general well-being, and no increases in psychopathology (SCL-90-R) were reported., Discussion and Conclusion: Our results suggest that the experience induced by the standardized DMT + harmine formulation induces a phenomenologically rich psychedelic experience, demonstrates good psychological safety and tolerability, is well tolerated, and induces beneficial psychological processes that could possibly support psychotherapy. Further studies are required to investigate the psychotherapeutic potential in patients., Competing Interests: DD and MS declare that they co-founded Reconnect Labs, an academic spin-off at the University of Zurich, focused on the development of psychedelic medicines for mental health. MM and RR declare that they own shares and receive salary from Reconnect Labs. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Aicher, Mueller, Dornbierer, Suay, Elsner, Wicki, Meling, Caflisch, Hempe, Steinhart, Mueller, Von Rotz, Kleim and Scheidegger.)

Recently, the Amazonian plant medicine "ayahuasca"-containing the psychedelic compound N,N-dimethyltryptamine (DMT) and numerous β-carboline alkaloids, such as harmine-has been suggested to exhibit beneficial effects in patients with affective and other mental health disorders. Although ayahuasca ingestion is considered safe, its pharmacokinetics/pharmacodynamics and tolerability profile pose some challenges and may limit the clinical applicability in vulnerable patient populations. While overdosing and the admixture of intolerable plant constituents may explain some of the common adverse reactions, the peroral route of administration may represent another relevant source of gastro-intestinal intolerabilities and unpredictable pharmacokinetics across users. To overcome these challenges, the present work aimed at creating ayahuasca-analogue formulations with improved pharmacokinetics and tolerability profiles. To this end, we developed peroral formulas and compared them with parenteral formulas specifically designed to circumvent the gastro-intestinal tract. In more detail, peroral administration of a capsule (containing purified DMT and harmine) was tested against a combined administration of an oromucosal harmine tablet and an intranasal DMT spray at two dose levels in an open-label within-subject study in 10 healthy male subjects. Pharmacokinetic and pharmacodynamic profiles were assessed by means of continuous blood sampling, vital sign monitoring, and psychometric assessments. Common side effects induced by traditional herbal ayahuasca such as nausea, vomiting, and diarrhea were significantly attenuated by our DMT/harmine formulations. While all preparations were well tolerated, the combined buccal/intranasal administration of harmine and DMT yielded substantially improved pharmacokinetic profiles, indicated by significantly reduced variations in systemic exposure. In conclusion, the combined buccal/intranasal administration of harmine and DMT is an innovative approach that may pave the way towards a safe, rapid-acting, and patient-oriented administration of DMT/harmine for the treatment of affective disorders. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04716335., Competing Interests: DD, MK, DK, and MS declare that they co-founded Reconnect Labs, an academic spin-off at the University of Zurich, focused on the development of psychedelic medicines for mental health. MM and RR are shareholders of Reconnect Labs. All other co-authors have no conflict of interest to declare related to this work., (Copyright © 2023 Dornbierer, Marten, Mueller, Aicher, Mueller, Boxler, Kometer, Kosanic, von Rotz, Puchkov, Kraemer, Landolt, Seifritz and Scheidegger.)

High-temperature stress limits plant growth and reproduction. Exposure to high temperature, however, also elicits a physiological response, which protects plants from the damage evoked by heat. This response involves a partial reconfiguration of the metabolome including the accumulation of the trisaccharide raffinose. In this study, we explored the intraspecific variation of warm temperature-induced raffinose accumulation as a metabolic marker for temperature responsiveness with the aim to identify genes that contribute to thermotolerance. By combining raffinose measurements in 250 Arabidopsis thaliana accessions following a mild heat treatment with genome-wide association studies, we identified five genomic regions that were associated with the observed trait variation. Subsequent functional analyses confirmed a causal relationship between TREHALOSE-6-PHOSPHATE SYNTHASE 1 (TPS1) and warm temperature-dependent raffinose synthesis. Moreover, complementation of the tps1-1 null mutant with functionally distinct TPS1 isoforms differentially affected carbohydrate metabolism under more severe heat stress. While higher TPS1 activity was associated with reduced endogenous sucrose levels and thermotolerance, disruption of trehalose 6-phosphate signalling resulted in higher accumulation of transitory starch and sucrose and was associated with enhanced heat resistance. Taken together, our findings suggest a role of trehalose 6-phosphate in thermotolerance, most likely through its regulatory function in carbon partitioning and sucrose homoeostasis., (© 2023 The Authors. Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Modern lifestyle is often at odds with endogenously driven rhythmicity, which can lead to circadian disruption and metabolic syndrome. One signature for circadian disruption is a reduced or altered metabolite cycling in the circulating tissue reflecting the current metabolic status. Drosophila is a well-established model in chronobiology, but day-time dependent variations of transport metabolites in the fly circulation are poorly characterized. Here, we sampled fly hemolymph throughout the day and analyzed diacylglycerols (DGs), phosphoethanolamines (PEs) and phosphocholines (PCs) using LC-MS. In wild-type flies kept on sugar-only medium under a light-dark cycle, all transport lipid species showed a synchronized bimodal oscillation pattern with maxima at the beginning and end of the light phase which were impaired in period 01 clock mutants. In wild-type flies under constant dark conditions, the oscillation became monophasic with a maximum in the middle of the subjective day. In strong support of clock-driven oscillations, levels of the targeted lipids peaked once in the middle of the light phase under time-restricted feeding independent of the time of food intake. When wild-type flies were reared on full standard medium, the rhythmic alterations of hemolymph lipid levels were greatly attenuated. Our data suggest that the circadian clock aligns daily oscillations of DGs, PEs, and PCs in the hemolymph to the anabolic siesta phase, with a strong influence of light on phase and modality., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Quantitative magnetic resonance imaging (qMRI) measures have provided insights into the composition, quality, and structure-function of musculoskeletal tissues. Low signal-to-noise ratio has limited application to tendon. Advances in scanning sequences and sample positioning have improved signal from tendon allowing for evaluation of structure and function. The purpose of this study was to elucidate relationships between tendon qMRI metrics (T1, T2, T1ρ and diffusion tensor imaging [DTI] metrics) with tendon tissue mechanics, collagen concentration and organization. Sixteen human Achilles tendon specimens were collected, imaged with qMRI, and subjected to mechanical testing with quantitative polarized light imaging. T2 values were related to tendon mechanics [peak stress (r sp  = 0.51, p = 0.044), equilibrium stress (r sp  = 0.54, p = 0.033), percent relaxation (r sp  = -0.55, p = 0.027), hysteresis (r sp  = -0.64, p = 0.007), linear modulus (r sp  = 0.67, p = 0.009)]. T1ρ had a statistically significant relationship with percent relaxation (r = 0.50, p = 0.048). Collagen content was significantly related to DTI measures (range of r = 0.56-0.62). T2 values from a single slice of the midportion of human Achilles tendons were strongest predictors of tendon tensile mechanical metrics. DTI diffusivity indices (mean diffusivity, axial diffusivity, radial diffusivity) were strongly correlated with collagen content. These findings build on a growing body of literature supporting the feasibility of qMRI to characterize tendon tissue and noninvasively measure tendon structure and function. Statement of Clinical Significance: Quantitative MRI can be applied to characterize tendon tissue and is a noninvasive measure that relates to tendon composition and mechanical behavior., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Heat stress triggers the accumulation of triacylglycerols in Arabidopsis leaves, which increases basal thermotolerance. However, how triacylglycerol synthesis is linked to thermotolerance remains unclear and the mechanisms involved remain to be elucidated. It has been shown that triacylglycerol and starch degradation are required to provide energy for stomatal opening induced by blue light at dawn. To investigate whether triacylglycerol turnover is involved in heat-induced stomatal opening during the day, we performed feeding experiments with labeled fatty acids. Heat stress strongly induced both triacylglycerol synthesis and degradation to channel fatty acids destined for peroxisomal ß-oxidation through the triacylglycerol pool. Analysis of mutants defective in triacylglycerol synthesis or peroxisomal fatty acid uptake revealed that triacylglycerol turnover and fatty acid catabolism are required for heat-induced stomatal opening in illuminated leaves. We show that triacylglycerol turnover is continuous (1.2 mol% per min) in illuminated leaves even at 22°C. The ß-oxidation of triacylglycerol-derived fatty acids generates C 2 carbon units that are channeled into the tricarboxylic acid pathway in the light. In addition, carbohydrate catabolism is required to provide oxaloacetate as an acceptor for peroxisomal acetyl-CoA and maintain the tricarboxylic acid pathway for energy and amino acid production during the day., (© 2023 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

The negative impact of juvenile undernourishment on adult behavior has been well reported for vertebrates, but relatively little is known about invertebrates. In honeybees, nutrition has long been known to affect task performance and timing of behavioral transitions. Whether and how a dietary restriction during larval development affects the task performance of adult honeybees is largely unknown. We raised honeybees in-vitro , varying the amount of a standardized diet (150 µl, 160 µl, 180 µl in total). Emerging adults were marked and inserted into established colonies. Behavioral performance of nurse bees and foragers was investigated and physiological factors known to be involved in the regulation of social organization were quantified. Surprisingly, adult honeybees raised under different feeding regimes did not differ in any of the behaviors observed. No differences were observed in physiological parameters apart from weight. Honeybees were lighter when undernourished (150 µl), while they were heavier under the overfed treatment (180 µl) compared to the control group raised under a normal diet (160 µl). These data suggest that dietary restrictions during larval development do not affect task performance or physiology in this social insect despite producing clear effects on adult weight. We speculate that possible effects of larval undernourishment might be compensated during the early period of adult life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schilcher, Hilsmann, Ankenbrand, Krischke, Mueller, Steffan-Dewenter and Scheiner.)

Plants and algae are faced with a conundrum: harvesting sufficient light to drive their metabolic needs while dissipating light in excess to prevent photodamage, a process known as nonphotochemical quenching. A slowly relaxing form of energy dissipation, termed qH, is critical for plants' survival under abiotic stress; however, qH location in the photosynthetic membrane is unresolved. Here, we tested whether we could isolate subcomplexes from plants in which qH was induced that would remain in an energy-dissipative state. Interestingly, we found that chlorophyll (Chl) fluorescence lifetimes were decreased by qH in isolated major trimeric antenna complexes, indicating that they serve as a site for qH-energy dissipation and providing a natively quenched complex with physiological relevance to natural conditions. Next, we monitored the changes in thylakoid pigment, protein, and lipid contents of antenna with active or inactive qH but did not detect any evident differences. Finally, we investigated whether specific subunits of the major antenna complexes were required for qH but found that qH was insensitive to trimer composition. Because we previously observed that qH can occur in the absence of specific xanthophylls, and no evident changes in pigments, proteins, or lipids were detected, we tentatively propose that the energy-dissipative state reported here may stem from Chl-Chl excitonic interaction., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Sphingolipid long-chain bases (LCBs) are building blocks for membrane-localized sphingolipids, and are involved in signal transduction pathways in plants. Elevated LCB levels are associated with the induction of programmed cell death and pathogen-derived toxin-induced cell death. Therefore, levels of free LCBs can determine survival of plant cells. To elucidate the contribution of metabolic pathways regulating high LCB levels, we applied the deuterium-labeled LCB D-erythro-sphinganine-d7 (D 7 -d18:0), the first LCB in sphingolipid biosynthesis, to Arabidopsis leaves and quantified labeled LCBs, LCB phosphates (LCB-Ps), and 14 abundant ceramide (Cer) species over time. We show that LCB D 7 -d18:0 is rapidly converted into the LCBs d18:0P, t18:0, and t18:0P. Deuterium-labeled ceramides were less abundant, but increased over time, with the highest levels detected for Cer(d18:0/16:0), Cer(d18:0/24:0), Cer(t18:0/16:0), and Cer(t18:0/22:0). A more than 50-fold increase of LCB-P levels after leaf incubation in LCB D 7 -d18:0 indicated that degradation of LCBs via LCB-Ps is important, and we hypothesized that LCB-P degradation could be a rate-limiting step to reduce high levels of LCBs. To functionally test this hypothesis, we constructed a transgenic line with dihydrosphingosine-1-phosphate lyase 1 (DPL1) under control of an inducible promotor. Higher expression of DPL1 significantly reduced elevated LCB-P and LCB levels induced by Fumonisin B 1 , and rendered plants more resistant against this fungal toxin. Taken together, we provide quantitative data on the contribution of major enzymatic pathways to reduce high LCB levels, which can trigger cell death. Specifically, we provide functional evidence that DPL1 can be a rate-limiting step in regulating high LCB levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lambour, Glenz, Forner, Krischke, Mueller, Fekete and Waller.)

Purpose: Midfoot movement dysfunction, as measured by heel rise performance, is associated with midfoot deformity in people with diabetes and peripheral neuropathy. Understanding contributors of midfoot movement dysfunction may help clinicians understand deformity progression. The purpose of this study was to determine the factors associated with midfoot angle at peak heel rise., Methods: The outcomes of fifty-eight participants with type 2 diabetes mellitus and peripheral neuropathy were analyzed. Midfoot (forefoot on hindfoot) sagittal kinematics during unilateral heel rise task were measured using 3-dimensional motion analysis. A multivariate linear regression model was used to predict midfoot sagittal movements at peak heel rise. Independent variables that were entered in the model were (in order of entry): age, body mass index, intrinsic foot muscle volume, and maximum available midfoot plantarflexion range of motion. Intrinsic foot muscle volume was obtained from magnetic resonance imaging and maximum available midfoot motion was measured during non-weightbearing plantarflexion using 3-dimensional motion analysis., Results: Body mass index (R 2 = 30.5%, p < 0.001) and maximum available midfoot plantarflexion range of motion (R 2 = 10.9%, p = 0.001) were significant factors that accounted for 41.4% of variance of midfoot angle at peak heel rise, while age and intrinsic foot muscle volume were not significant predictors., Conclusions: Greater body mass index and less available midfoot plantarflexion range of motion were associated with greater midfoot movement dysfunction. These two significant predictors are potentially modifiable, suggesting possible improvements in midfoot movements with reduction in body weight and increasing midfoot plantarflexion range of motion. Health care professionals should consider patient's weight and joint motion when prescribing foot exercise(s) to prevent excessive midfoot collapse during weightbearing tasks., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Women with urgency/frequency predominant lower urinary tract symptoms (UF-LUTS) may have elevated pelvic floor muscle (PFM) position at rest and limited mobility with PFM contraction and bearing down, but this has not been quantified., Objectives: To compare PFM position and mobility using transperineal ultrasound (TPUS) at rest, maximal PFM contraction (perineal elevation), and bearing down (perineal descent) in women with and without UF-LUTS. We hypothesized that women with UF-LUTS would demonstrate elevated resting position and decreased excursion of pelvic landmarks during contraction and bearing down as compared to women without UF-LUTS., Study Design: Case-control study., Methods: Women with UF-LUTS were matched 1:1 on age, body mass index and vaginal parity to women without UF-LUTS. TPUS videos were obtained during 3 conditions: rest, PFM contraction, and bearing down. Levator plate angle (LPA) and puborectalis length (PR length), were measured for each condition. Paired t-tests or Wilcoxon signed rank tests compared LPA and PR length between cases and controls., Results: 21 case-control pairs (42 women): Women with UF-LUTS demonstrated greater LPA at rest (66.8 ± 13.2 degrees vs 54.9 ± 9.8 degrees; P=0.006), and less PR lengthening from rest to bearing down (0.2 ± 3.1 mm vs 2.1 ± 2.9 mm; P=.03)., Conclusion: Women with UF-LUTS demonstrated more elevated (cranioventral) position of the PFM at rest and less PR muscle lengthening with bearing down. These findings highlight the importance of a comprehensive PFM examination and possible treatment for women with UF-LUTS to include PFM position and mobility.

Background: Volumetric measures of intrinsic foot muscle and intermuscular adipose tissue (IMAT) infiltration are important in understanding foot injury and disease. We questioned whether measures of muscle and fat derived from computed tomography (CT) and magnetic resonance (MR) would be comparable., Methods: This study determined the correlation and level of agreement between CT and MR measurements of foot muscle and IMAT from 32 subjects with diabetes and peripheral neuropathy. Volumetric CT and DIXON 3T MR scans were obtained. Intermuscular adipose tissue and muscle volumes used to create the IMAT to muscle ratio were obtained by segmenting the forefoot muscle compartment from each modality., Results: Computed tomography IMAT ratios were significantly correlated (r = 0.85, P < 0.0001) with MR IMAT ratios. Computed tomography and MR IMAT ratio mean difference between CT and MR was small (0.044 unit, Bland-Altman plots)., Conclusions: The CT and MR IMAT ratio measurements were highly correlated, indicating both modalities represent tissue quantification similarly.Level of Evidence: 2Technical Efficacy: 1., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Sphingolipid long chain bases (LCBs) are building blocks of sphingolipids and can serve as signalling molecules, but also have antimicrobial activity and were effective in reducing growth of a range of human pathogens. In plants, LCBs are linked to cell death processes and the regulation of defence reactions against pathogens, but their role in directly influencing growth of plant-interacting microorganisms has received little attention. Therefore, we tested the major plant LCB phytosphingosine in in vitro tests with the plant pathogenic fungi Verticillium longisporum, Fusarium graminearum and Sclerotinia sclerotiorum, the plant symbiotic fungal endophyte Serendipita indica, the bacterial pathogens Pseudomonas syringae pv. tomato (Pst), Agrobacterium tumefaciens, and the related beneficial strain Rhizobium radiobacter. Phytosphingosine inhibited growth of these organisms at micromolar concentrations. Among the fungal pathogens, S. sclerotiorum was the most, and F. graminearum was the least sensitive. 15.9 μg/mL phytosphingosine effectively killed 95% of the three bacterial species. Plant disease symptoms and growth of Pst were also inhibited by phytosphingosine when co-infiltrated into Arabidopsis leaves, with no visible negative effect on host tissue. Taken together, we demonstrate that the plant LCB phytosphingosine inhibits growth of plant-interacting microorganisms. We discuss the potential of elevated LCB levels to enhance plant pathogen resistance., (© 2022. The Author(s).)

In vitro rearing of honeybee larvae is an established method that enables exact control and monitoring of developmental factors and allows controlled application of pesticides or pathogens. However, only a few studies have investigated how the rearing method itself affects the behavior of the resulting adult honeybees. We raised honeybees in vitro according to a standardized protocol: marking the emerging honeybees individually and inserting them into established colonies. Subsequently, we investigated the behavioral performance of nurse bees and foragers and quantified the physiological factors underlying the social organization. Adult honeybees raised in vitro differed from naturally reared honeybees in their probability of performing social tasks. Further, in vitro-reared bees foraged for a shorter duration in their life and performed fewer foraging trips. Nursing behavior appeared to be unaffected by rearing condition. Weight was also unaffected by rearing condition. Interestingly, juvenile hormone titers, which normally increase strongly around the time when a honeybee becomes a forager, were significantly lower in three- and four-week-old in vitro bees. The effects of the rearing environment on individual sucrose responsiveness and lipid levels were rather minor. These data suggest that larval rearing conditions can affect the task performance and physiology of adult bees despite equal weight, pointing to an important role of the colony environment for these factors. Our observations of behavior and metabolic pathways offer important novel insight into how the rearing environment affects adult honeybees.

Diagnostic imaging modalities, like computed tomography (CT) and magnetic resonance imaging (MRI), can be used to assess in vivo muscle quality. Quantitative assessment using these techniques is time-intensive and costly due in part to extensive post-processing needs. The purpose of this study was to identify whether a subset of slices on CT and MRI would yield comparable results to the full number of slices for a measure of muscle quality (muscle deterioration ratio = fat volume/muscle volume) in the foot intrinsic muscles of people with diabetes and peripheral neuropathy. CT (0.6 mm slice thickness) and MRI (3.5 mm slice thickness) scans were obtained using previously described methods. The total number of slices acquired during the scan was compared to several conditions using a portion of slices. Bland-Altman plots and Lin's concordance correlation coefficient were used to test agreement. Any condition using at least three slices yielded substantial to almost perfect agreement with the total number of slices on both CT and MRI (Range of Lin's concordance correlation coefficient: 0.947-0.999). Using a single slice in the middle of the region of interest demonstrated poor to moderate agreement with the total number of slices. The findings of this study suggest that using a limited number of slices to quantify muscle deterioration ratio on CT or MRI is a viable way to balance the combined need for measurement accuracy with feasibility in research and clinical settings., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Evidence related to physical therapist-led intervention for patients with chronic hip-related groin pain (HRGP) is limited. The purpose was to assess sustainability of treatment effects for people with HRGP undergoing two physical therapist-led interventions. We completed an ancillary analysis of a pilot multicenter, randomized clinical trial. Forty-six patients with chronic HRGP, 15-40 years, were enrolled. Patients were randomized to participate in 10 sessions over 12 weeks of either movement pattern training (MoveTrain) or traditional strength/flexibility (Standard). Participants completed self-report questionnaires before treatment and 6 and 12 months after treatment completion. Outcome measures included Hip disability and Osteoarthritis and Outcome Score (HOOS), Patient Specific Functional Scale and Numeric Pain Rating Scale for average and worst pain. Continuous data were analyzed with mixed model repeated measures analysis of variance (RM-ANOVA) within each group. Numeric pain rating scale (NPRS) was analyzed using multinomial generalized estimating equations (GEE) with a cumulative logit. Reported p values are from statistical contrasts within the RM-ANOVAs and GEEs testing a priori hypotheses regarding change from pretest to month 6, and pretest to month 12. A total of 43/46 (93.5%) participants completed treatment, 40 (87.0%) completed 6 and 38 (82.6%) completed 12 month questionnaires. At 6 and 12 months, both groups demonstrated clinically significant improvements, compared to pretest, in all subscales of HOOS (p < 0.01), Patient Specific Functional Scale (p < 0.001), and NPRS (p < 0.0001). Among patients with chronic HRGP, both MoveTrain and Standard resulted in improved outcomes that were sustained 12 months after treatment. Further investigation in a larger sample is needed to confirm our findings., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Animals need to balance competitive behaviors to maintain internal homeostasis. The underlying mechanisms are complex but typically involve neuroendocrine signaling. Using Drosophila, we systematically manipulated signaling between energy-mobilizing endocrine cells producing adipokinetic hormone (AKH), octopaminergic neurons, and the energy-storing fat body to assess whether this neuroendocrine axis involved in starvation-induced hyperactivity also balances activity levels under ad libitum access to food. Our results suggest that AKH signals via two divergent pathways that are mutually competitive in terms of activity and rest. AKH increases activity via the octopaminergic system during the day, while it prevents high activity levels during the night by signaling to the fat body. This regulation involves feedback signaling from octopaminergic neurons to AKH-producing cells (APCs). APCs are known to integrate a multitude of metabolic and endocrine signals. Our results add a new facet to the versatile regulatory functions of APCs by showing that their output contributes to shape the daily activity pattern under ad libitum access to food., Competing Interests: Declaration of interests P.M.I. is selling and provides service to flyPAD devices through https://www.flypad.rocks. The other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Interaction of plants with the environment affects lipid metabolism. Changes in the pattern of phospholipids have been reported in response to abiotic stress, particularly accumulation of triacylglycerols, but less is known about the alteration of lipid metabolism in response to biotic stress and leaves have been more intensively studied than roots. This work investigates the levels of lipids in roots as well as leaves of Arabidopsis thaliana in response to pathogens and elicitor molecules by UPLC-TOF-MS. Triacylglycerol levels increased in roots and systemically in leaves upon treatment of roots with the fungus Verticillium longisporum . Upon spray infection of leaves with the bacterial pathogen Pseudomonas syringae , triacylglycerols accumulated locally in leaves but not in roots. Treatment of roots with a bacterial lipopolysaccharide elicitor induced a strong triacylglycerol accumulation in roots and leaves. Induction of the expression of the bacterial effector AVRRPM1 resulted in a dramatic increase of triacylglycerol levels in leaves, indicating that elicitor molecules are sufficient to induce accumulation of triacylglycerols. These results give insight into local and systemic changes to lipid metabolism in roots and leaves in response to biotic stresses.

Soil salinity is an increasingly global problem which hampers plant growth and crop yield. Plant productivity depends on optimal water-use efficiency and photosynthetic capacity balanced by stomatal conductance. Whether and how stomatal behavior contributes to salt sensitivity or tolerance is currently unknown. This work identifies guard cell-specific signaling networks exerted by a salt-sensitive and salt-tolerant plant under ionic and osmotic stress conditions accompanied by increasing NaCl loads. We challenged soil-grown Arabidopsis thaliana and Thellungiella salsuginea plants with short- and long-term salinity stress and monitored genome-wide gene expression and signals of guard cells that determine their function. Arabidopsis plants suffered from both salt regimes and showed reduced stomatal conductance while Thellungiella displayed no obvious stress symptoms. The salt-dependent gene expression changes of guard cells supported the ability of the halophyte to maintain high potassium to sodium ratios and to attenuate the abscisic acid (ABA) signaling pathway which the glycophyte kept activated despite fading ABA concentrations. Our study shows that salinity stress and even the different tolerances are manifested on a single cell level. Halophytic guard cells are less sensitive than glycophytic guard cells, providing opportunities to manipulate stomatal behavior and improve plant productivity., (© 2021 The Authors. New Phytologist © 2021 New Phytologist Foundation.)

Objective: To evaluate regional calf muscle microcirculation in people with diabetes mellitus (DM) with and without foot ulcers, compared to healthy control people without DM, using contrast-free magnetic resonance imaging methods., Methods: Three groups of subjects were recruited: non-DM controls, DM, and DM with foot ulcers (DM + ulcer), all with ankle brachial index (ABI) > 0.9. Skeletal muscle blood flow (SMBF) and oxygen extraction fraction (SMOEF) in calf muscle were measured at rest and during a 5-min isometric ankle plantarflexion exercise. Subjects completed the Yale physical activity survey., Results: The exercise SMBF (ml/min/100 g) of the medial gastrocnemius muscle were progressively impaired: 63.7 ± 18.9 for controls, 42.9 ± 6.7 for DM, and 36.2 ± 6.2 for DM + ulcer, p  < 0.001. Corresponding exercise SMOEF was the lowest in DM + ulcers (0.48 ± 0.09). Exercise SMBF in the soleus muscle was correlated moderately with the Yale physical activity survey ( r  = 0.39, p  < 0.01)., Conclusions: Contrast-free MR imaging identified progressively impaired regional microcirculation in medial gastrocnemius muscles of people with DM with and without foot ulcers. Exercise SMBF in the medial gastrocnemius muscle was the most sensitive index and was associated with HbA1c. Lower exercise SMBF in the soleus muscle was associated with lower Yale score.

Background: Urgency and frequency are common lower urinary tract symptoms (UF-LUTS) in women. There is limited evidence to guide physical therapist-led treatment., Objectives: To compare hip and pelvic floor muscle strength between women with and without UF-LUTS. We hypothesized women with UF-LUTS would demonstrate 1) diminished hip external rotator and abductor strength and 2) equivalent pelvic floor strength and diminished endurance compared to controls., Study Design: A matched case-control study., Methods: Women with UF-LUTS (cases) and controls were matched on age, body mass index (BMI), vaginal parity. Examiner measured participants' 1) hip external rotator and abductor strength via dynamometry (maximum voluntary effort against fixed resistance) and 2) pelvic floor muscle strength (peak squeeze pressure) and endurance (squeeze pressure over a 10 second hold) via vaginal manometry. Values compared between cases and controls with paired-sample t-tests (hip) or Wilcoxon signed rank tests (pelvic floor)., Results: 21 pairs (42 women): Hip external rotation (67.0 ± 19.0 N vs 83.6 ± 21.5 N; P=0.005) and hip abduction strength (163.1 ± 48.1 N vs 190.1 ± 53.1 N; P=0.04) were significantly lower in cases than controls. There was no significant difference in pelvic floor strength (36.8 ± 19.9 cmH 2 0 vs 41.8 ± 21.0 cmH 2 0; P =0.40) or endurance (234.0 ± 149.6 cmH 2 0*seconds vs 273.4 ± 149.1 cmH 2 0*seconds; P =0.24)., Conclusion: Women with UF-LUTS had weaker hip external rotator and abductor muscles, but similar pelvic floor strength and endurance compared to controls. Hip strength may be important to assess in patients with UF-LUTS, further research is needed.

Objective: The objective of this study was to examine the effects of diabetes mellitus and peripheral neuropathy (DMPN), limited joint mobility, and weight-bearing on foot and ankle sagittal movements and characterize the foot and ankle position during heel rise., Methods: Sixty people with DMPN and 22 controls participated. Primary outcomes were foot (forefoot on hindfoot) and ankle (hindfoot on shank) plantar-flexion/dorsiflexion angle during 3 tasks: unilateral heel rise, bilateral heel rise, and non-weight-bearing ankle plantar flexion. A repeated-measures analysis of variance and Fisher exact test were used., Results: Main effects of task and group were significant, but not the interaction in both foot and ankle plantar flexion. Foot and ankle plantar flexion were less in people with DMPN compared with controls in all tasks. Both DMPN and control groups had significantly less foot and ankle plantar flexion with greater weight-bearing; however, the linear trend across tasks was similar between groups. The DMPN group had a greater percentage of individuals in foot and/or ankle dorsiflexion at peak unilateral heel rise compared with controls, but the foot and ankle position was similar at peak bilateral heel rise between DMPN and control groups., Conclusion: Foot and ankle plantar flexion is less in people with DMPN. Less plantar flexion in non-weight-bearing suggests that people with DMPN have limited joint mobility. However, peak unilateral and bilateral heel rise is less than the available plantar flexion range of motion measured in non-weight-bearing, indicating that limited joint mobility does not limit heel rise performance. A higher frequency of people with DMPN are in foot and ankle dorsiflexion at peak unilateral heel rise compared with controls, but the position improved with lower weight-bearing., Impact: Proper resistance should be considered with physical therapist interventions utilizing heel rise because foot and ankle plantar flexion position could be improved by reducing the amount of weight-bearing., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: A toe-extension movement pattern may contribute to metatarsophalangeal joint deformity and ulceration in people with diabetes. We sought to quantify the relationship between toe extension magnitude and variability during three functional tasks (ankle range of motion, sit to stand, walking) with metatarsophalangeal joint deformity, and identify potential mechanisms associated with a toe-extension movement pattern., Methods: Individuals with diabetes and peripheral neuropathy were included (n = 60). Metatarsophalangeal joint deformity was assessed using computed tomography (CT). Toe-extension movement was quantified using 3-dimensional motion capture. Linear regression was used to investigate the role of toe-extension movement pattern on metatarsophalangeal joint deformity. Regression analysis was used to identify mechanisms (neuropathy severity, foot intrinsic muscle deterioration ratio, ankle dorsiflexion range of motion) contributing to toe-extension movement pattern., Findings: Toe extension with each functional task as well as the mean and coefficient of variation across all tasks were significantly related to metatarsophalangeal joint deformity (range of correlation coefficients = (-0.386, 0.692), p ≤ 0.001). Ankle dorsiflexion range of motion was associated with mean toe extension across all tasks (r sp  = -0.282, p = 0.029). Neuropathy severity and foot intrinsic muscle deterioration ratio were associated with toe extension variability (r sp  = -0.373, p = 0.003 and r sp  = -0.266, p = 0.043; respectively)., Interpretation: Greater magnitude and lower variability of a toe-extension movement pattern was found to be associated with metatarsophalangeal joint deformity. These findings may support clinical assessment and treatment of movement across more than one task., (Copyright © 2021. Published by Elsevier Ltd.)

Physical activity is an essential part of general health and diabetes management. However, recommending weight-bearing physical activity for people with plantar diabetic foot ulcers is controversial, even when gold standard offloading devices are used, as it is commonly thought to delay healing. We aimed to narratively review relevant studies investigating the relationship between plantar diabetic foot ulcer healing and weight-bearing activity, plantar pressure and device adherence. We defined relevant studies as those from two systematic reviews, along with those identified since using a similar updated Pubmed search strategy. We identified six studies. One study found that more daily steps were associated with worse ulcer healing, three found no significant association between steps and ulcer healing, and in two others the association was unclear. Thus, there is weak evidence for an inverse relationship between weight-bearing physical activity and plantar ulcer healing while utilizing offloading devices. We propose a Diabetic foot Offloading and Activity framework to guide future research to find the optimal balance between the positive and negative effects of weight-bearing activity in the context of foot ulcers. We hope such future studies will shed more conclusive light on the impact of weight-bearing activity on healing of plantar diabetic foot ulcers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GJ is a consultant for Novo Nordisk and PAL has been a speaker consultant for Sanofi, Australia, but do not consider these relevant conflicts for this paper. JJvN, RTC, BN and MJM have no conflicts of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Carotenoid levels in plant tissues depend on the relative rates of synthesis and degradation of the molecules in the pathway. While plant carotenoid biosynthesis has been extensively characterized, research on carotenoid degradation and catabolism into apocarotenoids is a relatively novel field. To identify apocarotenoid metabolic processes, we characterized the transcriptome of transgenic Arabidopsis (Arabidopsis thaliana) roots accumulating high levels of β-carotene and, consequently, β-apocarotenoids. Transcriptome analysis revealed feedback regulation on carotenogenic gene transcripts suitable for reducing β-carotene levels, suggesting involvement of specific apocarotenoid signaling molecules originating directly from β-carotene degradation or after secondary enzymatic derivatizations. Enzymes implicated in apocarotenoid modification reactions overlapped with detoxification enzymes of xenobiotics and reactive carbonyl species (RCS), while metabolite analysis excluded lipid stress response, a potential secondary effect of carotenoid accumulation. In agreement with structural similarities between RCS and β-apocarotenoids, RCS detoxification enzymes also converted apocarotenoids derived from β-carotene and from xanthophylls into apocarotenols and apocarotenoic acids in vitro. Moreover, glycosylation and glutathionylation-related processes and translocators were induced. In view of similarities to mechanisms found in crocin biosynthesis and cellular deposition in saffron (Crocus sativus), our data suggest apocarotenoid metabolization, derivatization and compartmentalization as key processes in (apo)carotenoid metabolism in plants., (© American Society of Plant Biologists 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

While rhodopsin-based optogenetics has revolutionized neuroscience 1,2 , poor expression of opsins and the absence of the essential cofactor all-trans-retinal has complicated the application of rhodopsins in plants. Here, we demonstrate retinal production in plants and improved rhodopsin targeting for green light manipulation of plant cells using the Guillardia theta light-gated anion channelrhodopsin GtACR1 3 . Green light induces a massive increase in anion permeability and pronounced membrane potential changes when GtACR1 is expressed, enabling non-invasive manipulation of plant growth and leaf development. Using light-driven anion loss, we could mimic drought conditions and bring about leaf wilting despite sufficient water supply. Expressed in pollen tubes, global GtACR1 activation triggers membrane potential depolarizations due to large anion currents. While global illumination was associated with a reversible growth arrest, local GtACR1 activation at the flanks of the apical dome steers growth direction away from the side with increased anion conductance. These results suggest a crucial role of anion permeability for the guidance of pollen tube tip growth. This plant optogenetic approach could be expanded to create an entire pallet of rhodopsin-based tools 4 , greatly facilitating dissection of plant ion-signalling pathways.

Background: Midfoot and ankle movement dysfunction in people with diabetes mellitus and peripheral neuropathy (DMPN) is associated with midfoot deformity and increased plantar pressures during gait. If midfoot and ankle motion during heel rise and push-off of gait have similar mechanics, heel rise performance could be a clinically feasible way to identify abnormal midfoot and ankle function during gait., Research Question: Is midfoot and ankle joint motion during a heel rise associated with midfoot and ankle motion at push-off during gait in people with DMPN?, Methods: Sixty adults with DMPN completed double-limb heel rise, single-limb heel rise, and walking. A modified Oxford multi-segment foot model (forefoot, hindfoot, shank) was used to analyze midfoot (forefoot on hindfoot) and ankle (hindfoot on shank) sagittal angle during heel rise and gait. Pearson correlation was used to test the relationship between heel rise and gait kinematic variables (n = 60). Additionally, we classified 60 participants into two subgroups based on midfoot and ankle position at peak heel rise: midfoot and ankle dorsiflexed (dorsiflexed; n = 23) and midfoot and ankle plantarflexed (plantarflexed; n = 20). Movement trajectories of midfoot and ankle motion during single-limb heel rise and gait of the subgroups were examined., Results: Peak double-limb heel rise and gait midfoot and ankle angles were significantly correlated (r = 0.49 and r = 0.40, respectively). Peak single-limb heel rise and gait midfoot and ankle angles were significantly correlated (r = 0.63 and r = 0.54, respectively). The dorsiflexed subgroup, identified by heel rise performance showed greater midfoot and ankle dorsiflexion during gait compared to the plantarflexed subgroup (mean difference between subgroups: midfoot 3°, ankle 3°)., Significance: People with DMPN who fail to plantarflex the midfoot and ankle during heel rise have difficulty plantarflexing the midfoot and ankle during gait. Utilizing a heel rise task may help identify midfoot and ankle dysfunction associated with gait in people with DMPN., (Copyright © 2020 Elsevier B.V. All rights reserved.)