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Similarly, epinephrine-induced increases in the mRNA expression of hepatic adrenergic receptors (Adra1/2a, Adrb1), and glucose-6-phosphatase (G6pc) were greater in sedentary compared to trained mice. The mRNA expression of cAMP-degrading enzymes phosphodiesterase 3B and 4B (Pde3b, Pde4b) was greater in trained compared to sedentary mice. Taken together, our data suggest that prior exercise training reduces the liver's response to epinephrine. This could be beneficial in the context of training-induced glycogen sparing during exercise. © 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.Fungal effector proteins facilitate host-plant colonization and have generally been characterized as small secreted proteins (SSPs). We classified and functionally tested SSPs from the secretomes of three closely related necrotrophic phytopathogens Ciborinia camelliae, Botrytis cinerea, and Sclerotinia sclerotiorum. Alignment of predicted SSPs identified a large protein family that share greater than 41% amino acid identity and that have key characteristics of previously described microbe-associated molecular patterns (MAMPs). Strikingly, 73 of the 75 SSP family members were predicted within the secretome of the host-specialist C. camelliae with single-copy homologs identified in the secretomes of the host generalists S. sclerotiorum and B. cinerea. To explore the potential function of this family of SSPs, 10 of the 73 C. camelliae proteins, together with the single-copy homologs from S. sclerotiorum (SsSSP3) and B. cinerea (BcSSP2), were cloned and expressed as recombinant proteins. Infiltration of SsSSP3 and BcSSP2 into host tissue induced rapid necrosis. In contrast, only one of the 10 tested C. camelliae SSPs was able to induce a limited amount of necrosis. Analysis of chimeric proteins consisting of domains from both a necrosis-inducing and a non-necrosis-inducing SSP demonstrated that the C-terminus of the S. sclerotiorum SSP is essential for necrosis-inducing function. Deletion of the BcSSP2 homolog from B. cinerea did not affect growth or pathogenesis. Thus, this research uncovered a family of highly conserved SSPs present in diverse ascomycetes that exhibit contrasting necrosis-inducing functions. © 2020 The Authors. Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.PURPOSE The purpose of this study was to determine the relationship between objective and subjective findings of motor function measures in older adults following a 12-week adapted tango intervention. METHODS A quasi-experimental repeated-measures design was used. Secondary analysis of the experimental group (Tango) data is reported here. The study took place in diverse senior independent living communities in an urban metropolitan area. Sixty-two older adults participated (n = 62, age M = 82.3, SD = 8.8 years). Participants were assigned to 20 sessions of 90-min tango classes over 12 weeks. Motor function, depression, mental, and physical quality of life were measured before and after intervention. At post-test, satisfaction and subjective measures of motor function were assessed by participants indicating their level of agreement with statements that they improved in objective domains of motor function. Correlations were performed between subjectively rated agreement and changes in motor function, depression, and quality of life. RESULTS A strong negative correlation was found between subjective ratings and empirically observed improvements in balance (r = -.423) and endurance (r = -.241), although participant ratings correlated moderately with manual dual tasking (r = .319) and weakly correlated with lower body strength (r = .188). Decreased depression was correlated with subjectively improved lower body strength (r = .271) and endurance (r = .254). Improved mental quality of life was strongly (r = .423) correlated with subjectively improved balance and moderately correlated with improved manual dual tasking (r = .306). CONCLUSION After rehabilitation, even with improved depression and quality of life, older adults may not perceive empirically observed motor function improvements, particularly in balance and lower body strength. This study informs clinicians on the importance of assessing subjective data during rehabilitation to provide older adults with person-centred care. © 2020 John Wiley & Sons, Ltd.Small-molecule inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclinical species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clinical trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-molecule TGFβRI inhibitor, BMS-986260, in rats and dogs. selleckchem Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathology at systemic exposures that would have been targeted clinically, preventing further development with this dosing schedule. These toxicities were not observed in either species in 1-month studies using the same doses on an intermittent-dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3-month studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1-month study was that the rats in the 3-month study were 2 weeks younger at the start of dosing. Therefore, a follow-up 1-month study was conducted to evaluate whether the age of rats influences sensitivity to target-mediated toxicity. Using the same dosing schedule and similar doses as in the 3-month study, there was no difference in the toxicity of BMS-986260 in young (8 weeks) or adult (8 months) rats. In summary, an intermittent-dosing schedule mitigated target-based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS-986260 was terminated. © 2020 John Wiley & Sons, Ltd.Moderate-intensity exercise sessions are incorporated into heat-acclimation and hypoxic-training protocols to improve performance in hot and hypoxic environments, respectively. Consequently, a training effect might contribute to aerobic performance gains, at least in less fit participants. To explore the interaction between fitness level and a training stimulus commonly applied during acclimation protocols, we recruited 10 young males of a higher (more fit-MF, peak aerobic power [VO2peak ] 57.9 [6.2] ml·kg-1 ·min-1 ) and 10 of a lower (less fit-LF, VO2peak 41.7 [5.0] ml·kg-1 ·min-1 ) fitness level. They underwent 10 daily exercise sessions (60 min@50% peak power output [Wpeak ]) in thermoneutral conditions. The participants performed exercise testing on a cycle ergometer before and after the training period in normoxic (NOR), hypoxic (13.5% Fi O2 ; HYP), and hot (35°C, 50% RH; HE) conditions in a randomized and counterbalanced order. Each test consisted of two stages; a steady-state exercise (30 min@40% NOR Wpeak to evaluate thermoregulatory function) followed by incremental exercise to exhaustion. VO2peak increased by 9.2 (8.5)% (p = .024) and 10.2 (15.4)% (p = .037) only in the LF group in NOR and HE, respectively. Wpeak increases were correlated with baseline values in NOR (r = -.58, p = .010) and HYP (r = -.52, p = .018). MF individuals improved gross mechanical efficiency in HYP. Peak sweat rate increased in both groups in HE, whereas MF participants activated the forehead sweating response at lower rectal temperatures post-training. In conclusion, an increase in VO2peak but not mechanical efficiency seems probable in LF males after a 10-day moderate-exercise training protocol. © 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.While poly(acyclic orthoester)s (PAOEs) have many appealing features for drug delivery, their application is significantly hindered by a lack of facile synthetic methods. Reported here is a simple method for synthesizing acyclic diketene acetal monomers from diols and vinyl ether, and their polymerization with a diol to first synthesize PAOEs. The PAOEs rapidly hydrolyze at lysosomal pH. With the help of a cationic lipid, ovalbumin, a model vaccine antigen was efficiently loaded into PAOEs nanoparticles using a double emulsion method. These nanoparticles efficiently delivered ovalbumin into the cytosol of dendritic cells and demonstrated enhanced antigen presentation over poly(lactic-co-glycolic acid) (PLGA) nanoparticles. PAOEs are promising vehicles for intracellular delivery of biopharmaceuticals and could increase the utility of poly(orthoesters) in biomedical research. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.Liquid Chromatography coupled to Tandem Mass Spectrometry (LC-MS/MS) based methods are currently the top choice for high-throughput, quantitative measurements of the proteome. While traditional proteomics LC-MS/MS methods can suffer from issues such as low reproducibility and quantitative accuracy due to its stochastic nature, recent improvements in acquisition protocols have resulted in methods that can overcome these challenges. Data-independent acquisition (DIA) is a novel mass spectrometric method that does so by using a deterministic acquisition strategy. These new approaches will allow researchers to apply MS on more complex samples, however, existing heuristic and expert-knowledge based methods will struggle with keeping pace of the increasing complexity of the resulting data. Deep learning (DL) based methods have been shown to be more adept at handling large amounts of complex data than traditional methods in many other fields, such as computer vision and natural language processing. Proteomics is also entering a phase where the size and complexity of the data will require us to look towards scalable and data-driven DL pipelines. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.Biocompatible and proteolysis-resistant poly-β-peptides have broad applications and are dominantly synthesized via the harsh and water-sensitive ring-opening polymerization of β-lactams in a glovebox or using a Schlenk line, catalyzed by the strong base LiN(SiMe3 )2 . We have developed a controllable and water-insensitive ring-opening polymerization of β-amino acid N-thiocarboxyanhydrides (β-NTAs) that can be operated in open vessels to prepare poly-β-peptides in high yields, with diverse functional groups, variable chain length, narrow dispersity and defined architecture. These merits imply wide applications of β-NTA polymerization and resulting poly-β-peptides, which is validated by the finding of a HDP-mimicking poly-β-peptide with potent antimicrobial activities. The living β-NTA polymerization enables the controllable synthesis of random, block copolymers and easy tuning of both terminal groups of polypeptides, which facilitated the unravelling of the antibacterial mechanism using the fluorophore-labelled poly-β-peptide.
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