IL-27 maintains cytotoxic Ly6C+ γδ T cells that arise from immature precursors.

In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αß-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFNγ-producing γδ T cells. We found that CD27+ Ly6C- cells convert into CD27+Ly6C+ cells, and these CD27+Ly6C+ cells control cancer progression in mice, while the CD27+Ly6C- cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature γδ-T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human Vδ2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C- cell and human Vδ1+ cell functions. These data reveal increased complexity within IFNγ-producing γδ-T cells, comprising immature and terminally differentiated subsets, that offer new insights into unconventional T-cell biology.

Undercarboxylated osteocalcin and ibandronate combination ameliorates hindlimb immobilization-induced muscle wasting.

Immobilization leads to muscle wasting and insulin resistance, particularly during ageing. It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti-osteoporosis treatment, might protect muscle wasting independent of ucOC. We hypothesize that the combination of ucOC and ibandronate (IBN) treatments has superior protective effects against immobilization-induced muscle wasting and insulin resistance than either treatment alone. C57BL/6J mice were hindlimb-immobilized for two weeks, with injections of vehicle, ucOC (90 ng/g daily) and/or IBN (2 µg/g weekly). Insulin/oral glucose tolerance tests (ITT/OGTT) were performed. Immediately after immobilization, muscles (extensor digitorum longus (EDL), soleus, tibialis anterior, gastrocnemius and quadriceps) were isolated and measured for muscle mass. Insulin-stimulated glucose uptake (EDL and soleus) was examined. Phosphorylation/expression of proteins in anabolic/catabolic pathways were examined in quadriceps. Primary human myotubes derived from older adult muscle biopsies were treated with ucOC and/or IBN, then signalling proteins were analysed. Combined treatment, but not individual treatments, significantly increased the muscle weight/body weight ratio in immobilized soleus (31.7%; P = 0.013) and quadriceps (20.0%; P = 0.0008) muscles, concomitant with elevated p-Akt (S473)/Akt ratio (P = 0.0047). Combined treatment also enhanced whole-body glucose tolerance (16.6%; P = 0.0011). In human myotubes, combined treatment stimulated greater activation of ERK1/2 (P = 0.0067 and 0.0072) and mTOR (P = 0.036), and led to a lesser expression of Fbx32 (P = 0.049) and MuRF1 (P = 0.048) than individual treatments. These findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing. KEY POINTS: It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti-osteoporosis treatment, might protect against muscle wasting independent of ucOC. The combination treatment of ucOC and ibandronate was shown to exert a greater therapeutic effect against immobilization-induced muscle wasting, and led to greater activation of anabolic pathway and less expression of catabolic signalling proteins in myotubes derived from older adults, compared with individual treatments. The combination treatment was found to improve whole-body glucose tolerance. Our findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing.

Chemokine receptors coordinately regulate macrophage dynamics and mammary gland development.

Macrophages are key regulators of developmental processes, including those involved in mammary gland development. We have previously demonstrated that the atypical chemokine receptor ACKR2 contributes to the control of ductal epithelial branching in the developing mammary gland by regulating macrophage dynamics. ACKR2 is a chemokine-scavenging receptor that mediates its effects through collaboration with inflammatory chemokine receptors (iCCRs). Here, we reveal reciprocal regulation of branching morphogenesis in the mammary gland, whereby stromal ACKR2 modulates levels of the shared ligand CCL7 to control the movement of a key population of CCR1-expressing macrophages to the ductal epithelium. In addition, oestrogen, which is essential for ductal elongation during puberty, upregulates CCR1 expression on macrophages. The age at which girls develop breasts is decreasing, which raises the risk of diseases including breast cancer. This study presents a previously unknown mechanism controlling the rate of mammary gland development during puberty and highlights potential therapeutic targets.

Unpacking and validating the "integration" core concept of physiology by an Australian team.

Consensus was reached on seven core concepts of physiology using the Delphi method, including "integration," outlined by the descriptor "cells, tissues, organs, and organ systems interact to create and sustain life." This core concept was unpacked by a team of 3 Australian physiology educators into hierarchical levels, identifying 5 themes and 10 subthemes, up to 1 level deep. The unpacked core concept was then circulated among 23 experienced physiology educators for comments and to rate both level of importance and level of difficulty for each theme and subtheme. Data were analyzed using a one-way ANOVA to compare between and within themes. The main theme (theme 1: the body is organized within a hierarchy of structures, from atoms to molecules, cells, tissues, organs, and organ systems) was almost universally rated as Essential. Interestingly, the main theme was also rated between Slightly Difficult to Not Difficult, which was significantly different from all other subthemes. There were two separate subsets of themes in relation to importance, with three themes rating between Essential and Important and the two other themes rating as Important. Two subsets in the difficulty of the main themes were also identified. While many core concepts can be taught concurrently, Integration requires the application of prior knowledge, with the expectation that learners should be able to apply concepts from "cell-cell communication," "homeostasis," and "structure and function," before understanding the overall Integration core concept. As such, themes from the Integration core concept should be taught within the endmost semesters of a Physiology program.NEW & NOTEWORTHY This article proposes the inclusion of a core concept regarding "integration" into physiology-based curricula, with the descriptor "cells, tissues, organs, and organ systems interact to create and sustain life." This concept expands prior knowledge and applies physiological understanding to real-world scenarios and introduces contexts such as medications, diseases, and aging to the student learning experience. To comprehend the topics within the Integration core concept, students will need to apply learned material from earlier semesters.

Unpacking the "movement of substances" core concept of physiology by an Australian team.

Australia-wide consensus was reached on seven core concepts of physiology. The "movement of substances" core concept with the descriptor "the movement of substances (ions or molecules) is a fundamental process that occurs at all levels of organization in the organism" was unpacked by a team of three Australian physiology educators from the Delphi Task Force into hierarchical levels. There were 10 themes and 23 subthemes arranged in a hierarchy, some 3 levels deep. Using a 5-point Likert scale, the unpacked core concept was then rated for level of importance for students to understand (ranging from 1 = Essential to 5 = Not Important) and level of difficulty for students (ranging from 1 = Very Difficult to 5 = Not Difficult) by the 23 physiology educators from different Australian universities, all with a broad range of teaching and curriculum experience. Survey data were analyzed using a one-way ANOVA to compare between and within concept themes. The main themes all were rated on average as important. There was a wide range of difficulty ratings and more variation for this concept compared with the other core concepts. This may in part be due to the physical forces such as gravity, electrochemistry, resistance, and thermodynamics that underpin this concept, which in themselves are inherently complex. Separation of concepts into subthemes can help prioritize learning activities and time spent on difficult concepts. Embedding of core concepts across curricula will allow commonality and consistency between programs of study and inform learning outcomes, assessment, and teaching and learning activities.NEW & NOTEWORTHY This article unpacks the core concept of the "movement of substances" within the body, with the aim to produce a resource that will help guide the teaching of physiology at tertiary education institutes in Australia. The concept introduces fundamental knowledge of the factors that drive substance movement and then applies them in physiological contexts.

Unpacking and validating the "physiological adaptation" core concept of physiology.

A national Task Force of 25 Australian physiology educators used the Delphi protocol to develop seven physiology core concepts that were agreed to nationally. The aim of the current study was to unpack the "physiological adaptation" core concept with the descriptor "organisms adjust and adapt to acute and chronic changes in the internal and external environments across the lifespan." This core concept was unpacked by three Task Force members and a facilitator into four themes and nine subthemes that encompass the role of stressors and disturbed homeostasis in adaptation and the capacity for, and the nature of, the physiological adaptation. Twenty-two Task Force members then provided feedback and rated the themes and subthemes for level of importance and difficulty for students to learn via an online survey using a five-point Likert scale. Seventeen respondents completed all survey questions. For all themes/subthemes, importance was typically rated 1 (Essential) or 2 (Important) (n = 17, means ±SD ranged from 1.1 ± 0.3 to 2.2 ± 0.9), and difficulty was typically rated 3 (Moderately Difficult) (n = 17, means ranged from 2.9 ± 0.7 to 3.4 ± 0.9). Subtle differences in the proportion of importance scores (n = 17, Fisher's exact: P = 0.004, ANOVA: F12,220 = 2.630, P = 0.003; n = 22, Fisher's exact: P = 0.002, ANOVA: F12,281 = 2.743, P < 0.001), but not difficulty scores, were observed between themes/subthemes, and free-text feedback was minor. The results suggest successful unpacking of the physiological adaptation core concept. The themes and subthemes can inform the design of learning outcomes, assessment, and teaching and learning activities that have commonality and consistency across curricula.NEW & NOTEWORTHY An Australian Task Force of physiology educators identified physiological adaptation as a core concept of physiology. It was subsequently unpacked into four themes and nine subthemes. These were rated, by the Task Force, Essential or Important and Moderately Difficult for students to learn. The themes and subthemes can inform the design of learning outcomes, assessments, and teaching and learning activities that have commonality and consistency across curricula.

Unpacking the renal system component of the "structure and function" core concept of physiology by an Australian team.

An Australia-wide consensus was reached on seven core concepts of physiology, one of which was "structure and function" with the descriptor "Structure and function are intrinsically related to all levels of the organism. In all physiological systems, the structure from a microscopic level to an organ level dictates its function." As a framework for the structure and function core concept, the renal system was unpacked by a team of 5 Australian Physiology educators from different universities with extensive teaching experience into hierarchical levels, with 5 themes and 25 subthemes up to 3 levels deep. Within theme 1, the structures that comprise the renal system were unpacked. Within theme 2, the physiological processes within the nephron such as filtration, reabsorption, and secretion were unpacked. Within theme 3, the processes involved in micturition were unpacked. In theme 4, the structures and processes involved in regulating renal blood flow and glomerular filtration were unpacked; and within theme 5, the role of the kidney in red blood cell production was unpacked. Twenty-one academics rated the difficulty and importance of each theme/subtheme, and results were analyzed using a one-way ANOVA. All identified themes were validated as "essential" to "important"/"moderately important" and rated between "difficult" to "not difficult." A similar framework consisting of structure, physiological processes, physical processes, and regulation can be used to unpack other body systems. Unpacking of the body systems will provide a list of what students should be taught in curricula across Australian universities and inform assessment and learning activities.NEW & NOTEWORTHY This is the first attempt to unpack and validate the "structure and function" core concept in physiology with all Australian educators. We unpacked the renal system into themes with hierarchical levels, which were validated by an experienced team of Australian physiology educators. Our unpacking of the "structure and function" core concept provides a specific framework for educators to apply this important concept in physiology education.

Unpacking and validating the "cell-cell communication" core concept of physiology by an Australian team.

An Australia-wide consensus was reached on seven core concepts of physiology, one of which was cell-cell communication. Three physiology educators from a "core concepts" Delphi task force "unpacked" this core concept into seven different themes and 60 subthemes. Cell-cell communication, previously unpacked and validated, was modified for an Australian audience to include emerging knowledge and adapted to increase student accessibility. The unpacked hierarchical framework for this core concept was rated by 24 physiology educators from separate Australian universities, using a five-point scale for level of importance for student understanding (ranging from 1 = Essential to 5 = Not Important) and level of difficulty (ranging from 1 = Very Difficult to 5 = Not Difficult). Data were analyzed with the Kruskal-Wallis test with Dunn's multiple comparison test. The seven themes were rated within a narrow range of importance (1.13-2.4), with ratings of Essential or Important, and statistically significant differences between the themes (P < 0.0001, n = 7). The variance for the difficulty rating was higher than for importance, ranging from 2.15 (Difficult) to 3.45 (between Moderately Difficult and Slightly Difficult). Qualitatively, it was suggested that some subthemes were similar and that these could be grouped. However, all themes and subthemes were ranked as Important, validating this framework. Once finalized and adopted across Australian universities, the unpacked core concept for cell-cell communication will enable the generation of tools and resources for physiology educators and improvements in consistency across curricula.NEW & NOTEWORTHY Seven core concepts, including cell-cell communication, were identified by an Australian Delphi task force of physiology educators. The previously "unpacked" concept was adapted for Australian educators and students to develop a framework with seven themes and 60 subthemes. The framework was successfully validated by the original Delphi panel of educators and will provide a valuable resource for teaching and learning in Australian universities.

Unpacking and validating the "cell membrane" core concept of physiology by an Australian team.

A task force of physiology educators from 25 Australian universities generated an Australia-wide consensus on seven core concepts for physiology curricula. One adopted core concept was "cell membrane," defined as "Cell membranes determine what substances enter or leave the cell and its organelles. They are essential for cell signaling, transport, and other cellular functions." This concept was unpacked by a team of 3 Australian physiology educators into 4 themes and 33 subthemes arranged in a hierarchical structure up to 5 levels deep. The four themes related to defining the cell membrane, cell membrane structure, transport across cell membranes, and cell membrane potentials. Subsequently, 22 physiology educators with a broad range of teaching experience reviewed and assessed the 37 themes and subthemes for importance for students to understand and the level of difficulty for students on a 5-point Likert scale. The majority (28) of items evaluated were rated as either Essential or Important. Theme 2: cell membrane structure was rated as less important than the other three themes. Theme 4: membrane potential was rated most difficult, while theme 1: defining cell membranes was rated as the easiest. The importance of cell membranes as a key aspect of biomedical education received strong support from Australian educators. The unpacking of the themes and subthemes within the cell membrane core concept provides guidance in the development of curricula and should facilitate better identification of the more challenging aspects within this core concept and help inform the time and resources required to support student learning.NEW & NOTEWORTHY The "cell membrane" core concept was unpacked by a team of Australian physiology educators into a conceptual framework to provide guidance for students and educators. Key themes in the cell membrane core concept were cell membrane definition and structure, transport across cell membranes, and membrane potentials. Australian educators reviewing the framework identified cell membrane as an essential yet relatively simple core concept, suggesting that this is well-placed in foundational physiology courses across a diverse range of degrees.

Mapping the core concepts of physiology across Australian university curricula.

Core concepts in physiology, designed by physiology educators to promote improved learning and teaching, have existed for over a decade. This study aimed to investigate the extent to which a set of 15 core concepts of physiology (developed by Michael and McFarland, U.S.-based educators) are reflected in the learning outcomes (LOs) of units (subjects) comprising physiology curricula in Australian universities. From publicly accessible online information, we identified 17 Australian universities that offered a physiology major for undergraduate degree students and downloaded 788 LOs from the 166 units that comprised the majors. Each LO was blindly mapped against the 15 core concepts by 8 physiology educators from 3 Australian universities. Additionally, text-matching software was employed to match keywords and phrases (identified as descriptors of the 15 core concepts) against the LOs. The frequency of individual words and two-word phrases for each core concept was calculated and ranked. There was variability in rating LOs for the same university among academic mappers; nevertheless, many of the 15 core concepts did not appear to be adequately covered in the LOs. Two core concepts most matched manually were in the top three most mapped by the software. These were, from most common, structure/function and interdependence. Our findings suggest a lack of alignment of LOs with the core concepts across Australian physiology curricula. This highlights the need for Australia-wide agreement on a set of core concepts in physiology as the first step in collaboratively improving assessment and learning and teaching practice in physiology.NEW & NOTEWORTHY This is the first time an existing set of core concepts for physiology, developed by Michael and McFarland (U.S.-based educators), have been mapped against unit (subject) learning outcomes across physiology curricula in Australian universities to gauge uptake and the need for agreement on a set of core concepts in the Australian higher education context.

Unpacking the homeostasis core concept in physiology: an Australian perspective.

Australia-wide consensus was reached on seven core concepts of physiology, which included homeostasis, a fundamental concept for students to understand as they develop their basic knowledge of physiological regulatory mechanisms. The term homeostasis is most commonly used to describe how the internal environment of mammalian systems maintains relative constancy. The descriptor "the internal environment of the organism is actively regulated by the responses of cells, tissues, and organs through feedback systems" was unpacked by a team of three Australian Physiology educators into 5 themes and 18 subthemes arranged in a hierarchy. Using a five-point Likert scale, the unpacked concept was rated by 24 physiology educators from 24 Australian Universities for level of importance and level of difficulty for students. Survey data were analyzed using a one-way ANOVA to compare between and within concept themes and subthemes. There were no differences in main themes for level of importance, with all ratings between essential or important. Theme 1: the organism has regulatory mechanisms to maintain a relatively stable internal environment, a process known as homeostasis was almost unanimously rated as essential. Difficulty ratings for unpacked concept themes averaged between slightly difficult and moderately difficult. The Australian team concurred with published literature that there are inconsistencies in the way the critical components of homeostatic systems are represented and interpreted. We aimed to simplify the components of the concept so that undergraduates would be able to easily identify the language used and build on their knowledge.NEW & NOTEWORTHY The homeostasis core concept of physiology was defined and unpacked by an Australian team with the goal of constructing a resource that will improve learning and teaching of this core physiology concept in an Australian Higher Education context.

Establishing consensus for the core concepts of physiology in the Australian higher education context using the Delphi method.

A set of core concepts ("big ideas") integral to the discipline of physiology are important for students to understand and demonstrate their capacity to apply. We found poor alignment of learning outcomes in programs with physiology majors (or equivalent) from 17 Australian universities and the 15 core concepts developed by a team in the United States. The objective of this project was to reach Australia-wide consensus on a set of core concepts for physiology, which can be embedded in curricula across Australian universities. A four-phase Delphi method was employed, starting with the assembling of a Task Force of physiology educators with extensive teaching and curriculum development expertise from 25 Australian universities. After two online meetings and a survey, the Task Force reached agreement on seven core concepts of physiology and their descriptors, which were then sent out to the physiology educator community across Australia for agreement. The seven core concepts and their associated descriptions were endorsed through this process (n = 138). In addition, embedding the core concepts across the curriculum was supported by both Task Force members (85.7%) and educators (82.1%). The seven adopted core concepts of human physiology were Cell Membrane, Cell-Cell Communication, Movement of Substances, Structure and Function, Homeostasis, Integration, and Physiological Adaptation. The core concepts were subsequently unpacked into themes and subthemes. If adopted, these core concepts will result in consistency across curricula in undergraduate physiology programs and allow for future benchmarking.NEW & NOTEWORTHY This is the first time Australia-wide agreement has been reached on the core concepts of physiology with the Delphi method. Embedding of the core concepts will result in consistency in physiology curricula, improvements to teaching and learning, and benchmarking across Australian universities.

A blended learning exercise physiology theory module that supports student autonomy and improves academic performance.

A limited number of studies have explored the impact of blended exercise physiology theory curricula on student learning and experience. This study aimed to investigate the impact of an exercise physiology blended learning theory module on student performance, engagement, and perceptions. The module, which comprised a range of elements (student guide, lecturer-recorded videos, supplementary videos, formative quizzes, workshops, and discussion forum), was implemented in a third-year subject taken by students in nonspecialist undergraduate science, technology, engineering, and mathematics (STEM) degrees. Students chose which elements to engage with to support their learning. Exam performance was assessed by comparing exam marks from fully face-to-face delivery to the blended delivery with an independent t test. Student perceptions were determined via an end-of-module questionnaire comprised of Likert-scale questions and open-ended questions. Descriptive statistical analysis was conducted on the Likert-scale responses, and qualitative content analysis was conducted on the open-ended responses. Student engagement with online resources was determined through analysis of access statistics from the learning management system. Student exam marks in the blended learning student group were significantly higher (P < 0.0001) than in the face-to-face group, even though the questions were of a higher Bloom's level in the blended learning group. Students preferred blended delivery over fully face-to-face delivery. Most students accessed the student guide, lecturer-recorded videos, and quizzes, with supplementary videos, workshops, and discussion forums accessed by fewer students. In conclusion, a blended exercise physiology theory module improved student exam performance and was positively perceived by students, and engagement with the elements of the module was varied.NEW & NOTEWORTHY Few studies have explored the impact of blended delivery of exercise physiology theory curricula on student learning and experience. This study investigated the impact of a novel blended model on student learning and experience. The module comprised a range of elements (student guide, lecturer-recorded videos, supplementary videos, formative quizzes, workshops, and discussion forum), where students were able to choose which elements to engage with to support their learning.

The regulation of polyamine pathway proteins in models of skeletal muscle hypertrophy and atrophy: a potential role for mTORC1.

Polyamines have been shown to be absolutely required for protein synthesis and cell growth. The serine/threonine kinase, the mechanistic target of rapamycin complex 1 (mTORC1), also plays a fundamental role in the regulation of protein turnover and cell size, including in skeletal muscle, where mTORC1 is sufficient to increase protein synthesis and muscle fiber size, and is necessary for mechanical overload-induced muscle hypertrophy. Recent evidence suggests that mTORC1 may regulate the polyamine metabolic pathway, however, there is currently no evidence in skeletal muscle. This study examined changes in polyamine pathway proteins during muscle hypertrophy induced by mechanical overload (7 days), with and without the mTORC1 inhibitor, rapamycin, and during muscle atrophy induced by food deprivation (48 h) and denervation (7 days) in mice. Mechanical overload induced an increase in mTORC1 signaling, protein synthesis and muscle mass, and these were associated with rapamycin-sensitive increases in adenosylmethione decarboxylase 1 (Amd1), spermidine synthase (SpdSyn), and c-Myc. Food deprivation decreased mTORC1 signaling, protein synthesis, and muscle mass, accompanied by a decrease in spermidine/spermine acetyltransferase 1 (Sat1). Denervation, resulted increased mTORC1 signaling and protein synthesis, and decreased muscle mass, which was associated with an increase in SpdSyn, spermine synthase (SpmSyn), and c-Myc. Combined, these data show that polyamine pathway enzymes are differentially regulated in models of altered mechanical and metabolic stress, and that Amd1 and SpdSyn are, in part, regulated in a mTORC1-dependent manner. Furthermore, these data suggest that polyamines may play a role in the adaptive response to stressors in skeletal muscle.

Undercarboxylated osteocalcin has no adverse effect on endothelial function in rabbit aorta or human vascular cells.

Undercarboxylated osteocalcin (ucOC) improves glucose metabolism; however, its effects on endothelial cell function are unclear. We examined the biological effect of ucOC on endothelial function in animal models ex vivo and human cells in vitro. Isometric tension and immunohistochemistry techniques were used on the aorta of male New Zealand white rabbits and cell culture techniques were used on human aortic endothelial cells (HAECs) to assess the effect of ucOC in normal and high-glucose environments. Overall, ucOC, both 10 and 30 ng/ml, did not significantly alter acetylcholine-induced blood vessel relaxation in rabbits (p > .05). UcOC treatment did not cause any significant changes in the immunoreactivity of cellular signalling markers (p > .05). In HAEC, ucOC did not change any of the assessed outcomes (p > .05). UcOC has no negative effects on endothelial function which is important to reduce the risks of off target adverse effects if it will be used as a therapeutic option for metabolic disease in the future.

Feasibility and adherence to moderate intensity cardiovascular fitness training following stroke: a pilot randomized controlled trial.

BACKGROUND: Stroke is a leading cause of disability worldwide and the cardiovascular fitness levels of stroke survivors are diminished to an extent that impairs functioning and activities of daily living performance. While cardiovascular training seems an empirically appropriate intervention, the optimal dosage and intensity of cardiovascular training in stroke survivors remains unclear. The aim was to determine the safety and feasibility of moderate-intensity cardiovascular training following stroke, including measurement of adherence to training. METHODS: A pilot, prospective, patient- and assessor-blinded randomised controlled trial conducted in a tertiary, metropolitan hospital-based community rehabilitation centre. Eligibility criteria included ambulant (> 100 m), 6 weeks-12 months post stroke. Moderate-intensity fitness training or control (low-intensity) exercise was offered biweekly for 12 weeks. Outcome measures included adverse events, peak oxygen uptake (VO2), functional exercise capacity (6-Minute Walk Test, 10-m Walk Test) and health-related quality of life (Short Form-36) and mood (Patient Health Questionnaire, PHQ9). RESULTS: Feasibility: Seventy-one (50%) of 141 screened participants were eligible (29% did not agree to participate). Twenty participants (10 intervention, 10 control) were recruited. The median (%; IQR) supervised sessions was 19.5 (81%; 12, 20); and 20 (83%; 19, 22) in the intervention and control groups, respectively. Progression of duration and intensity was limited; mean of 10 sessions to achieve target duration (30 min). There were no adverse events. Baseline peak oxygen uptake (VO2) levels were low (15.94 ml/kg/min). Significant improvements in VO2 peak in both groups were observed (p < 0.05). Although there were no significant between-group differences, this feasibility trial was not powered to detect change. CONCLUSIONS: Moderate-intensity fitness training was safe but achievement of target duration and intensity was challenging for stroke survivors. A definitive adequately-powered randomised trial is required. Alternative fitness training protocols may need to be explored. TRIAL REGISTRATION: The trial protocol was prospectively registered on the Australian New Zealand Clinical Trials Registry ( ACTRN 12613000822785 ) on 25/07/2013.

Associations of sarcopenia components with physical activity and nutrition in Australian older adults performing exercise training.

BACKGROUND: The risk of progressive declines in skeletal muscle mass and strength, termed sarcopenia, increases with age, physical inactivity and poor diet. The purpose of this study was to explore and compare associations of sarcopenia components with self-reported physical activity and nutrition in older adults participating in resistance training at Helsinki University Research [HUR] and conventional gyms for over a year, once a week, on average. METHODS: The study looked at differences between HUR (n = 3) and conventional (n = 1) gyms. Muscle strength (via handgrip strength and chair stands), appendicular lean mass (ALM; via dual energy X-ray absorptiometry) and physical performance (via gait speed over a 4-m distance, short physical performance battery, timed up and go and 400-m walk tests) were evaluated in 80 community-dwelling older adults (mean ± SD 76.5 ± 6.5 years). Pearson correlations explored associations for sarcopenia components with self-reported physical activity (via Physical Activity Scale for the Elderly [PASE]) and nutrition (via Australian Eating Survey). RESULTS: No differences in PASE and the Australian Recommended Food Score (ARFS) were observed between HUR and conventional gyms, however HUR gym participants had a significantly higher self-reported protein intake (108 ± 39 g vs 88 ± 27 g; p = 0.029) and a trend to have higher energy intake (9698 ± 3006 kJ vs 8266 ± 2904 kJ; p = 0.055). In both gym groups, gait speed was positively associated with self-reported physical activity (r = 0.275; p = 0.039 and r = 0.423; p = 0.044 for HUR and conventional gyms, respectively). ALM was positively associated with protein (p = 0.047, r = 0.418) and energy (p = 0.038, r = 0.435) intake in the conventional gym group. Similar associations were observed for ALM/h2 in the HUR group. None of the sarcopenia components were associated with ARFS in either gym group. CONCLUSION: Older adults attending HUR and conventional gyms had similar self-reported function and nutrition (but not protein intake). Inadequate physical activity was associated with low gait speed and inadequate nutrition and low protein ingestion associated with low lean mas, even in older adults participating in exercise programs. Optimal physical activity and nutrition are important for maintaining muscle mass and function in older adults.

Natural killer cell mobilization and egress following acute exercise in men with prostate cancer.

NEW FINDINGS: What is the central question of this study? What are the characteristics of the NK cell response following acute moderate-intensity aerobic exercise in prostate cancer survivors and is there a relationship between stress hormones and NK cell mobilization? What is the main finding and its importance? NK cell numbers and proportions changed similarly between prostate cancer survivors and controls following acute exercise. Consecutive training sessions can likely be used without adverse effects on the immune system during prostate cancer treatment. ABSTRACT: Prostate cancer treatment affects multiple physiological systems, although the immune response during exercise has been minimally investigated. The objective was to characterize the natural killer (NK) cell response following acute exercise in prostate cancer survivors. Prostate cancer survivors on androgen deprivation therapy (ADT) and those without (PCa) along with non-cancer controls (CON) completed a moderate intensity cycling bout. NK cells were phenotyped before and 0, 2 and 24 h after acute exercise using flow cytometry. CD56 total NK cell frequency increased by 6.2% at 0 h (P < 0.001) and decreased by 2.5% at 2 h (P < 0.01) with similar findings in CD56dim cells. NK cell counts also exhibited a biphasic response. Independent of exercise, ADT had intracellular interferon γ (IFNγ) expression that was nearly twofold higher than CON (P < 0.01). PCa perforin expression was reduced by 11.4% (P < 0.05), suggesting these cells may be more prone to degranulation. CD57- NK cells demonstrated increased perforin and IFNγ frequencies after exercise with no change within the CD57+ populations. All NK and leukocyte populations returned to baseline by 24 h. NK cell mobilization and egress with acute exercise appear normal, as cell counts and frequencies in prostate cancer survivors change similarly to CON. However, lower perforin proportions (PCa) and higher IFNγ expression (ADT) may alter NK cytotoxicity and require further investigation. The return of NK cell proportions to resting levels overnight suggests that consecutive training sessions can be used without adverse effects on the immune system during prostate cancer treatment.

The Atypical Chemokine Receptor Ackr2 Constrains NK Cell Migratory Activity and Promotes Metastasis.

Chemokines have been shown to be essential players in a range of cancer contexts. In this study, we demonstrate that mice deficient in the atypical chemokine receptor Ackr2 display impaired development of metastasis in vivo in both cell line and spontaneous models. Further analysis reveals that this relates to increased expression of the chemokine receptor CCR2, specifically by KLRG1+ NK cells from the Ackr2-/- mice. This leads to increased recruitment of KLRG1+ NK cells to CCL2-expressing tumors and enhanced tumor killing. Together, these data indicate that Ackr2 limits the expression of CCR2 on NK cells and restricts their tumoricidal activity. Our data have important implications for our understanding of the roles for chemokines in the metastatic process and highlight Ackr2 and CCR2 as potentially manipulable therapeutic targets in metastasis.

Putative Nox2 inhibitors worsen homocysteine-induced impaired acetylcholine-mediated relaxation.

BACKGROUND AND AIM: Increased homocysteine (Hcy) is associated with coronary artery disease (CAD). Hcy increases reactive oxygen species (ROS) via NADPH oxidases (Nox), reducing acetylcholine-mediated vasorelaxation. We aimed to determine if putative Nox2 inhibitors prevent Hcy-impaired acetylcholine-mediated vasorelaxation. METHODS AND RESULTS: New Zealand White rabbit and wild-type (C57BL/6) and Nox2-/- (NOX) mice aortic rings were mounted in organ baths. Rabbit rings were incubated with either apocynin (10 µM), gp91ds-tat (GP, 1 µM) or PhoxI2 (1 µM) and mice rings GP (1 µM) only. Some rabbit rings were incubated with 3 mM Hcy, before pre-contraction, followed by dose-response relaxation to acetylcholine (ACh; 0.01µM-10µM). In rabbit rings treated with Hcy and GP, O2‾ donor pyrogallol (1 µM) or Akt activator SC79 (1 µM) was added 5 min before ACh. Mice rings were used to compare Nox2 deletion to normal acetylcholine-mediated relaxation. In rabbits, Hcy reduced acetylcholine-mediated relaxation vs. control (p < 0.0001). Treatment + Hcy reduced relaxation compared with treatment alone (p < 0.0001). Pyrogallol and SC79 reversed the response of GP + Hcy (p = 0.0001). In mice, Nox2 deletion reduced acetylcholine-mediated vasorelaxation. Rabbit tissue analysis revealed that Hcy reduced eNOS phosphorylation at Thr495 and increased eNOS phosphorylation at Ser1177; no further alteration at Thr495 was observed with GP. In contrast, GP prevented increased phosphorylation at Ser1177. CONCLUSIONS: Apocynin, GP and PhoxI2 worsens acetylcholine-mediated vascular relaxation in rabbit aorta, which is supported by results from mouse Nox2 deletion data. These inhibitors worsen Hcy-induced vascular dysfunction, suggesting that current putative Nox2 inhibitors might not be useful in treating HHcy.