Classifying Intensity Domains From Arm Cycle Ergometry Differs Versus Leg Cycling Ergometry.

ABSTRACT: Astorino, TA, Robson, T, and McMillan, DW. Classifying intensity domains from arm cycle ergometry differs versus leg cycling ergometry. J Strength Cond Res 37(11): 2192-2199, 2023-This study compared the distribution of exercise intensity domains in response to progressive leg cycle ergometry (LCE) and arm cycle ergometry (ACE). Seventeen active men and women (age and body fat = 26 ± 7 years and 18 ± 3%) initially performed graded exercise on each modality to assess maximal oxygen uptake (V̇o2max) and peak power output (PPO). Using a randomized crossover design, they subsequently performed moderate intensity continuous exercise consisting of three 15-minute bouts at 20, 40, and 60% PPO on each modality. Gas exchange data (V̇o2, V̇co2, and VE), respiratory exchange ratio, heart rate (HR), blood lactate concentration (BLa), and perceptual responses were acquired. Only 2 subjects were classified in the same intensity domains across modalities, with LCE eliciting more subjects exercising at "vigorous" and "near-maximal" intensities than ACE. Time spent above 70 (22 ± 7 vs. 15 ± 8 minutes, d = 1.03) and 80 %HRmax (15 ± 6 vs. 9 ± 6 minutes, d = 1.04) was significantly greater with LCE vs. ACE. Compared with ACE, LCE revealed significantly higher (p < 0.05) peak (94 ± 6 vs. 88 ± 9 %HRmax, d = 0.81) and mean HR (73 ± 6 vs. 66 ± 6 %HRmax, d = 1.20), V̇o2 (54 ± 5 vs. 50 ± 7 %V̇o2max, d = 0.68), and BLa (5.5 ± 2.0 vs. 4.7 ± 1.5 mM, d = 0.48). The results exhibit that progressive leg cycling at identical intensities elicits a greater cardiometabolic stimulus than ACE.

Effect of infusion set replacement intervals on catheter-related bloodstream infections (RSVP): a randomised, controlled, equivalence (central venous access device)-non-inferiority (peripheral arterial catheter) trial.

BACKGROUND: The optimal duration of infusion set use to prevent life-threatening catheter-related bloodstream infection (CRBSI) is unclear. We aimed to compare the effectiveness and costs of 7-day (intervention) versus 4-day (control) infusion set replacement to prevent CRBSI in patients with central venous access devices (tunnelled cuffed, non-tunnelled, peripherally inserted, and totally implanted) and peripheral arterial catheters. METHODS: We did a randomised, controlled, assessor-masked trial at ten Australian hospitals. Our hypothesis was CRBSI equivalence for central venous access devices and non-inferiority for peripheral arterial catheters (both 2% margin). Adults and children with expected greater than 24 h central venous access device-peripheral arterial catheter use were randomly assigned (1:1; stratified by hospital, catheter type, and intensive care unit or ward) by a centralised, web-based service (concealed before allocation) to infusion set replacement every 7 days, or 4 days. This included crystalloids, non-lipid parenteral nutrition, and medication infusions. Patients and clinicians were not masked, but the primary outcome (CRBSI) was adjudicated by masked infectious diseases physicians. The analysis was modified intention to treat (mITT). This study is registered with the Australian New Zealand Clinical Trials Registry ACTRN12610000505000 and is complete. FINDINGS: Between May 30, 2011, and Dec, 9, 2016, from 6007 patients assessed, we assigned 2944 patients to 7-day (n=1463) or 4-day (n=1481) infusion set replacement, with 2941 in the mITT analysis. For central venous access devices, 20 (1·78%) of 1124 patients (7-day group) and 16 (1·46%) of 1097 patients (4-day group) had CRBSI (absolute risk difference [ARD] 0·32%, 95% CI -0·73 to 1·37). For peripheral arterial catheters, one (0·28%) of 357 patients in the 7-day group and none of 363 patients in the 4-day group had CRBSI (ARD 0·28%, -0·27% to 0·83%). There were no treatment-related adverse events. INTERPRETATION: Infusion set use can be safely extended to 7 days with resultant cost and workload reductions. FUNDING: Australian National Health and Medical Research Council.

Characterization of an experimental model to determine streptococcal M protein-induced autoimmune cardiac and neurobehavioral abnormalities.

Group A streptococcal (GAS) infection is associated with a spectrum of autoimmune diseases including acute rheumatic fever/rheumatic heart disease (ARF/RHD) and neurobehavioral abnormalities. Antibodies against GAS M proteins cross-react with host tissue proteins in the heart and brain leading to the symptomatology observed in ARF/RHD. As throat carriage of Streptococcus dysgalactiae subspecies equisimilis (SDSE) has been reported to be relatively high in some ARF/RHD endemic regions compared with GAS, and both SDSE and GAS express coiled-coil surface protein called M protein, we hypothesized that streptococci other than GAS can also associated with ARF/RHD and neurobehavioral abnormalities. Neurobehavioral assessments and electrocardiography were performed on Lewis rats before and after exposure to recombinant GAS and SDSE M proteins. Histological assessments were performed to confirm inflammatory changes in cardiac and neuronal tissues. ELISA and Western blot analysis were performed to determine the cross-reactivity of antibodies with host connective, cardiac and neuronal tissue proteins. Lewis rats injected with M proteins either from GAS or SDSE developed significant cardiac functional and neurobehavioral abnormalities in comparison to control rats injected with phosphate-buffered saline. Antibodies against GAS and SDSE M proteins cross-reacted with cardiac, connective and neuronal proteins. Serum from rats injected with streptococcal antigens showed higher immunoglobulin G binding to the striatum and cortex of the brain. Cardiac and neurobehavioral abnormalities observed in our experimental model were comparable to the cardinal symptoms observed in patients with ARF/RHD. Here for the first time, we demonstrate in an experimental model that M proteins from different streptococcal species could initiate and drive the autoimmune-mediated cardiac tissue damage and neurobehavioral abnormalities.

Energy expenditure and nutrient intake after spinal cord injury: a comprehensive review and practical recommendations.

Many persons with spinal cord injury (SCI) have one or more preventable chronic diseases related to excessive energetic intake and poor eating patterns. Appropriate nutrient consumption relative to need becomes a concern despite authoritative dietary recommendations from around the world. These recommendations were developed for the non-disabled population and do not account for the injury-induced changes in body composition, hypometabolic rate, hormonal dysregulation and nutrition status after SCI. Because evidence-based dietary reference intake values for SCI do not exist, ensuring appropriate consumption of macronutrient and micronutrients for their energy requirements becomes a challenge. In this compressive review, we briefly evaluate aspects of energy balance and appetite control relative to SCI. We report on the evidence regarding energy expenditure, nutrient intake and their relationship after SCI. We compare these data with several established nutritional guidelines from American Heart Association, Australian Dietary Guidelines, Dietary Guidelines for Americans, Institute of Medicine Dietary Reference Intake, Public Health England Government Dietary Recommendations, WHO Healthy Diet and the Paralyzed Veterans of America (PVA) Clinical Practice Guidelines. We also provide practical assessment and nutritional recommendations to facilitate a healthy dietary pattern after SCI. Because of a lack of strong SCI research, there are currently limited dietary recommendations outside of the PVA guidelines that capture the unique nutrient needs after SCI. Future multicentre clinical trials are needed to develop comprehensive, evidence-based dietary reference values specific for persons with SCI across the care continuum that rely on accurate, individual assessment of energy need.

Use of low-frequency contact ultrasonic debridement with and without polyhexamethylene biguanide in hard-to-heal leg ulcers: an RCT.

OBJECTIVE: The primary aim of this research was to investigate the combination effect of polyhexamethylene biguanide (PHMB) and low-frequency contact ultrasonic debridement (LFCUD) on the bacterial load in hard-to-heal wounds in adults, compared with ultrasonic debridement alone. Secondary outcomes included wound healing, quality of life (QoL) and pain scores. METHOD: In this single-blinded, randomised, controlled trial participants were randomised to two groups. All participants received LFCUD weekly for six weeks, plus six weeks of weekly follow-up. The intervention group received an additional 15-minute topical application of PHMB post-LFCUD, at each dressing change and in a sustained dressing product. The control group received non-antimicrobial products and the wounds were cleansed with clean water or saline. Wound swabs were taken from all wounds for microbiological analysis at weeks 1, 3, 6 and 12. RESULTS: A total of 50 participants took part. The intervention group (n=25) had a lower bacterial load at week 12 compared with the control group (n=25) (p<0.001). There was no difference in complete wound healing between the groups (p=0.47) or wound-related QoL (p=0.15). However, more wounds deteriorated in the control group (44%) compared with the intervention group (8%, p=0.01). A higher proportion of wounds reduced in size in the intervention group (61% versus 12%, p=0.019). Pain was lower in the intervention group at week six, compared with controls (p=0.04). CONCLUSION: LFCUD without the addition of an antimicrobial agent such as PHMB, cannot be recommended. Further research requires longer follow-up time and would benefit from being powered sufficiently to test the effects of multiple covariates.

Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms.

Autoantibodies against leucine-rich glioma inactivated 1 (LGI1) are found in patients with limbic encephalitis and focal seizures. Here, we generate patient-derived monoclonal antibodies (mAbs) against LGI1. We explore their sequences and binding characteristics, plus their pathogenic potential using transfected HEK293T cells, rodent neuronal preparations, and behavioural and electrophysiological assessments in vivo after mAb injections into the rodent hippocampus. In live cell-based assays, LGI1 epitope recognition was examined with patient sera (n = 31), CSFs (n = 11), longitudinal serum samples (n = 15), and using mAbs (n = 14) generated from peripheral B cells of two patients. All sera and 9/11 CSFs bound both the leucine-rich repeat (LRR) and the epitempin repeat (EPTP) domains of LGI1, with stable ratios of LRR:EPTP antibody levels over time. By contrast, the mAbs derived from both patients recognized either the LRR or EPTP domain. mAbs against both domain specificities showed varied binding strengths, and marked genetic heterogeneity, with high mutation frequencies. LRR-specific mAbs recognized LGI1 docked to its interaction partners, ADAM22 and ADAM23, bound to rodent brain sections, and induced internalization of the LGI1-ADAM22/23 complex in both HEK293T cells and live hippocampal neurons. By contrast, few EPTP-specific mAbs bound to rodent brain sections or ADAM22/23-docked LGI1, but all inhibited the docking of LGI1 to ADAM22/23. After intrahippocampal injection, and by contrast to the LRR-directed mAbs, the EPTP-directed mAbs showed far less avid binding to brain tissue and were consistently detected in the serum. Post-injection, both domain-specific mAbs abrogated long-term potentiation induction, and LRR-directed antibodies with higher binding strengths induced memory impairment. Taken together, two largely dichotomous populations of LGI1 mAbs with distinct domain binding characteristics exist in the affinity matured peripheral autoantigen-specific memory pools of individuals, both of which have pathogenic potential. In human autoantibody-mediated diseases, the detailed characterization of patient mAbs provides a valuable method to dissect the molecular mechanisms within polyclonal populations.

Substrate metabolism during recovery from circuit resistance exercise in persons with spinal cord injury.

INTRODUCTION: Whole body energy expenditure and lipid oxidation (Lox) are upregulated during and after exercise. Persons with spinal cord injury (SCI) generally have a blunted ability to utilize fat during exercise, but it is unknown if their substrate partitioning is affected during recovery from exercise. PURPOSE: To determine the effect of a single session of upper body circuit resistance exercise (CRE) on energy expenditure and Lox during exercise recovery in persons with and without SCI. METHODS: Twenty four persons (3 groups; 7 male and 1 female per group) without paralysis (neurologically intact; N) or with chronic (≥ 1 yr) paraplegia (P) or tetraplegia (T) participated. Energy expenditure and substrate partitioning were assessed via indirect calorimetry before, during, and three times after (up to 120 min after) a single session of CRE, or time-matched seated control (CON). RESULTS: During CRE, all groups experienced a similar relative increase in oxygen consumption (49 ± 13, 55 ± 11, and 48 ± 15% VO2peak for N, P, and T, respectively). The Post0-120 energy expenditure was greater following CRE vs. CON (P < 0.01) and independent of injury characteristics (10.6, 22.6, and 14.3% higher than CON for N, P, and T; P = 0.21). The absolute increase in Lox above CON during recovery was similar for N, P, and T (5.74 ± 2.81, 6.62 ± 3.10, and 4.50 ± 3.91 g, respectively; P = 0.45). CONCLUSIONS: Energy expenditure and lipid utilization was increased similarly following circuit exercise in persons without and with spinal cord injury in a manner independent of level of injury.

Physiological responses to moderate intensity continuous and high-intensity interval exercise in persons with paraplegia.

STUDY DESIGN: Randomized crossover. OBJECTIVES: To test differences in the duration and magnitude of physiological response to isocaloric moderate intensity continuous (MICE) and high-intensity interval exercise (HIIE) sessions in persons with spinal cord injury (SCI). SETTING: Academic medical center in Miami, FL, USA. METHODS: Ten adult men (mean ± s.d.; 39 ± 10 year old) with chronic (13.2 ± 8.8 year) paraplegia (T2-T10) completed a graded exercise test. Then, in a randomized order, participants completed MICE and HIIE for a cost of 120 kcal. MICE was performed at 24.6% POpeak. During HIIE, exercise was completed in 2 min work and recovery phases at 70%:10% POpeak. RESULTS: MICE and HIIE were isocaloric (115.9 ± 21.8 and 116.6 ± 35.0 kcal, respectively; p = 0.903), but differed in duration (39.8 ± 4.6 vs 32.2 ± 6.2 min; p < 0.001) and average respiratory exchange ratio (RER; 0.90 ± 0.08 vs 1.01 ± 0.07; p = 0.002). During MICE, a workrate of 24.6 ± 6.7% POpeak elicited a V̇O2 of 53.1 ± 6.5% V̇O2peak (10.1 ± 2.2 ml kg-1 min-1). During HIIE, a workrate at 70% POpeak elicited 88.3 ± 6.7% V̇O2peak (16.9 ± 4.2 ml kg-1 min-1), and 29.4 ± 7.7% of the session was spent at or above 80% V̇O2peak. During HIIE working phase, RER declined from the first to last interval (1.08 ± 0.07 vs 0.98 ± 0.09; p < 0.001), reflecting an initially high but declining glycolytic rate. CONCLUSIONS: Compared with MICE, HIIE imposed a greater physiological stimulus while requiring less time to achieve a target caloric expenditure. Thus, exercise intensity might be an important consideration in the tailoring of exercise prescription to address the cardiometabolic comorbidities of SCI.

Use of low-frequency contact ultrasonic debridement with and without polyhexamethylene biguanide in hard-to-heal leg ulcers: an RCT protocol.

OBJECTIVE: The purpose of this research is to investigate the effect of low-frequency contact ultrasonic debridement therapy (LFCUD) in hard-to-heal wounds with suspected biofilm, and compare the effect with or without a surfactant antimicrobial on bacterial colony counts and wound healing rates. METHOD: A single-blinded randomised controlled trial (RCT) will investigate the combination of LFCUD and the antiseptic polyhexamethylene biguanide with a surfactant betaine (referred to in this paper as PHMB) as a topical solution post-treatment and in a sustained dressing, compared with use of LFCUD alone. Potential participants from a community wound clinic (n=50) will be invited to take part in the 12-week trial. Wound swabs and tissue samples will be analysed for bacterial type and quantity, before and after treatments, using traditional culture techniques and advanced molecular methods. Wound healing, pain, quality of life and biofilm (via a specifically designed tool) will also be measured. DISCUSSION: Bacteria have the potential to cause a hard-to-heal wound, particularly when antibiotics are too frequently and unnecessarily prescribed, resulting in antibiotic-resistant microorganisms. Appropriate care is vital when caring for hard-to-heal wounds to avoid these scenarios. With no simple laboratory method available to identify or treat wound biofilm, clinicians rely on their expertise in wound management. This study aims to provide in vivo evidence on the effectiveness of PHMB, to prevent the reformation of biofilm when applied after LFCUD. The aim is to provide evidence-based and more cost-effective wound care.

Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A.

Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral ß-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open ß-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties.

Sense of community, pathway to, or bridge from alienation?

Psychological Sense of Community (PSOC) represents a formative conceptual offering of Community Psychology to the social sciences. Nearly five decades ago, PSOC offered a window into the influence of ecological factors to understanding the emotional and behavioral well-being of members of disenfranchised and underserved segments of the population, especially members of minority and low-income subgroups. Our discipline's founders viewed PSOC as one promising vehicle for pursuing the desired paradigmatic shift from individual to systemically focused interventions to achieve intended outcomes of the emerging community mental health movement. This Commentary reflects the authors' shared thoughts to the adoption of PSOC by conservative spokespersons to explain the resistance of some to the diversification of the population and growing voice of progressive advocates.

Dressings and securements for the prevention of peripheral intravenous catheter failure in adults (SAVE): a pragmatic, randomised controlled, superiority trial.

BACKGROUND: Two billion peripheral intravenous catheters (PIVCs) are used globally each year, but optimal dressing and securement methods are not well established. We aimed to compare the efficacy and costs of three alternative approaches to standard non-bordered polyurethane dressings. METHODS: We did a pragmatic, randomised controlled, parallel-group superiority trial at two hospitals in Queensland, Australia. Eligible patients were aged 18 years or older and required PIVC insertion for clinical treatment, which was expected to be required for longer than 24 h. Patients were randomly assigned (1:1:1:1) via a centralised web-based randomisation service using random block sizes, stratified by hospital, to receive tissue adhesive with polyurethane dressing, bordered polyurethane dressing, a securement device with polyurethane dressing, or polyurethane dressing (control). Randomisation was concealed before allocation. Patients, clinicians, and research staff were not masked because of the nature of the intervention, but infections were adjudicated by a physician who was masked to treatment allocation. The primary outcome was all-cause PIVC failure (as a composite of complete dislodgement, occlusion, phlebitis, and infection [primary bloodstream infection or local infection]). Analysis was by modified intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000769987. FINDINGS: Between March 18, 2013, and Sept 9, 2014, we randomly assigned 1807 patients to receive tissue adhesive with polyurethane (n=446), bordered polyurethane (n=454), securement device with polyurethane (n=453), or polyurethane (n=454); 1697 patients comprised the modified intention-to-treat population. 163 (38%) of 427 patients in the tissue adhesive with polyurethane group (absolute risk difference -4·5% [95% CI -11·1 to 2·1%], p=0·19), 169 (40%) of 423 of patients in the bordered polyurethane group (-2·7% [-9·3 to 3·9%] p=0·44), 176 (41%) of 425 patients in the securement device with poplyurethane group (-1·2% [-7·9% to 5·4%], p=0·73), and 180 (43%) of 422 patients in the polyurethane group had PIVC failure. 17 patients in the tissue adhesive with polyurethane group, two patients in the bordered polyurethane group, eight patients in the securement device with polyurethane group, and seven patients in the polyurethane group had skin adverse events. Total costs of the trial interventions did not differ significantly between groups. INTERPRETATION: Current dressing and securement methods are commonly associated with PIVC failure and poor durability, with simultaneous use of multiple products commonly required. Cost is currently the main factor that determines product choice. Innovations to achieve effective, durable dressings and securements, and randomised controlled trials assessing their effectiveness are urgently needed. FUNDING: Australian National Health and Medical Research Council.

Antibacterial 5α-Spirostane Saponins from the Fruit of Cordyline manners-suttoniae.

Antibacterial-activity-guided fractionation of a dichloromethane extract from the fruit of Cordyline manners-suttoniae and subsequent structure-activity investigations resulted in the identification of 10 new (1-10) and one known (11) 5α-spirostane saponin. The structures of the new compounds were established by 1D and 2D NMR analyses. The absolute configurations of the isolated compounds were determined by X-ray diffraction analysis or chemical derivatizations. The most active compound, suttonigenin F (6), inhibited the Gram-positive bacteria Staphylococcus aureus with MIC75 values that were comparable to those of the antibiotic chloramphenicol. Structure-activity relationships were also obtained from the assessment of antibacterial and cytotoxic activities of the isolated saponins.

IL-1/inhibitory κB kinase ε-induced glycolysis augment epithelial effector function and promote allergic airways disease.

BACKGROUND: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma. OBJECTIVES: We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma. METHODS: We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis. RESULTS: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1ß into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1ß or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1ß- or IL-1α-mediated proinflammatory responses and the stimulatory effects of IL-1ß on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1ß and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1ß levels, and lactate content correlated negatively with lung function. CONCLUSIONS: Collectively, these findings demonstrate that IL-1ß/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.

Group G Streptococcus Induces an Autoimmune Carditis Mediated by Interleukin 17A and Interferon γ in the Lewis Rat Model of Rheumatic Heart Disease.

Acute rheumatic fever and rheumatic heart disease (ARF/RHD) have long been described as autoimmune sequelae of Streptococcus pyogenes or group A streptococcal (GAS) infection. Both antibody and T-cell responses against immunodominant GAS virulence factors, including M protein, cross-react with host tissue proteins, triggering an inflammatory response leading to permanent heart damage. However, in some ARF/RHD-endemic regions, throat carriage of GAS is low. Because Streptococcus dysgalactiae subspecies equisimilis organisms, also known as ß-hemolytic group C streptococci and group G streptococci (GGS), also express M protein, we postulated that streptococci other than GAS may have the potential to initiate or exacerbate ARF/RHD. Using a model initially developed to investigate the uniquely human disease of ARF/RHD, we have discovered that GGS causes interleukin 17A/interferon γ-induced myocarditis and valvulitis, hallmarks of ARF/RHD. Remarkably the histological, immunological, and functional changes in the hearts of rats exposed to GGS are identical to those exposed to GAS. Furthermore, antibody cross-reactivity to cardiac myosin was comparable in both GGS- and GAS-exposed animals, providing additional evidence that GGS can induce and/or exacerbate ARF/RHD.

The Aminotriazole Antagonist Cmpd-1 Stabilises a Distinct Inactive State of the Adenosine 2A Receptor.

The widely expressed G-protein coupled receptors (GPCRs) are versatile signal transducer proteins that are attractive drug targets but structurally challenging to study. GPCRs undergo a number of conformational rearrangements when transitioning from the inactive to the active state but have so far been believed to adopt a fairly conserved inactive conformation. Using 19 F NMR spectroscopy and advanced molecular dynamics simulations we describe a novel inactive state of the adenosine 2A receptor which is stabilised by the aminotriazole antagonist Cmpd-1. We demonstrate that the ligand stabilises a unique conformation of helix V and present data on the putative binding mode of the compound involving contacts to the transmembrane bundle as well as the extracellular loop 2.

Epitope determines efficacy of therapeutic anti-Tau antibodies in a functional assay with human Alzheimer Tau.

In Alzheimer's disease (AD) and other tauopathies, the cytosolic protein Tau misfolds and forms intracellular aggregates which accumulate within the brain leading to neurodegeneration. Clinical progression is tightly linked to the progressive spread of Tau pathology throughout the brain, and several lines of evidence suggest that Tau aggregates or "seeds" may propagate pathology by spreading from cell to cell in a "prion like" manner. Accordingly, blocking the spread of extracellular seeds with an antibody could be a viable therapeutic approach. However, as the structure of Tau seeds is unknown, it is only possible to rationally design therapeutic Tau antibodies by making a priori assumptions. To avoid this, we developed a robust and quantitative cell based assay and employed an unbiased screening approach to identify the antibody with the highest activity against human Tau seeds. The selected antibody (D), directed to the mid-region of Tau (amino acids 235-250), potently blocked the seeding of human AD Tau and was also fully efficacious against seeds from progressive supranuclear palsy. When we compared this antibody with previously described reference antibodies, we were surprised to find that none of these antibodies showed comparable efficacy against human pathological seeds. Our data highlight the difficulty of predicting antibody accessible epitopes on pathological Tau seeds and question the potential efficacy of some of the Tau antibodies that are currently in clinical development.

Hierarchically Patterned Noncovalent Functionalization of 2D Materials by Controlled Langmuir-Schaefer Conversion.

Noncovalent monolayer chemistries are often used to functionalize 2D materials. Nanoscopic ligand ordering has been widely demonstrated (e.g., lying-down lamellar phases of functional alkanes); however, combining this control with micro- and macroscopic patterning for practical applications remains a significant challenge. A few reports have demonstrated that standing phase Langmuir films on water can be converted into nanoscopic lying-down molecular domains on 2D substrates (e.g., graphite), using horizontal dipping (Langmuir-Schaefer, LS, transfer). Molecular patterns are known to form at scales up to millimeters in Langmuir films, suggesting the possibility of transforming such structures into functional patterns on 2D materials. However, to our knowledge, this approach has not been investigated, and the rules governing LS conversion are not well understood. In part, this is because the conversion process is mechanistically very different from classic LS transfer of standing phases; challenges also arise due to the need to characterize structure in noncovalently adsorbed ligand layers <0.5 nm thick, at scales ranging from millimeters to nanometers. Here, we show that scanning electron microscopy enables diynoic acid lying-down phases to be imaged across this range of scales; using this structural information, we establish conditions for LS conversion to create hierarchical microscopic and nanoscopic functional patterns. Such control opens the door to tailoring noncovalent surface chemistry of 2D materials to pattern local interactions with the environment.

Ablation of Glutaredoxin-1 Modulates House Dust Mite-Induced Allergic Airways Disease in Mice.

Protein S-glutathionylation (PSSG) is an oxidant-induced post-translational modification of protein cysteines that impacts structure and function. The oxidoreductase glutaredoxin-1 (Glrx1) under physiological conditions catalyzes deglutathionylation and restores the protein thiol group. The involvement of Glrx1/PSSG in allergic inflammation induced by asthma-relevant allergens remains unknown. In the present study, we examined the impact of genetic ablation of Glrx1 in the pathogenesis of house dust mite (HDM)-induced allergic airways disease in mice. Wild-type (WT) or Glrx1(-/-) mice were instilled intranasally with HDM on 5 consecutive days for 3 weeks. As expected, overall PSSG was increased in Glrx1(-/-) HDM mice as compared with WT animals. Total cells in bronchoalveolar lavage fluid were similarly increased in HDM-treated WT and Glrx1(-/-) mice. However, in response to HDM, mice lacking Glrx1 demonstrated significantly more neutrophils and macrophages but fewer eosinophils as compared with HDM-exposed WT mice. mRNA expression of the Th2-associated cytokines IL-13 and IL-6, as well as mucin-5AC (Muc5ac), was significantly attenuated in Glrx1(-/-) HDM-treated mice. Conversely, mRNA expression of IFN-γ and IL-17A was increased in Glrx1(-/-) HDM mice compared with WT littermates. Restimulation of single-cell suspensions isolated from lungs or spleens with HDM resulted in enhanced IL-17A and decreased IL-5 production in cells derived from inflamed Glrx1(-/-) mice compared with WT animals. Finally, HDM-induced tissue damping and elastance were significantly attenuated in Glrx1(-/-) mice compared with WT littermates. These results demonstrate that the Glrx1-PSSG axis plays a pivotal role in HDM-induced allergic airways disease in association with enhanced type 2 inflammation and restriction of IFN-γ and IL-17A.

Perceptual Changes in Response to Two Regimens of Interval Training in Sedentary Women.

This study examined acute and chronic changes in perceptual measures (rating of perceived exertion [RPE], affect, and arousal) in response to 2 regimens of high-intensity interval training (HIIT). Twenty-three healthy sedentary women (mean ± SD age and V[Combining Dot Above]O2max = 23.0 ± 5.7 years and 30.1 ± 4.4 ml·kg·min, respectively) were randomized to complete 12 weeks of one of 2 HIIT regimes, whereas an additional 7 women served as sedentary controls. Training was performed 3 days per week on a cycle ergometer and consisted of up to ten 1-minute bouts at moderate (60-80%Wmax = moderate intensity [MOD]) or more intense (80-90%Wmax = HI) workloads separated by active recovery. At baseline and every 3 weeks, RPE, affect, and arousal were measured during training using validated scales. Repeated measures analysis of variance was used to examine acute and chronic changes in these variables to HIIT. Data revealed significant (p < 0.001) increases in RPE and arousal and decreases (p < 0.001) in affect during acute HIIT, with RPE responses differing (p ≤ 0.05) between HI and MOD. However, acute changes in affect and arousal were similar in HI and MOD. Training led to a significant reduction in RPE, whereas both affect and arousal were unchanged (p > 0.05) after HIIT. Completion of moderate or more intense interval training reduces perceptions of RPE during training yet does not alter arousal or affect. RPE was reduced via training, yet large dependence on anaerobic metabolism during HIIT may minimize training-induced changes in affect.