The current landscape of exercise and female fertility research: a narrative review.

In brief: Females with obesity may experience infertility and can improve their fertility through exercise. This review found that most exercise interventions improve fertility outcomes regardless of technique, intensity, or duration. More detailed reporting through the lens of exercise prescription should be included in future studies. Abstract: Female infertility disproportionately affects people with obesity. Exercise often improves fertility outcomes for this population, however, there is limited prescriptive evidence. Specifically, there is a lack of information on the ideal type, frequency, intensity, and setting of exercise to improve fertility outcomes. Using principles of exercise prescription, this review aimed to describe the scope of exercise interventions that have been explored and fertility outcomes measured for people with female infertility and obesity. A search was completed in PubMed, Embase, Cochrane, and CINAHL, identifying 16 relevant published articles. Overall, exercise had a positive impact on female fertility outcomes in people with obesity, though there were large variations in the exercise interventions prescribed and outcomes measured. Cyclic exercise (i.e. walking and cycling) was the most common technique incorporated, though a combination of cyclic, acyclic (i.e. circuit training and boot camp), or individualization was often used. Several fertility outcomes were reported; however, the rate of conception, pregnancy, and live birth rates were the most common, which, we suggest, should always be reported in fertility intervention research. We stress that future studies provide more thorough descriptions of their implemented exercise interventions to facilitate reproducibility and comparisons between studies. Closer attention to the principles of exercise prescription when developing and reporting exercise interventions will help improve fertility outcomes, mainly live birth rates, for those with female infertility and obesity.

A Physics-Informed Convolutional Neural Network with Custom Loss Functions for Porosity Prediction in Laser Metal Deposition.

Physics-informed machine learning is emerging through vast methodologies and in various applications. This paper discovers physics-based custom loss functions as an implementable solution to additive manufacturing (AM). Specifically, laser metal deposition (LMD) is an AM process where a laser beam melts deposited powder, and the dissolved particles fuse to produce metal components. Porosity, or small cavities that form in this printed structure, is generally considered one of the most destructive defects in metal AM. Traditionally, computer tomography scans measure porosity. While this is useful for understanding the nature of pore formation and its characteristics, purely physics-driven models lack real-time prediction ability. Meanwhile, a purely deep learning approach to porosity prediction leaves valuable physics knowledge behind. In this paper, a hybrid model that uses both empirical and simulated LMD data is created to show how various physics-informed loss functions impact the accuracy, precision, and recall of a baseline deep learning model for porosity prediction. In particular, some versions of the physics-informed model can improve the precision of the baseline deep learning-only model (albeit at the expense of overall accuracy).

Cell Kinetics in the Adult Neurogenic Niche and Impact of Diet-Induced Accelerated Aging.

Neurogenesis in the adult brain, a powerful mechanism for neuronal plasticity and brain repair, is altered by aging and pathological conditions, including metabolic disorders. The search for mechanisms and therapeutic solutions to alter neurogenesis requires understanding of cell kinetics within neurogenic niches using a high-throughput quantitative approach. The challenge is in the dynamic nature of the process and multiple cell types involved, each having several potential modes of division or cell fate. Here we show that cell kinetics can be revealed through a combination of the BrdU/EdU pulse-chase, based on the circadian pattern of DNA replication, and a differential equations model that describes time-dependent cell densities. The model is validated through the analysis of cell kinetics in the cerebellar neurogenic niche of normal young adult male zebrafish, with cells quantified in 2D (sections), and with neuronal fate and reactivation of stem cells confirmed in 3D whole-brain images (CLARITY). We then reveal complex alterations in cell kinetics associated with accelerated aging due to chronic high caloric intake. Low activity of neuronal stem cells in this condition persists 2 months after reverting to normal diet, and is accompanied by overproduction of transient amplifying cells, their accelerated cell death, and slow migration of postmitotic progeny. This combined experimental and mathematical approach should allow for relatively high-throughput analysis of early signs of pathological and age-related changes in neurogenesis, evaluation of specific therapeutic targets, and drug efficacy.SIGNIFICANCE STATEMENT Understanding normal cell kinetics of adult neurogenesis and the type of cells affected by a pathological process is needed to develop effective prophylactic and therapeutic measures directed at specific cell targets. Complex time-dependent mechanisms involved in the kinetics of multiple cell types require a combination of experimental and mathematical modeling approaches. This study demonstrates such a combined approach by comparing normal neurogenesis with that altered by diet-induced accelerated aging in adult zebrafish.

University-based physical literacy programming for children: Canadian community stakeholders' recommendations.

'Physical literacy' (PL) education-that is, teaching foundational skills, attitudes, behaviors and knowledge about lifelong involvements in physical activities, is an important aspect for health promotion among children. Universities have been playing a critical role by teaching future PL professionals. Additionally, various universities have offered university-based PL programming for neighborhood children as a way of public health promotion service and community engagement. However, this additional role of universities and the ways of promoting the quality of this type of health promotion service programming have not been investigated in the current research literature. Therefore, the purpose of this study was to identify the practicable strategies to enhance the quality of university-based PL programming for children from the perspectives of community stakeholders. Overall, 24 community stakeholders who held professional positions that are related to PL education participated in a 90-min focus group interview. This grounded theory study identified that university-based PL programming for children should be (i) inclusive, (ii) collaborative, (iii) welcoming and (iv) responsive. Practical suggestions and recommendations were also provided. This study has provided empirical knowledge to prioritize aspects for the future actions in planning and implementing university-based PL programming for children and informed for further cross-cultural comparisons amongst the perspectives of participants, university service providers and community stakeholders. The knowledge acquired from this research will also be translated to university service providers who operate similar type of health promotion service programming to the public.

Evaluation of the accuracy and availability of cancer-related physical activity and sedentary behaviour information on English-language websites.

PURPOSE: To assess the quality and accuracy of cancer-related physical activity (PA) and sedentary behaviour (SB) information provided on major cancer websites from English-speaking countries. DESIGN: The study used a cross-sectional design. SAMPLE: A list of major cancer websites (N = 11) was generated from countries that speak English primarily (e.g., Canada, Australia). METHODS: These websites were assessed for quality and accuracy based on a detailed coding framework (e.g., PA guidelines, PA and cancer prevention). Frequencies and descriptive statistics were derived for website characteristics of interest. FINDINGS: All sites reviewed within this study offered PA information for cancer prevention and cancer survivorship. However, while 81% of the sites presented information for SB and cancer prevention, very little information was presented for SB and cancer survivorship, with only 18.2% of the information being offered. CONCLUSIONS: The quality and accuracy of cancer-related PA and SB information presented on leading cancer websites is variable. Further information is warranted in the areas of SB, resistance training, and behaviour change strategies. IMPLICATIONS: Websites have considerable value as knowledge translation tools and, therefore, presenting evidence-based information that is easy to understand may positively impact the health and behaviours of cancer populations, as well as the general population.

The role of the built environment in a randomized controlled trial to increase physical activity among men with prostate cancer: the PROMOTE trial.

PURPOSE: The purpose of the study was to examine the association between the built environment and physical activity (PA) in prostate cancer survivors (PCS), as well as whether built environment factors (walkability, count of sports complexes) were effect modifiers of a PA intervention. METHODS: Our study included 165 PCS residing in Edmonton, Alberta, from the PROMOTE trial. The PROMOTE trial was a randomized controlled trial of a behaviour change intervention to increase PA and quality of life in PCS. In the PROMOTE trial, 423 PCS were randomly assigned to a standard physical activity recommendation, self-administered implementation intention, or telephone-assisted implementation intention group. PA and quality of life outcomes were assessed at baseline, 1, and 3 months. To explore the role of the built environment, this study examined walkability and count of sport complexes. RESULTS: Linear regression analyses revealed that the self-administered intervention group had an increase in self-reported PA minutes/week (ß = 133.4, 95% CI = -18.9 to 285.6); however, none of the built environment variables were found to be significantly associated with PA. The logistic regression showed that the self-administered intervention group had a significantly greater likelihood of meeting the PA guidelines (OR = 2.1, 95% CI = 0.9 to 4.9), though no built environment variables were associated with PA levels. CONCLUSIONS: Our findings suggest that the built environment was not associated with PA and was not an effect modifier in a PA behaviour change intervention for PCS. Further research is needed before clear conclusions can be generated ( ClinicalTrials.gov number NCT01410656).

Impaired Sleep, Circadian Rhythms and Neurogenesis in Diet-Induced Premature Aging.

Chronic high caloric intake (HCI) is a risk factor for multiple major human disorders, from diabetes to neurodegeneration. Mounting evidence suggests a significant contribution of circadian misalignment and sleep alterations to this phenomenon. An inverse temporal relationship between sleep, activity, food intake, and clock mechanisms in nocturnal and diurnal animals suggests that a search for effective therapeutic approaches can benefit from the use of diurnal animal models. Here, we show that, similar to normal aging, HCI leads to the reduction in daily amplitude of expression for core clock genes, a decline in sleep duration, an increase in scoliosis, and anxiety-like behavior. A remarkable decline in adult neurogenesis in 1-year old HCI animals, amounting to only 21% of that in age-matched Control, exceeds age-dependent decline observed in normal 3-year old zebrafish. This is associated with misalignment or reduced amplitude of daily patterns for principal cell cycle regulators, cyclins A and B, and p20, in brain tissue. Together, these data establish HCI in zebrafish as a model for metabolically induced premature aging of sleep, circadian functions, and adult neurogenesis, allowing for a high throughput approach to mechanistic studies and drug trials in a diurnal vertebrate.

Randomized controlled trial of a behavior change intervention to increase physical activity and quality of life in prostate cancer survivors.

BACKGROUND: Physical activity improves health in prostate cancer survivors; however, participation rates are low. PURPOSE: This study aims to determine the effects of an implementation intention intervention on physical activity and quality of life in prostate cancer survivors. METHODS: Prostate cancer survivors (N = 423) were randomly assigned to a standard physical activity recommendation, a self-administered implementation intention, or a telephone-assisted implementation intention. Physical activity and quality of life were assessed at baseline, 1, and 3 months. RESULTS: Analyses of covariance using multiple imputation showed that physical activity at 1 month increased by 86 min/week in the standard physical activity recommendation group compared with 168 min/week in the self-administered implementation intention group (P = 0.023) and 105 min/week in the telephone-assisted implementation intention group (P = 0.35). CONCLUSIONS: A self-administered implementation intention intervention resulted in a meaningful short-term increase in physical activity. Supplementation with additional intervention strategies and more frequent intervention may improve longer-term exercise.

A novel benzazepinone sodium channel blocker with oral efficacy in a rat model of neuropathic pain.

A series of benzazepinones were synthesized and evaluated for block of Nav1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.

Sport participation in colorectal cancer survivors: an unexplored approach to promoting physical activity.

PURPOSE: Physical activity improves health outcomes in colorectal cancer (CRC) survivors, but participation rates are low. One understudied strategy for increasing physical activity in CRC survivors may be sport participation. Here, we report the sport participation rate, sport preferences, and correlates of sport participation among CRC survivors. METHODS: A provincial, population-based mailed survey of CRC survivors in Alberta, Canada was performed and included measures of sport participation, sport preferences, sport benefits and barriers, and medical and demographic variables. RESULTS: A total of 600 CRC survivors completed the survey (34 % response rate). Almost a quarter (23.0 %) of CRC survivors reported participating in a sport in the past month, with the most common sport being golf (58.7 %). In multivariate regression analysis, 33.0 % (p = 0.001) of the variance in sport participation was explained by being male (ß = 0.12; p = 0.006), in better general health (ß = 0.12; p = 0.006), and ≥ 5 years post-diagnosis (ß = 0.09; p = 0.031). The most common barriers to sport participation were time, age/agility, and no interest/dislike of sports. The most common anticipated benefits of sport participation were improved physical fitness, meeting people, and improved health. Over half (57.2 %) of CRC survivors were possibly interested in learning about sport participation opportunities. CONCLUSIONS: Promotion of sport participation may be a potentially fruitful strategy for increasing physical activity in CRC survivors.

Integrative rare disease biomedical profile based network supporting drug repurposing or repositioning, a case study of glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor; however, treatment remains a significant challenge. This study aims to identify drug repurposing or repositioning candidates for GBM by developing an integrative rare disease profile network containing heterogeneous types of biomedical data. METHODS: We developed a Glioblastoma-based Biomedical Profile Network (GBPN) by extracting and integrating biomedical information pertinent to GBM-related diseases from the NCATS GARD Knowledge Graph (NGKG). We further clustered the GBPN based on modularity classes which resulted in multiple focused subgraphs, named mc_GBPN. We then identified high-influence nodes by performing network analysis over the mc_GBPN and validated those nodes that could be potential drug repurposing or repositioning candidates for GBM. RESULTS: We developed the GBPN with 1,466 nodes and 107,423 edges and consequently the mc_GBPN with forty-one modularity classes. A list of the ten most influential nodes were identified from the mc_GBPN. These notably include Riluzole, stem cell therapy, cannabidiol, and VK-0214, with proven evidence for treating GBM. CONCLUSION: Our GBM-targeted network analysis allowed us to effectively identify potential candidates for drug repurposing or repositioning. Further validation will be conducted by using other different types of biomedical and clinical data and biological experiments. The findings could lead to less invasive treatments for glioblastoma while significantly reducing research costs by shortening the drug development timeline. Furthermore, this workflow can be extended to other disease areas.

Integrative Rare Disease Biomedical Profile based Network Supporting Drug Repurposing, a case study of Glioblastoma.

Background Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor; however, treatment remains a significant challenge. This study aims to identify drug repurposing candidates for GBM by developing an integrative rare disease profile network containing heterogeneous types of biomedical data. Methods We developed a Glioblastoma-based Biomedical Profile Network (GBPN) by extracting and integrating biomedical information pertinent to GBM-related diseases from the NCATS GARD Knowledge Graph (NGKG). We further clustered the GBPN based on modularity classes which resulted in multiple focused subgraphs, named mc_GBPN. We then identified high-influence nodes by performing network analysis over the mc_GBPN and validated those nodes that could be potential drug repositioning candidates for GBM. Results We developed the GBPN with 1,466 nodes and 107,423 edges and consequently the mc_GBPN with forty-one modularity classes. A list of the ten most influential nodes were identified from the mc_GBPN. These notably include Riluzole, stem cell therapy, cannabidiol, and VK-0214, with proven evidence for treating GBM. Conclusion Our GBM-targeted network analysis allowed us to effectively identify potential candidates for drug repurposing. This could lead to less invasive treatments for glioblastoma while significantly reducing research costs by shortening the drug development timeline. Furthermore, this workflow can be extended to other disease areas.

Two weeks of high-intensity interval training increases skeletal muscle mitochondrial respiration via complex-specific remodeling in sedentary humans.

Aerobic training remodels the quantity and quality (function per unit) of skeletal muscle mitochondria to promote substrate oxidation, however, there remain key gaps in understanding the underlying mechanisms during initial training adaptations. We used short-term high-intensity interval training (HIIT) to determine changes to mitochondrial respiration and regulatory pathways that occur early in remodeling. Fifteen normal-weight sedentary adults started seven sessions of HIIT over 14 days and 14 participants completed the intervention. We collected vastus lateralis biopsies before and 48 h after HIIT to determine mitochondrial respiration, RNA sequencing, and Western blotting for proteins of mitochondrial respiration and degradation via autophagy. HIIT increased respiration per mitochondrial protein for lipid (+23% P = 0.020), complex I (+18%, P = 0.0015), complex I + II (+14%, P < 0.0001), and complex II (+24% P < 0.0001). Transcripts that increased with HIIT identified several gene sets of mitochondrial respiration, particularly for complex I, whereas transcripts that decreased identified pathways of DNA and chromatin remodeling. HIIT lowered protein abundance of autophagy markers for p62 (-19%, P = 0.012) and LC3 II/I (-20%, P = 0.004) in whole tissue lysates but not isolated mitochondria. Meal tolerance testing revealed HIIT increased the change in whole body respiratory exchange ratio and lowered cumulative plasma insulin concentrations. Gene transcripts and respiratory function indicate remodeling of mitochondria within 2 wk of HIIT. Overall changes are consistent with increased protein quality driving rapid improvements in substrate oxidation.NEW & NOTEWORTHY Aerobic training stimulates mitochondrial metabolism in skeletal muscle that is linked to improvements to whole body fuel metabolism. The mechanisms driving changes to the quantity and quality (function per unit) of mitochondria are less known. We used seven sessions of high-intensity interval training (HIIT) to determine functional changes and mechanisms of mitochondrial remodeling in skeletal muscle. HIIT increased mitochondrial respiration per mass for fatty acids, complex I, and complex II substrates. HIIT-induced remodeling pathways including gene transcripts for mitochondrial respiration (via RNA sequencing of muscle tissue) and proteins related to complex I respiration. We conclude that an early feature of aerobic training is increased mitochondrial protein quality via improved respiration and induction of mitochondrial transcriptional patterns.

High-fat diet increases electron transfer flavoprotein synthesis and lipid respiration in skeletal muscle during exercise training in female mice.

High-fat diet (HFD) and exercise remodel skeletal muscle mitochondria. The electron transfer flavoproteins (ETF) transfer reducing equivalents from ß-oxidation into the electron transfer system. Exercise may stimulate the synthesis of ETF proteins to increase lipid respiration. We determined mitochondrial remodeling for lipid respiration through ETF in the context of higher mitochondrial abundance/capacity seen in female mice. We hypothesized HFD would be a greater stimulus than exercise to remodel ETF and lipid pathways through increased protein synthesis alongside increased lipid respiration. Female C57BL/6J mice (n = 15 per group) consumed HFD or low-fat diet (LFD) for 4 weeks then remained sedentary (SED) or completed 8 weeks of treadmill training (EX). We determined mitochondrial lipid respiration, RNA abundance, individual protein synthesis, and abundance for ETFα, ETFß, and ETF dehydrogenase (ETFDH). HFD increased absolute and relative lipid respiration (p = 0.018 and p = 0.034) and RNA abundance for ETFα (p = 0.026), ETFß (p = 0.003), and ETFDH (p = 0.0003). HFD increased synthesis for ETFα and ETFDH (p = 0.0007 and p = 0.002). EX increased synthesis of ETFß and ETFDH (p = 0.008 and p = 0.006). Higher synthesis rates of ETF were not always reflected in greater protein abundance. Greater synthesis of ETF during HFD indicates mitochondrial remodeling which may contribute higher mitochondrial lipid respiration through enhanced ETF function.

ARGUS: Visualization of AI-Assisted Task Guidance in AR.

The concept of augmented reality (AR) assistants has captured the human imagination for decades, becoming a staple of modern science fiction. To pursue this goal, it is necessary to develop artificial intelligence (AI)-based methods that simultaneously perceive the 3D environment, reason about physical tasks, and model the performer, all in real-time. Within this framework, a wide variety of sensors are needed to generate data across different modalities, such as audio, video, depth, speech, and time-of-flight. The required sensors are typically part of the AR headset, providing performer sensing and interaction through visual, audio, and haptic feedback. AI assistants not only record the performer as they perform activities, but also require machine learning (ML) models to understand and assist the performer as they interact with the physical world. Therefore, developing such assistants is a challenging task. We propose ARGUS, a visual analytics system to support the development of intelligent AR assistants. Our system was designed as part of a multi-year-long collaboration between visualization researchers and ML and AR experts. This co-design process has led to advances in the visualization of ML in AR. Our system allows for online visualization of object, action, and step detection as well as offline analysis of previously recorded AR sessions. It visualizes not only the multimodal sensor data streams but also the output of the ML models. This allows developers to gain insights into the performer activities as well as the ML models, helping them troubleshoot, improve, and fine-tune the components of the AR assistant.

The effect of a multifaceted efficacy intervention on exercise behavior in relatives of colon cancer patients.

BACKGROUND: Regular physical activity (PA) provides health benefits; however, at least 60% of the population fails to engage in the recommended amount of PA required to produce these health benefits. PURPOSE: The primary purpose of the study was to examine over a 12-week structured exercise program the effect of a multifaceted efficacy intervention (MEI-i.e., task and specific types of self-regulatory efficacy) on objectively measured exercise behavior. Secondary purposes were to examine the effect of the MEI on both task and self-regulatory efficacy levels; and to determine whether efficacy beliefs could predict exercise behavior. METHODS: Relatives of colon cancer patients (N = 140) were enrolled in an exercise program, and were randomized to either a MEI or attention control condition, and took part in classroom sessions. Behavior was assessed throughout the 12-week program using objective measures of frequency, duration, and intensity of exercise, and dropout rates, while self-reported task, barrier, scheduling, goal-setting, and relapse prevention efficacy were assessed at baseline and weeks 4, 8, and 12. RESULTS: The MEI group exercised for longer duration in the early phase of the program (i.e., 0-4 weeks); however, no significant differences were noted for exercise frequency and intensity. Differential dropout was found favoring the MEI group at weeks 8 and 12. No treatment condition differences were found for reported efficacy beliefs. Proceeding self-efficacious beliefs were associated with objective measures of behavior. CONCLUSIONS: A MEI grounded in Social Cognitive Theory was partially effective in influencing colon cancer relatives' exercise behavior.

The Actiheart in adolescents: a doubly labelled water validation.

BACKGROUND/OBJECTIVE: This study investigated the validity of the Actiheart device for estimating free-living physical activity energy expenditure (PAEE) in adolescents. SUBJECTS/METHODS: Total energy expenditure (TEE) was measured in eighteen Canadian adolescents, aged 15-18 years, by DLW. Physical activity energy expenditure was calculated as 0.9 X TEE minus resting energy expenditure, assuming 10% for the thermic effect of feeding. Participants wore the chest mounted Actiheart device which records simultaneously minute-by-minute acceleration (ACC) and heart rate (HR). Using both children and adult branched equation modeling, derived from laboratory-based activity, PAEE was estimated from the ACC and HR data. Linear regression analyses examined the association between PAEE derived from the Actiheart and DLW method where DLW PAEE served as the dependent variable. Measurement of agreement between the two methods was analyzed using the Bland-Altman procedure. RESULTS: A nonsignificant association was found between the children derived Actiheart and DLW PAEE values (R = .23, R(2) = .05, p = .36); whereas a significant association was found between the adult derived Actiheart and DLW PAEE values (R = .53, R(2) = .29, p < .05). Both the children and adult equation models lead to overestimations of PAEE by the Actiheart compared with the DLW method, by a mean difference of 31.42 kcal.kg(-1).d(-1) (95% limits of agreement: -45.70 to -17.15 kcal.kg(-1).d(-1) and 9.80 kcal.kg(-1).d(-1) (95% limits of agreement: -21.22-1.72 kcal.kg(-1).d(-1)), respectively. CONCLUSION: There is relatively poor measurement of agreement between the Actiheart and DLW for assessing free-living PAEE in adolescents. Future work should develop group based branched equation models specifically for adolescents to improve the utility of the device in this population.

Impact of 4 weeks of western diet and aerobic exercise training on whole-body phenotype and skeletal muscle mitochondrial respiration in male and female mice.

High dietary fat intake induces significant whole-body and skeletal muscle adaptations in mice, including increased capacity for fat oxidation and mitochondrial biogenesis. The impact of a diet that is high in fat and simple sugars (i.e., western diet [WD]), particularly on regulation of skeletal muscle mitochondrial function, is less understood. The purpose of the current study was to determine physiologic adaptations in mitochondrial respiratory capacity in skeletal muscle during short-term consumption of WD, including if adaptive responses to WD-feeding are modified by concurrent exercise training or may be sex-specific. Male and female C57BL/6J mice were randomized to consume low-fat diet (LFD) or WD for 4 weeks, with some WD-fed mice also performing concurrent treadmill training (WD + Ex). Group sizes were n = 4-7. Whole-body metabolism was measured using in-cage assessment of food intake and energy expenditure, DXA body composition analysis and insulin tolerance testing. High-resolution respirometry of mitochondria isolated from quadriceps muscle was used to determine skeletal muscle mitochondrial respiratory function. Male mice fed WD gained mass (p < 0.001), due to increased fat mass (p < 0.001), and displayed greater respiratory capacity for both lipid and non-lipid substrates compared with LFD mice (p < 0.05). There was no effect of concurrent treadmill training on maximal respiration (WD + Ex vs. WD). Female mice had non-significant changes in body mass and composition as a function of the interventions, and no differences in skeletal muscle mitochondrial oxidative capacity. These findings indicate 4 weeks of WD feeding can increase skeletal muscle mitochondrial oxidative capacity among male mice; whereas WD, with or without exercise, had minimal impact on mass gain and skeletal muscle respiratory capacity among female mice. The translational relevance is that mitochondrial adaptation to increases in dietary fat intake that model WD may be related to differences in weight gain among male and female mice.

Tetraspanin CD82 restrains phagocyte migration but supports macrophage activation.

Phagocytes migrate into tissues to combat infection and maintain tissue homeostasis. As dysregulated phagocyte migration and function can lead to inflammation or susceptibility to infection, identifying molecules that control these processes is critical. Here, we show that the tetraspanin CD82 restrains the migration of neutrophils and macrophages into tissues. Cd82 -/- phagocytes exhibited excessive migration during in vivo models of peritoneal inflammation, superfusion of CXCL1, retinopathy of prematurity, and infection with the protozoan parasite L. mexicana. However, with the latter, while Cd82 -/- macrophages infiltrated infection sites at higher proportions, cutaneous L. mexicana lesions were larger and persisted, indicating a failure to control infection. Analyses of in vitro bone-marrow-derived macrophages showed CD82 deficiency altered cellular morphology, and impaired gene expression and metabolism in response to anti-inflammatory activation. Altogether, this work reveals an important role for CD82 in restraining phagocyte infiltration and mediating their differentiation in response to stimulatory cues.

A potent and selective indole N-type calcium channel (Ca(v)2.2) blocker for the treatment of pain.

N-type calcium channels (Ca(v)2.2) have been shown to play a critical role in pain. A series of low molecular weight 2-aryl indoles were identified as potent Ca(v)2.2 blockers with good in vitro and in vivo potency.