CRISPR-Cas9 potential for identifying novel therapeutic targets in muscle-invasive bladder cancer.

Gene editing technologies help identify the genetic perturbations driving tumour initiation, growth, metastasis and resistance to therapeutics. This wealth of information highlights tumour complexity and is driving cancer research towards precision medicine approaches based on an individual's tumour genetics. Bladder cancer is the 11th most common cancer in the UK, with high rates of relapse and low survival rates in patients with muscle-invasive bladder cancer (MIBC). MIBC is highly heterogeneous and encompasses multiple molecular subtypes, each with different responses to therapeutics. This evidence highlights the need to identify innovative therapeutic targets to address the challenges posed by this heterogeneity. CRISPR-Cas9 technologies have been used to advance our understanding of MIBC and determine novel drug targets through the identification of drug resistance mechanisms, targetable cell-cycle regulators, and novel tumour suppressor and oncogenes. However, the use of these technologies in the clinic remains a substantial challenge and will require careful consideration of dosage, safety and ethics. CRISPR-Cas9 offers considerable potential for revolutionizing bladder cancer therapies, but substantial research is required for validation before these technologies can be used in the clinical setting.

Resistance training and cardiometabolic risk in women with metabolically healthy and unhealthy obesity.

Despite some reported benefits, there is a low quality of evidence for resistance training (RT) improving metabolic health of individuals with overweight or obesity. We evaluated the impact of RT on body composition, cardiorespiratory fitness (CRF) and physical performance, lipid-lipoprotein profile, inflammation, and glucose-insulin homeostasis in 51 postmenopausal women versus 29 controls matched for age, obesity, and physical activity. Exercised women were further subdivided for comparison of RT effects into those presenting metabolically healthy obesity (MHO) and those with metabolically unhealthy obesity (MUHO) classified according to Karelis and Rabasa-Lhoret or an approach based on adipose tissue secretory dysfunction using the plasma adiponectin(A)/leptin (L) ratio. Participants followed a 4-month weekly RT program targeting major muscle groups (3 × 10 repetitions at 80% one repetition maximum (1-RM)). Percent fat marginally decreased and lean body mass increased (0.01 < p < 0.05) while CRF and muscular strength improved in all women, after RT (effect size (ES): 0.11-1.21 (trivial to large effects), p ˂ 0.01). Fasting plasma triacylglycerol and high-density lipoprotein-cholesterol levels slightly increased and decreased, respectively, in participants with MHO using the A/L ratio approach (ES: -0.47 to 1.07 (small to large effects), p ˂ 0.05). Circulating interleukin-6 soluble receptor decreased in both groups and soluble tumor necrosis factor receptor-1/soluble tumor necrosis factor receptor-2 in women with MUHO only, irrespective of definition (ES: -0.42 to -0.84 (small to large effects), p ˂ 0.05). Glucose-insulin homeostasis was unchanged regardless of group or definition. RT improved physical performance and body composition but had a lesser impact on cardiometabolic risk in women with obesity, irrespective of their metabolic phenotype.

Taenia solium Cysticercosis and Taeniosis Reporting in the Current Medical and Veterinary Diseases Reporting Systems in Tanzania: A Cross-Sectional Study.

Taenia solium cysticercosis and taeniosis (TSCT) are two forms of a zoonotic disease caused by T. solium tapeworm. Towards promotion of a One Health approach to the control of TSCT, we assessed TSCT reporting in the medical and veterinay sectors in Tanzania. We conducted a cross-sectional study between January and April 2020 in Babati and Mbulu districts (northern Tanzania), Kongwa district (central Tanzania), Mbinga and Nyasa districts (southern Tanzania), and the Zonal Veterinary Centres in Iringa (southern Tanzania) and Arusha (northern Tanzania) regions. A questionnaire was administered to 154 officers in charge (OsIC) of primary healthcare facilities (PHFs) and 110 meat inspectors (MIs) to collect quantitative data. Key informant interviews (KIIs) were conducted to 16 medical and 17 veterinary officers from level one healthcare facilities and district livestock offices, respectively, to their respective ministries. OsIC admitted absence of specific reporting (100%, n = 154) of T. solium taeniosis and neurocysticercosis (NCC) in the medical diseases reporting system (MDRS) despite the presence of optimum facilitation in terms of report preparation and submission (92.2%, n = 154) with 83.8% (n = 154) timely report submission rate. The veterinary diseases reporting system (VDRS) accommodated porcine cysticercosis (PCC) reporting. Nevertheless, approximately 77.3% (n = 110) of the MIs admitted inadequate facilitation in VDRS that hindered efficient reporting of PCC among other diseases. In addition, all MIs admitted that disease reports submitted were incomplete, submitted late (73.3%, n = 110), or not submitted at all (88.8%, n = 110). Similarly, KIIs results revealed suboptimal facilitation and reporting efficiency in VDRS than it was with the MDRS. It is concluded that the MDRS did not provide for specific reporting of taeniosis and NCC. Inadequate facilitation of the general VDRS hindered efficient PCC reporting despite its provision for PCC reporting. A One Health approach in strengthening the medical and veterinary diseases reporting systems for efficient TSCT reporting is recommended.

Perspectives of wheelchair users with chronic spinal cord injury following a walking program using a wearable robotic exoskeleton.

PURPOSE: To examine the perspectives of wheelchair users with spinal cord injury (WUSCI) regarding their participation in a 16-week walking program using a wearable robotic exoskeleton (WRE); and explore concerns and expectations regarding potential use of this device and intervention in the context of a home or community-based adapted physical activity program. METHOD: Semi-structured interviews were conducted using a narrative research, 3 weeks post-intervention. Thematic analysis resulted in 6 themes and 21 subthemes. RESULTS: Seven men and 4 women aged between 32 and 72 years were interviewed; 8 of them had a complete SCI. After the walking program, WUSCI reported positive psychological aspects (having fun and motivation) and experiencing improvements in physical aspects (strength, endurance, balance and flexibility, blood circulation and intestinal transit). The structural aspects of the WRE device were acceptable in a lab with research personnel (appearance, size, weight, and comfort). Participants had concerns about safety on uneven surfaces, and possibility of falling. They expressed the desire to use the WRE for more life habits than just walking. CONCLUSION: This is the first study in which WUSCI report that the WRE should be implemented in initial rehabilitation. Lack of availability for community use after rehabilitation remains a concern.

Participation in a walking training program using a wearable robotic exoskeleton, 1-3 times weekly over several weeks, may be well tolerated and provide physical and psychological benefits for wheelchair users with spinal cord injuries.Using a robotic exoskeleton during initial rehabilitation may be well received and help with regaining strength, endurance, balance, and flexibility as well as promoting blood circulation and intestinal transit.The use of the wearable robotic exoskeleton always needs supervision of a clinician for walking and can't be used independently by wheelchair users; there is no possibility for hands free for household tasks (e.g., washing floors, accessing cupboards or reaching shelves, using stairs), and for recreation (e.g., exercising, taking walks, cultural activities, concerts).

Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer.

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular circadian rhythms in noncancerous and cancerous human breast tissues and their clinical relevance are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For noncancerous breast tissue, inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of luminal A samples exhibit continued, albeit dampened and reprogrammed rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude luminal A tumors. Surprisingly, patients with high-magnitude tumors had reduced 5-y survival. Correspondingly, 3D luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis.

Characterization of a partially saturated and glycosylated apocarotenoid from wheat that is depleted upon leaf rust infection.

Recent semi-targeted metabolomics studies have highlighted a number of metabolites in wheat that associate with leaf rust resistance genes and/or rust infection. Here, we report the structural characterization of a novel glycosylated and partially saturated apocarotenoid, reminiscent of a reduced form of mycorradicin, (6E,8E,10E)-4,9-dimethyl-12-oxo-12-((3,4,5-trihydroxy-6-(2-hydroxyethoxy)tetrahydro-2H-pyran-2-yl)methoxy)-3-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)dodeca-6,8,10-trienoic acid, isolated from Triticum aestivum L. (Poaceae) variety 'Thatcher' (Tc) flag leaves. While its accumulation was not associated with any of Lr34, Lr67 or Lr22a resistance genes, infection of Tc with leaf rust was found to deplete it, consistent with the idea of this metabolite being a glycosylated-storage form of an apocarotenoid of possible relevance to plant defense. A comparative analysis of wheat transcriptomic changes shows modulation of terpenoid, carotenoid, UDP-glycosyltransferase and glycosylase -related gene expression profiles, consistent with anticipated biosynthesis and degradation mechanisms. However, details of the exact nature of the relevant pathways remain to be validated in the future. Together these findings highlight another example of the breadth of unique metabolites underlying plant host-fungal pathogen interactions.

Potential Effects of an Exoskeleton-Assisted Overground Walking Program for Individuals With Spinal Cord Injury Who Uses a Wheelchair on Imaging and Serum Markers of Bone Strength: Pre-Post Study.

BACKGROUND: As many as 60% of individuals use a wheelchair long term after a spinal cord injury (SCI). This mode of locomotion leads to chronic decline in lower-extremity weight-bearing activities and contributes to the development of severe sublesional osteoporosis and high rates of fragility fracture. Overground exoskeleton-assisted walking programs provide a novel opportunity to increase lower-extremity weight bearing, with the potential to improve bone health. OBJECTIVE: The aim of the study is to measure the potential effects of an exoskeleton-assisted walking program on lower-extremity bone strength and bone remodeling biomarkers in individuals with chronic (≥18 months) SCI who use a wheelchair. METHODS: In total, 10 participants completed a 16-week exoskeleton-assisted walking program (34 individualized 1-hour sessions, progressing from 1 to 3 per week). Bone mineral density and bone strength markers (dual-energy x-ray absorptiometry: total body, left arm, leg, total hip, and femoral neck and peripheral quantitative computed tomography: 25% of left femur and 66% of left tibia) as well as bone remodeling biomarkers (formation=osteocalcin and resorption=C-telopeptide) were measured before and after intervention and compared using nonparametric tests. Changes were considered significant and meaningful if the following criteria were met: P<0.1, effect size ≥0.5, and relative variation >5%. RESULTS: Significant and meaningful increases were observed at the femur (femoral neck bone mineral content, bone strength index, and stress-strain index) and tibia (cortical cross-sectional area and polar moment of inertia) after the intervention (all P<.10). We also noted a decrease in estimated femoral cortical thickness. However, no changes in bone remodeling biomarkers were found. CONCLUSIONS: These initial results suggest promising improvements in bone strength markers after a 16-week exoskeleton-assisted walking program in individuals with chronic SCI. Additional research with larger sample sizes, longer interventions (possibly of greater loading intensity), and combined modalities (eg, pharmacotherapy or functional electrical stimulation) are warranted to strengthen current evidence. TRIAL REGISTRATION: ClinicalTrials.gov NCT03989752; https://clinicaltrials.gov/ct2/show/NCT03989752. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/19251.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. MAIN BODY: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. CONCLUSION: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

Sublithospheric diamond ages and the supercontinent cycle.

Subduction related to the ancient supercontinent cycle is poorly constrained by mantle samples. Sublithospheric diamond crystallization records the release of melts from subducting oceanic lithosphere at 300-700 km depths1,2 and is especially suited to tracking the timing and effects of deep mantle processes on supercontinents. Here we show that four isotope systems (Rb-Sr, Sm-Nd, U-Pb and Re-Os) applied to Fe-sulfide and CaSiO3 inclusions within 13 sublithospheric diamonds from Juína (Brazil) and Kankan (Guinea) give broadly overlapping crystallization ages from around 450 to 650 million years ago. The intracratonic location of the diamond deposits on Gondwana and the ages, initial isotopic ratios, and trace element content of the inclusions indicate formation from a peri-Gondwanan subduction system. Preservation of these Neoproterozoic-Palaeozoic sublithospheric diamonds beneath Gondwana until its Cretaceous breakup, coupled with majorite geobarometry3,4, suggests that they accreted to and were retained in the lithospheric keel for more than 300 Myr during supercontinent migration. We propose that this process of lithosphere growth-with diamonds attached to the supercontinent keel by the diapiric uprise of depleted buoyant material and pieces of slab crust-could have enhanced supercontinent stability.

Experimenter administered Δ9-THC decreases nicotine self-administration in a rat model.

BACKGROUND: The co-use of nicotine and cannabis has been steadily rising in the United States. Rodent studies suggest that delta-9-tetrahydrocannabinol (THC) could increase addictive qualities of nicotine, but whether repeated THC exposure alters self-administration of nicotine has not been tested. We hypothesized that THC would increase the reinforcing effects of nicotine and alter nicotine intake. METHODS: Adult male and female Sprague-Dawley rats were treated with THC (0, 3, 30 mg/kg) daily for 14 days prior to and during training for intravenous self-administration of nicotine. Rats were allowed to self-administer nicotine for several weeks, then tested for sensitivity to nicotine dose through multiple determinations of a nicotine dose-effect curve with or without THC pretreatment. A separate set of rats were trained on fixed ratio responding for sucrose and assessed for THC effects on behavior. RESULTS: Post-session THC decreased nicotine self-administration in male and female rats throughout acquisition and maintenance and increased the latency to stable rates of nicotine intake during acquisition. Post-session THC shifted nicotine dose-effect curves downward, and pre-session THC suppressed responding at higher nicotine doses. Unlike nicotine, responding for sucrose was not affected by post-session THC. Pre-session THC decreased responding for sucrose, particularly for THC-naïve rats. CONCLUSIONS: Repeated post-session THC decreased nicotine-taking behaviors but did not alter sucrose responding. Thus, post-session THC may alter sensitivity to nicotine. Pre-session THC treatment decreased lever pressing in both sucrose and nicotine studies, indicating this effect was nonspecific. These studies show that THC modulates patterns of nicotine intake in rat models.

Computational remodeling of an enzyme conformational landscape for altered substrate selectivity.

Structural plasticity of enzymes dictates their function. Yet, our ability to rationally remodel enzyme conformational landscapes to tailor catalytic properties remains limited. Here, we report a computational procedure for tuning conformational landscapes that is based on multistate design of hinge-mediated domain motions. Using this method, we redesign the conformational landscape of a natural aminotransferase to preferentially stabilize a less populated but reactive conformation and thereby increase catalytic efficiency with a non-native substrate, resulting in altered substrate selectivity. Steady-state kinetics of designed variants reveals activity increases with the non-native substrate of approximately 100-fold and selectivity switches of up to 1900-fold. Structural analyses by room-temperature X-ray crystallography and multitemperature nuclear magnetic resonance spectroscopy confirm that conformational equilibria favor the target conformation. Our computational approach opens the door to targeted alterations of conformational states and equilibria, which should facilitate the design of biocatalysts with customized activity and selectivity.

Multiple Clonostachys rosea UDP-Glycosyltransferases Contribute to the Production of 15-Acetyl-Deoxynivalenol-3-O-Glycoside When Confronted with Fusarium graminearum.

Mycotoxins, derived from toxigenic fungi such as Fusarium, Aspergillus, and Penicillium species have impacted the human food chain for thousands of years. Deoxynivalenol (DON), is a tetracyclic sesquiterpenoid type B trichothecene mycotoxin predominantly produced by F. culmorum and F. graminearum during the infection of corn, wheat, oats, barley, and rice. Glycosylation of DON is a protective detoxification mechanism employed by plants. More recently, DON glycosylating activity has also been detected in fungal microparasitic (biocontrol) fungal organisms. Here we follow up on the reported conversion of 15-acetyl-DON (15-ADON) into 15-ADON-3-O-glycoside (15-ADON-3G) in Clonostachys rosea. Based on the hypothesis that the reaction is likely being carried out by a uridine diphosphate glycosyl transferase (UDP-GTase), we applied a protein structural comparison strategy, leveraging the availability of the crystal structure of rice Os70 to identify a subset of potential C. rosea UDP-GTases that might have activity against 15-ADON. Using CRISPR/Cas9 technology, we knocked out several of the selected UDP-GTases in the C. rosea strain ACM941. Evaluation of the impact of knockouts on the production of 15-ADON-3G in confrontation assays with F. graminearum revealed multiple UDP-GTase enzymes, each contributing partial activities. The relationship between these positive hits and other UDP-GTases in fungal and plant species is discussed.

Overexpression of IκB⍺ modulates NF-κB activation of inflammatory target gene expression.

Cells respond to inflammatory stimuli such as cytokines by activation of the nuclear factor-κB (NF-κB) signalling pathway, resulting in oscillatory translocation of the transcription factor p65 between nucleus and cytoplasm in some cell types. We investigate the relationship between p65 and inhibitor-κB⍺ (IκBα) protein levels and dynamic properties of the system, and how this interaction impacts on the expression of key inflammatory genes. Using bacterial artificial chromosomes, we developed new cell models of IκB⍺-eGFP protein overexpression in a pseudo-native genomic context. We find that cells with high levels of the negative regulator IκBα remain responsive to inflammatory stimuli and maintain dynamics for both p65 and IκBα. In contrast, canonical target gene expression is dramatically reduced by overexpression of IκBα, but can be partially rescued by overexpression of p65. Treatment with leptomycin B to promote nuclear accumulation of IκB⍺ also suppresses canonical target gene expression, suggesting a mechanism in which nuclear IκB⍺ accumulation prevents productive p65 interaction with promoter binding sites. This causes reduced target promoter binding and gene transcription, which we validate by chromatin immunoprecipitation and in primary cells. Overall, we show how inflammatory gene transcription is modulated by the expression levels of both IκB⍺ and p65. This results in an anti-inflammatory effect on transcription, demonstrating a broad mechanism to modulate the strength of inflammatory response.

Wrist-worn devices for the measurement of heart rate and energy expenditure: A validation study for the Apple Watch 6, Polar Vantage V and Fitbit Sense.

The purpose of this study was to investigate the accuracy of 3 recently released wrist-worn devices (Apple Watch 6, Polar Vantage V and Fitbit Sense) for heart rate and energy expenditure during various activities. The study population consisted of 60 young healthy individuals (30 men and 30 women; age: 24.9 ± 3.0 years, BMI: 23.1 ± 2.7 kg/m2). Heart rate and energy expenditure were measured using the Polar H10 and Metamax 3B, respectively (reference measures) as well as with the 3 wrist-worn devices during 5 different activities (sitting, walking, running, resistance exercises and cycling). The Apple Watch 6 displayed the highest level of accuracy for heart rate measurement with a coefficient of variation (CV) (%) of less than 5% for all 5 activities, whereas the Polar Vantage V and the Fitbit Sense presented various degrees of accuracy (from high to poor accuracy) dependent on the activity (CVs between 2.44-8.80% and 4.14-10.76%, respectively). As for energy expenditure, all 3 devices displayed poor accuracy for all 5 physical activities (CVs between 14.68-24.85% for Apple Watch 6, 16.54-25.78% for Polar Vantage V and 13.44-29.66% for Fitbit Sense). Results of the present study indicate that the Apple Watch 6 was the most accurate for measuring heart rate across all 5 activities, whereas variable levels of accuracy for heart rate measurement for the Polar Vantage V and the Fitbit Sense were observed depending on the activity. As for energy expenditure, all 3 devices showed poor accuracy during all activities.Highlights The Apple Watch 6 was the most accurate for measuring heart rate, whereas the Polar Vantage V and Fitbit Sense showed variable results dependent on the activityThe Apple Watch 6, Polar Vantage V and Fitbit Sense showed poor accuracy for energy expenditure during 5 different physical activitiesHealthcare care professionals, athletes/coaches and the general population may want to proceed with caution on the clinical utility of energy expenditure of these devices during the implementation of an exercise training or nutritional programme.

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds.

The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.

Pea and lentil 7S globulin crystal structures with comparative immunoglobulin epitope mapping.

Legumes represent an affordable high protein, nutrient dense food source. However, the vast majority of legume crops contain proteins that are known allergens for susceptible individuals. These include proteins from the 7S globulin family, which comprise a vast majority of seed storage proteins. Here, the crystal structures of 7S globulins from Pisum sativum L. (pea) and Lens culinaris Medicus (lentil) are presented for the first time, including pea vicillin and convicilin, and lentil vicilin. All three structures maintain the expected 7S globulin fold, with trimeric quaternary structure and monomers comprised of ß-barrel N- and C-modules. The potential impact of sequence differences on structure and packing in the different crystal space groups is noted, with potential relevance to packing upon seed deposition. Mapping on the obtained crystal structures highlights significant Ig epitope overlap between pea, lentil, peanut and soya bean and significant coverage of the entire seed storage protein, emphasizing the challenge in addressing food allergies. How recently developed biologicals might be refined to be more effective, or how these seed storage proteins might be modified in planta to be less immuno-reactive remain challenges for the future. With legumes representing an affordable, high protein, nutrient dense food source, this work will enable important research in the context of global food security and human health on an ongoing basis.

Multiple routes to help you roam: A comparison of training interventions to improve cognitive-motor dual-tasking in healthy older adults.

Cognitive-motor dual-tasking is a complex activity that predicts falls risk and cognitive impairment in older adults. Cognitive and physical training can both lead to improvements in dual-tasking; however, less is known about what mechanisms underlie these changes. To investigate this, 33 healthy older adults were randomized to one of three training arms: Executive function (EF; n = 10), Aerobic Exercise (AE; n = 10), Gross Motor Abilities (GMA; n = 13) over 12 weeks (1 h, 3×/week). Single and dual-task performance (gait speed, m/s; cognitive accuracy, %) was evaluated before and after training, using the 2-back as concurrent cognitive load. Training arms were designed to improve cognitive and motor functioning, through different mechanisms (i.e., executive functioning - EF, cardiorespiratory fitness - CRF, and energy cost of walking - ECW). Compared to baseline, we observed few changes in dual-task gait speed following training (small effect). However, dual-task cognitive accuracy improved significantly, becoming facilitated by walking (large effect). There were no differences in the magnitude of improvements across training arms. We also found that older adults with lower cognitive ability (i.e., MoCA score < 26; n = 14) improved more on the dual-task cognitive accuracy following training, compared to older adults with higher cognitive ability (i.e., MoCA ≥26; n = 18). Taken together, the results suggest that regardless of the type of intervention, training appears to strengthen cognitive efficiency during dual-tasking, particularly for older adults with lower baseline cognitive status. These gains appear to occur via different mechanisms depending on the form of intervention. Implications of this research are paramount, as we demonstrate multiple routes for improving cognitive-motor dual-tasking in older adults, which may help reduce risk of cognitive impairment.

Physical Activity and Mindfulness are Associated with Lower Anxiety in Different but Complementary Ways.

Introduction: Anxiety is the most prevalent mental illness worldwide. Physical activity and mindfulness both reduce anxiety. The two are highly related; however, the relative association of physical activity and mindfulness on anxiety has yet to be examined. The present study aimed to evaluate the unique variance accounted for by physical activity and mindfulness on anxiety. Methods: Fifty young adults from a student population (M ± SD = 19 ± 0.2 years old; 58% female) reported their physical activity, mindfulness, and anxiety symptoms at the start of the study and reported their change in state anxiety to an acute psychological stress test, Trier Social Stress Test. Results: Mindfulness explained more of the variance associated with anxiety symptoms at baseline, whereas physical activity explained more of the variance associated with change in state anxiety in response to the acute stressor. Females had higher rates of anxiety symptoms than males suggesting that females may benefit more from mindfulness. In contrast, both males and females reacted similarly to an acute stressor suggesting that both genders may benefit from physical activity. Conclusions: Our findings suggest that physical activity and trait mindfulness may have related, but distinct impacts on anxiety levels. These results have important implications for using these lifestyle interventions to support mental health and point to personalizing interventions to help ease the burden of anxiety felt by the individual.

Optogenetic stimulation of dynorphinergic neurons within the dorsal raphe activate kappa opioid receptors in the ventral tegmental area and ablation of dorsal raphe prodynorphin or kappa receptors in dopamine neurons blocks stress potentiation of cocaine reward.

Behavioral stress exposure increases the risk of drug-taking in individuals with substance use disorders by mechanisms involving the dynorphins, which are the endogenous neuropeptides for the kappa opioid receptor (KOR). KOR agonists have been shown to encode dysphoria, aversion, and changes in reward valuation, and kappa opioid antagonists are in clinical development for treating substance use disorders. In this study, we confirmed that KORs were expressed in dopaminergic neurons in the ventral tegmental area (VTA) of male C57BL6/J mice. Genetic ablation of KORs from dopamine neurons blocked the potentiating effects of repeated forced swim stress on cocaine conditioned place preference (CPP). KOR activation inhibited dopamine neuron GCaMP6m calcium activity in VTA during swim stress and caused a rebound enhancement during the period after stress exposure. Transient optogenetic inhibition of VTA dopamine neurons with AAV5-DIO-SwiChR was acutely aversive in a real time place preference assay and blunted cocaine CPP when inhibition was administered concurrently with cocaine conditioning. However, when inhibition preceded cocaine conditioning by 30 min, cocaine CPP was enhanced. Retrograde tracing with CAV2-DIO-ZsGreen identified a population of prodynorphinCre neurons in the dorsal raphe nucleus (DRN) projecting to the VTA. Optogenetic stimulation of dynorphinergic neurons within the DRN by Channelrhodopsin2 activated KOR in VTA and ablation of prodynorphin blocked stress potentiation of cocaine CPP. Together, these studies demonstrate the presence of a dynorphin/KOR midbrain circuit that projects from the DRN to VTA and is involved in altering the dynamic response of dopamine neuron activity to enhance drug reward learning.