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Background: Poor long-term recovery outcomes after treatment (e.g., readmission to inpatient treatment) are common among individuals with substance use disorders (SUDs). In-person mindfulness-based treatments (MBTs) are efficacious for SUDs and may improve recovery outcomes. However, existing MBTs for SUD have limited public health reach, and thus scalable delivery methods are needed. A digitally-delivered MBT for SUDs may hold promise. Methods: We recently developed Mindful Journey, a smartphone app-based adjunctive MBT for improving long-term recovery outcomes. In this paper, we present details on the app and describe the protocol for a single-site pilot feasibility randomized controlled trial of Mindful Journey. In this trial, individuals (n = 34) in an early phase of outpatient treatment for SUDs will be randomized to either treatment-as-usual (TAU) plus Mindful Journey, or TAU only. The trial will focus on testing the feasibility (e.g., engagement) and acceptability of the app (e.g., perceived usability and helpfulness for recovery), as well as feasibility of study procedures (e.g., assessment completion). The trial will incorporate ecological momentary assessment before and after treatment to assess mechanisms in real-time, including mindfulness, craving, difficulties with negative emotion regulation, and savoring. To examine the sensitivity to change of outcomes (substance use, substance-related problems, and psychological distress) and mechanism variables (noted above), we will test within-treatment-condition changes over time. Discussion: The proposed pilot trial will provide important preliminary data on whether Mindful Journey is feasible and acceptable among individuals with SUDs. Trial registration: ClinicalTrials.gov NCT05109507.

AbstractBackground/Objectives There is a great unmet need for accessible adjunctive interventions to promote long-term recovery from substance use disorder (SUD). This study aimed to iteratively develop and test the initial feasibility and acceptability of Mindful Journey, a novel digital mindfulness-based intervention for promoting recovery among individuals with SUD.Patients/Materials Ten adults receiving outpatient treatment for SUD.Methods Phase 1 (n = 5) involved developing and testing a single introductory digital lesson. Phase 2 included a separate sample (n = 5) and involved testing all 15 digital lessons (each 30- to 45-minutes) over a 6-week period, while also receiving weekly brief phone coaching for motivational/technical support.Results Across both phases, quantitative ratings (rated on a 5-point scale) were all at or above a 4 (corresponding with ‘agree’) for key acceptability dimensions, such as usability, understandability, appeal of visual content, how engaging the content was, and helpfulness for recovery. Additionally, in both phases, qualitative feedback indicated that participants particularly appreciated the BOAT (Breath, Observe, Accept, Take a Moment) tool for breaking down mindfulness into steps. Qualitative feedback was used to iteratively refine the intervention. For example, based on feedback, we added a second core mindfulness tool, the SOAK (Stop, Observe, Appreciate, Keep Curious), and we added more example clients and group therapy videos. In Phase 2, 4 out of 5 participants completed all 15 lessons, providing initial evidence of feasibility. Participants reported that the phone coaching motivated them to use the app. The final version of Mindful Journey was a smartphone app with additional features, including brief on-the-go audio exercises and a library of mindfulness practices. Although, participants used these additional features infrequently.Conclusions Based on promising initial findings, future acceptability and feasibility testing in a larger sample is warranted. Future versions might include push notifications to facilitate engagement in the additional app features.

ABSTRACTAlthough smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.

Abstract Objectives Complex physiological adaptations often involve the coordination of molecular responses across multiple tissues. Establishing transcriptomic resources for non-traditional model organisms with phenotypes of interest can provide a foundation for understanding the genomic basis of these phenotypes, and the degree to which these resemble, or contrast, those of traditional model organisms. Here, we present a one-of-a-kind gene expression dataset generated from multiple tissues of two hibernating brown bears (Ursus arctos). Data description This dataset is comprised of 26 samples collected from 13 tissues of two hibernating brown bears. These samples were collected opportunistically and are typically not possible to attain, resulting in a highly unique and valuable gene expression dataset. In combination with previously published datasets, this new transcriptomic resource will facilitate detailed investigation of hibernation physiology in bears, and the potential to translate aspects of this biology to treat human disease.

The coronavirus disease 2019 (COVID-19) pandemic has affected all Canadian families, with some impacted differently than others. Our study aims to: (1) determine the prevalence and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among Canadian families, (2) identify predictors of infection susceptibility and severity of SARS-CoV-2, and (3) identify health and psychosocial impacts of the COVID-19 pandemic. This study builds upon the CHILD Cohort Study, an ongoing multi-ethnic general population prospective cohort consisting of 3,454 Canadian families with children born in Vancouver, Edmonton, Manitoba, and Toronto between 2009 and 2012. During the pandemic, CHILD households were invited to participate in the CHILD COVID-19 Add-On Study involving: (1) brief biweekly surveys about COVID-19 symptoms and testing; (2) quarterly questionnaires assessing COVID-19 exposure and testing, vaccination status, physical and mental health, and pandemic-driven life changes; and (3) in-home biological sampling kits to collect blood and stool. In total, 1,462 households (5,378 participants) consented to the CHILD COVID-19 Add-On Study: 2,803 children (mean±standard deviation [SD], 9.0±2.7 years; range, 0-17 years) and 2,576 adults (mean±SD, 43.0±6.5 years; range, 18-85 years). We will leverage the wealth of pre-pandemic CHILD data to identify risk and resilience factors for susceptibility and severity to the direct and indirect pandemic effects. Our short-term findings will inform key stakeholders and knowledge users to shape current and future pandemic responses. Additionally, this study provides a unique resource to study the long-term impacts of the pandemic as the CHILD Cohort Study continues.

BackgroundPermanent synthetic meshes such as polypropylene (PP) have been utilized for hernia repair for decades, but concerns remain regarding potential long-term, mesh-related complications. A resorbable polymer such as poly-4-hydroxybutyrate (P4HB) represents an alternative with high initial strength, that gradually resorbs, leaving an abdominal wall that is at least as strong as it would be in its native state. We aimed to compare early wound morbidity and clinical outcomes associated with P4HB to traditional, permanent PP in umbilical and small to medium, routine ventral hernias using data from the Abdominal Core Health Quality Collaborative (ACHQC).MethodsInclusion criteria for the umbilical cohort included: all Centers for Disease Control and Prevention (CDC) wound classes, all Ventral Hernia Working Group (VHWG) hernia grades, and hernia defects

The detection of conserved motifs by pattern recognition receptors is a crucial component of the innate detection of pathogens and danger signals via conserved pattern recognition receptors. Here the authors define a pathway that transfers partially digested material from the phagolysosomal pathway of macrophages to release at the plasma membrane which is associated with enhanced inflammatory potential, by a process they introduce as eructophagy.

BackgroundPoly-4-hydroxybutyrate (P4HB) is a fully resorbable, biologically-produced polymer with a strength and flexibility comparable to permanent synthetic polymers. The objective was to identify/summarize all peer-reviewed publications involving P4HB mesh.MethodsA scoping review was conducted within PubMed and included articles published through October 2022.ResultsA total of n = 79 studies were identified (n = 12 in vitro/bench; n = 14 preclinical; n = 6 commentaries; n = 50 clinical). Of the clinical studies, n = 40 reported results applicable to hernia and n = 10 to plastic/reconstructive surgery and involved patients of all Centers for Disease Control (CDC) wound classes and Ventral Hernia Working Group (VHWG) grades.ConclusionP4HB mesh provides long-term hernia repair strength and exhibits promising clinical outcomes beyond its resorption period. Future studies should include randomized controlled trials comparing P4HB to other biomaterials, as well as optimal patient selection, operative technique, long-term outcomes, minimization of potential mesh-related complications, and potential contraindications/complications for P4HB in hernia/abdominal wall reconstruction.

Colorectal cancer (CRC) is a leading cause of the cancer-related deaths worldwide. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is urgent. Several studies, including ours, have reported a causal role for an upregulated claudin-1 expression in promoting CRC metastasis through the activation of the Src and β-catenin-signaling. In murine models of colon tumorigenesis, claudin-1 overexpression promotes oncogenic properties such as transformation and invasiveness. Conversely, the downregulation of claudin-1 inhibits colon tumorigenesis. Despite being a desirable target for cancer treatment, there are currently no known claudin-1 inhibitors with antitumor efficacy. Using a rigorous analytical design and implementing in- vitro and in-vivo testing and a brief medicinal chemistry campaign, we identified a claudin-1-specific inhibitor and named it I-6. Despite its high potency, I-6 was rapidly cleared in human liver microsomes. We, therefore, synthesized I-6 analogs and discovered a novel small molecule, PDS-0330. We determined that PDS0330 inhibits claudin-1-dependent CRC progression without exhibiting toxicity in in-vitro and in-vivo models of CRC and that it binds directly and specifically to claudin-1 with micromolar affinity. Further analyses revealed that PDS-0330 exhibits antitumor and chemosensitizer activities with favorable pharmacokinetic properties by inhibiting the association with metastatic oncogene Src. Overall, our data propose that PDS-0330 interferes with claudin-1/Src association to inhibit CRC progression and metastasis. Our findings are of direct clinical relevance and may open new therapeutic opportunities in colon cancer treatment and/or management by targeting claudin-1.

Purpose The objective of this study was to determine mechanical and histological properties of Phasix™ ST Mesh in various defect sizes and characterize the tissue replacing Phasix™ ST Mesh in a porcine model of ventral hernia repair. Methods Simulated hernia defects were surgically created in the midline of twenty-four (n = 24) Yucatan pigs. Treatment groups included 8 cm defect sutured closed (buttress) and unclosed 4 cm and 8 cm defect groups. Phasix™ ST Mesh (15 cm diameter circle) was implanted laparoscopically and fixated circumferentially with SorbaFix™ Absorbable Fixation System fasteners. The repair sites underwent mechanical, molecular weight, and histological evaluation at 48 and 72 weeks postimplantation. Results Mechanical testing of Phasix™ ST Mesh-repaired sites revealed similar strengths at both time points for all three repair types, p > 0.05 in all cases (48 weeks: 142.4 ± 6.0 N, 142.3 ± 16.5 N, and 168.8 ± 38.5 N; 72 weeks: 110.0 ± 18.3 N, 138.6 ± 42.2 N, and 160.6 ± 42.0 N for 4 cm defect, 8 cm defect, and 8 cm buttress, respectively. mean ± SEM) No significant differences were observed over time except at 72 weeks postimplantation when the 4 cm defect group exhibited significantly lower strength than the T0 strength of Phasix™ ST Mesh (204.6 ± 5.0 N, p

Abstract Obesity is associated with several skeletal muscle impairments which can be improved through an aerobic exercise prescription. The possibility that exercise responsiveness is diminished in people with obesity has been suggested but not well‐studied. The purpose of this study was to investigate how obesity influences acute exercise responsiveness in skeletal muscle and circulating amino metabolites. Non‐obese (NO; n = 19; 10F/9M; BMI = 25.1 ± 2.8 kg/m2) and Obese (O; n = 21; 14F/7M; BMI = 37.3 ± 4.6 kg/m2) adults performed 30 min of single‐leg cycling at 70% of VO2peak. 13C6‐Phenylalanine was administered intravenously for muscle protein synthesis measurements. Serial muscle biopsies (vastus lateralis) were collected before exercise and 3.5‐ and 6.5‐h post‐exercise to measure protein synthesis and gene expression. Targeted plasma metabolomics was used to quantitate amino metabolites before and 30 and 90 min after exercise. The exercise‐induced fold change in mixed muscle protein synthesis trended (p = 0.058) higher in NO (1.28 ± 0.54‐fold) compared to O (0.95 ± 0.42‐fold) and was inversely related to BMI (R2 = 0.140, p = 0.027). RNA sequencing revealed 331 and 280 genes that were differentially expressed after exercise in NO and O, respectively. Gene set enrichment analysis showed O had six blunted pathways related to metabolism, cell to cell communication, and protein turnover after exercise. The circulating amine response further highlighted dysregulations related to protein synthesis and metabolism in adults with obesity at the basal state and in response to the exercise bout. Collectively, these data highlight several unique pathways in individuals with obesity that resulted in a modestly blunted exercise response.

Introduction: During cardiopulmonary resuscitation (CPR), high quality chest compressions are critical to organ perfusion, especially the brain. Yet, the optimal location for chest compressions is unclear. It was hypothesized that compared with the standard chest compression (SCC) location, left ventricle chest compressions (LVCCs) would result in greater end-tidal carbon dioxide (ETCO2), blood pressure (BP), and cerebral blood velocity (CBV) during CPR in swine. Methods: Female Landrace swine (N = 32; 35 ± 2 kg) underwent two mins of untreated asphyxiated cardiac arrest (CA). Thereafter, swine were treated with three 2-min cycles of either SCC or LVCC mechanical basic life support CPR (LUCAS 3). ETCO2 (in-line sampling), BP (arterial catheter line), and CBV (transcranial Doppler) were measured during the pre-CA, untreated-CA, and CPR-treated phases. Results: ETCO2, BP, and CBV were similar between groups at pre- and during untreated-CA (P ≥ 0.188). During CPR, ETCO2 (36 ± 6 versus 24 ± 10 mmHg, P

In recent decades, GNSS radio occultation (RO) soundings have proven to be an invaluable input to global weather forecasting. The success of government programs such as COSMIC is now complemented by commercial low-cost cubesats. The result is access to more than 10,000 soundings per day. We examine aerial platforms for commercial GNSS-RO, specifically high-altitude balloons and commercial aviation. Meteorological balloons (radiosondes) are deployed daily in over 900 locations globally. Adding GNSS-RO capability to radiosondes would expand capability and enable local area monitoring. Commercial aviation offers scale with more than 100,000 flights daily. A barrier to entry for the inclusion of GNSS-RO sensors is cost and complexity, as GNSS-RO traditionally requires highly specialized equipment. This paper describes a low-cost and scalable approach to aerial GNSS-RO based on commercial-off-the-shelf (COTS) GNSS receivers. We present hardware prototypes and data processing techniques that demonstrate technical feasibility through the results from several flight testing campaigns.

Inflammation and mitochondrial-dependent oxidative stress are interrelated processes implicated in multiple neuroinflammatory disorders, including Alzheimer’s disease (AD) and depression. Exposure to elevated temperature (hyperthermia) is proposed as a non-pharmacological, anti-inflammatory treatment for these disorders; however, the underlying mechanisms are not fully understood. Here we asked if the inflammasome, a protein complex essential for orchestrating the inflammatory response and linked to mitochondrial stress, might be modulated by elevated temperatures. To test this, in preliminary studies, immortalized bone-marrow-derived murine macrophages (iBMM) were primed with inflammatory stimuli, exposed to a range of temperatures (37–41.5 °C), and examined for markers of inflammasome and mitochondrial activity. We found that exposure to mild heat stress (39 °C for 15 min) rapidly inhibited iBMM inflammasome activity. Furthermore, heat exposure led to decreased ASC speck formation and increased numbers of polarized mitochondria. These results suggest that mild hyperthermia inhibits inflammasome activity in the iBMM, limiting potentially harmful inflammation and mitigating mitochondrial stress. Our findings suggest an additional potential mechanism by which hyperthermia may exert its beneficial effects on inflammatory diseases.

Heterosis, also known as hybrid vigor, is the basis of modern maize production. The effect of heterosis on maize phenotypes has been studied for decades, but its effect on the maize-associated microbiome is much less characterized. To determine the effect of heterosis on the maize microbiome, we sequenced and compared the bacterial communities of inbred, open pollinated, and hybrid maize. Samples covered three tissue types (stalk, root, and rhizosphere) in two field experiments and one greenhouse experiment. Bacterial diversity was more affected by location and tissue type than genetic background for both within-sample (alpha) and between-sample (beta) diversity. PERMANOVA analysis similarly showed that tissue type and location had significant effects on the overall community structure, whereas the intraspecies genetic background and individual plant genotypes did not. Differential abundance analysis identified only 25 bacterial ASVs that significantly differed between inbred and hybrid maize. Predicted metagenome content was inferred with Picrust2, and it also showed a significantly larger effect of tissue and location than genetic background. Overall, these results indicate that the bacterial communities of inbred and hybrid maize are often more similar than they are different and that non-genetic effects are generally the largest influences on the maize microbiome.

Translating discovery scale vial-based batch reactions to continuous flow scale-up conditions is limited by significant time and resource constraints. Here, the authors report a photochemical droplet microfluidic platform, which enables high throughput reaction discovery in flow to generate pharmaceutically relevant compound libraries.

Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (P < 0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

Background Transcranial Doppler (TCD) ultrasound is an essential tool for the detection of cerebral vasospasm after subarachnoid hemorrhage (SAH) but is limited by the availability of skilled operators. We examined the clinical feasibility and concordance of a robotically assisted TCD system with artificial intelligence with routine handheld TCD after SAH. Methods We evaluated TCD velocities in the anterior cerebral artery (ACA) and middle cerebral artery (MCA) of two patients with high-grade SAH and angiographic evidence of vasospasm. A single channel TCD device with a handheld diagnostic probe as well as a robotically assisted TCD device was used, the relationship of the two tests was evaluated using the bootstrap method of resampling for the concordance correlation coefficient (CCC) paired with a Pearson’s correlation analysis, followed by a Bland-Altman plot. Results Patient 1 developed angiographic and TCD evidence of vasospasm in the proximal right MCA, but except for periods of disorientation remained neurologically intact. Angiographic, TCD and clinical evidence of ACA spasm occurred 6 days after ictus in patient 2. Robotically measured mean flow velocities were comparable to manual TCDs in the MCAs (CCC=0.83; 95% confidence interval [CI], 0.42 to 0.96; P=0.001) but not in the ACAs (CCC=0.26; 95% CI, –0.01 to 0.71; P=0.26). Conclusion Robotically assisted TCD system with artificial intelligence provides an alternative to manual TCD for assessment of MCA velocities in patients with SAH, expanding the availability of TCD to settings in which specialized clinicians are not available. Further studies for validation of this technology are warranted.

Arene dearomatization reactions allow chemists to rapidly build unique chemical architectures from largely available starting materials. Here, the authors show a photocatalytic carboamination/dearomatization cascade process leading to 1,4-cyclohexadiene-fused sultams via N-centered radicals.

Abstract Background Children with congenital heart disease (CHD) have an elevated risk of future cardiovascular disease but the underlying mechanisms are unclear. Abdominal obesity (measured as waist circumference) is a risk factor for adult onset of cardiovascular diseases and is correlated with low physical activity levels, commonly found in children with congenital heart disease. Elevated waist circumference may be a mechanism by which cardiovascular disease risk is elevated in children with CHD. The purpose of this study was to compare waist circumference between children with and without CHD, while considering potential confounders. We hypothesized that children with CHD would have higher measures of waist circumference when controlling for differences in birthweight, lean mass, and physical activity. Methods Thirty-two children with CHD (10.9 ± 2.6 years; 12 female) from the Children’s Healthy-Heart Activity Monitoring Program in Saskatchewan, and 23 healthy controls (11.7 ± 2.5 years; 10 female) were studied. Waist circumference, physical activity (physical activity questionnaire), body composition (lean mass; dual x-ray absorptiometry), and birthweight were assessed. Analysis of covariance, Mann-Whitney U, and independent sample t-tests were used to assess group differences (p 0.05). Conclusion Our findings generate a novel hypothesis—higher waist circumferences in children with CHD compared to age-matched controls, may contribute to an elevated risk of cardiovascular disease.

Nociceptors, the high-threshold primary sensory neurons that trigger pain, interact with immune cells in the periphery to modulate innate immune responses. Whether they also participate in adaptive and humoral immunity is, however, not known. In this study, we probed if nociceptors have a role in distinct airway and skin models of allergic inflammation. In both models, the genetic ablation and pharmacological silencing of nociceptors substantially reduced inflammatory cell infiltration to the affected tissue. Moreover, we also found a profound and specific deficit in IgE production in these models of allergic inflammation. Mechanistically, we discovered that the nociceptor-released neuropeptide substance P helped trigger the formation of antibody-secreting cells and their release of IgE. Our findings suggest that nociceptors, in addition to their contributions to innate immunity, play a key role in modulating the adaptive immune response, particularly B cell antibody class switching to IgE.

In response to the COVID-19 pandemic, immediate and scalable testing solutions are needed to direct return to full capacity planning in the general public and across the Department of Defense (DoD). To fully understand the extent to which a population has been affected by COVID-19, active monitoring approaches require an estimation of overall seroprevalence in addition to accurate, affordable, and rapid tests to detect current SARS-CoV-2 infection. In this study, researchers in the Air Force Research Laboratory's 711th Human Performance Wing, Airman Systems Directorate evaluated the performance of various testing methods for the detection of SARS-CoV-2 antibodies and viral RNA in asymptomatic adults working at Wright-Patterson Air Force Base and the surrounding area during the period of 23 July 2020–23 Oct 2020. Altogether, there was a seroprevalance of 3.09% and an active infection rate of 0.5% (determined via the testing of saliva samples) amongst individuals tested, both of which were comparable to local and national averages at the time. This work also presents technical and non-technical assessments of various testing strategies as compared to the gold standard approaches (e.g., lateral flow assays vs. ELISA and RT-LAMP vs. RT-PCR) in order to explore orthogonal supply chains and fieldability. Exploration and validation of multiple testing strategies will allow the DoD and other workforces to make informed responses to COVID-19 and future pandemics.

Podocyte injury and the appearance of proteinuria are key features of several progressive kidney diseases. Genetic deletion or selective inhibition of TRPC5 channels with small-molecule inhibitors protects podocytes in rodent models of kidney disease, but less is known about the human relevance and translatability of TRPC5 inhibition. Here, we investigate the effect of TRPC5 inhibition in puromycin aminonucleoside (PAN)-treated rats, human iPSC-derived podocytes, and kidney organoids. We first established that systemic administration of the TRPC5 inhibitor AC1903 was sufficient to protect podocyte cytoskeletal proteins and suppress proteinuria in PAN-induced nephrosis rats, an established model of podocyte injury. TRPC5 current was recorded in the human iPSC-derived podocytes and was blocked by AC1903. PAN treatment caused podocyte injury in human iPSC-derived podocytes and kidney organoids. Inhibition of TRPC5 channels reversed the effects of PAN-induced injury in human podocytes in both 2D and 3D culture systems. Taken together, these results revealed the relevance of TRPC5 channel inhibition in puromycin-aminonucleoside induced nephrosis models, highlighting the potential of this therapeutic strategy for patients.

Recent literature in the world-systems perspective has refocused attention on questions of ‘core’ and ‘periphery’ in historical capitalism, yet rarely critically examines the underlying assumptions regarding these zones. Drawing on a developing dataset on the world’s wealthiest individuals (the World-Magnates Database), we trace the development and expansion of sugar circuits across the Atlantic world from the sixteenth through the eighteenth centuries to explain how the sugar commodity chain leads us to rethink some prevailing notions of core and periphery. Namely, we challenge the notion that these zones consist of geographical spaces that, since very early in the development of the world-economy, became permanently specialized in the production of raw materials (periphery) or more sophisticated manufactures (core); and that labor forces have been trans-historically relatively free/better-paid in core activities and coerced/poorly-paid in peripheral ones. We argue that, prior to the nineteenth century, the world-economy is not only characterized by the uneven and combined emergence of various forms of labor exploitation, as usually argued within a world-systems perspective, but also one in which core-like and peripheral activities (that is, those providing access to relatively greater or lesser wealth) were not yet as clearly bounded geographically as they would become in the nineteenth and twentieth centuries. We find that a longue-durée analysis of sugar production by enslaved labor illustrates not merely processes of peripheralization, but of what we call coreification.

The potential contribution of high altitude permafrost as a climate feedback is unknown. Here the authors show seven years of sustained carbon emissions from snow-scoured alpine tundra including respiration of older carbon substrate from solifluction lobes associated with permafrost during the winter.

Abstract Background The objective of this biomechanical study is to compare two variations of single-row knotless techniques (Knotless repair and Rip-stop Knotless repair) against a single-row double-loaded anchor (DL) repair, focused on evaluating contact pressure and contact area amongst three different single-row techniques for rotator cuff repairs. Methods A total of 24 fresh frozen human shoulders were tested. Specimens were randomly assigned into one of the three single-row (SR) repair groups: A Knotted single-row double-loaded anchor (DL) repair, a Knotless (K) repair, or a Knotless Rip-Stop (KRS) repair. The footprint was measured after complete detachment of the supraspinatus tendon from the greater tuberosity, introducing pressure sensors between bony footprint and detached rotator cuff, and finally reconstructing it. All specimens were mounted onto a servohydraulic test system to analyze contact variables at 0° and 30° of abduction with 0 N, 30 N and 50 N of tension. Results Groups did not differ significantly in their footprint sizes: DL group 359.75 ± 58.37 mm2, K group 386.5 ± 102.13 mm2, KRS group 415.87 ± 93.80 mm2 (p = 0.84); nor in bone mineral density: DL group 0.25 ± 0.14 g/cm2, K group 0.32 ± 0.19 g/cm2, KRS group 0.32 ± 0.13 g/cm2, (p = 0.75) or average age. The highest mean pressurized contact area measured for the K repair was 248.1 ± 50.9 mm2, which equals a reconstruction of 67.1 ± 19.3% at 0° abduction and a 50 N supraspinatus load. This reconstructed area was significantly greater compared with the DL repair 152.8 ± 73.1 mm2, reconstructing 42.0 ± 18.5% on average when under the same conditions (p = 0.04). The mean contact pressure did not significantly differ amongst groups (p = 1.0): DL group 30.8 ± 17.4 psi, K group 30.9 ± 17.4 psi and KRS group 30.0 ± 10.9 psi. Neither the 30° abduction angle nor the supraspinatus load had a significant influence on the contact pressure in our study. Conclusion Both single-row knotless techniques resulted in significantly higher footprint reconstruction, providing larger contact area and a more uniform pressure distribution when compared with the single-row Knotted techniques. The mean contact pressure did not differ among groups significantly. These knotless techniques may be an alternative if the surgeon decides to perform a single-row rotator cuff repair. Level of evidence Basic Science Study, Biomechanics.

There is controversy whether a lifetime of heavy resistance training, providing pressure-overload, is harmful for left ventricular function. We compared left ventricular dimensions and function in elite Masters athletes involved in throwing events (requiring strength; n = 21, seven females, 60 ± 14 years) to those involved in endurance events (n = 65, 25 females, 59 ± 10 years) and sprinting (n = 68, 21 females, 57 ± 13 years) at the 2018 World Masters Athletic Championships. Left ventricular dimensions and function were assessed with B-mode ultrasound and Doppler. The ratio of left ventricular early diastolic peak filling velocity to peak velocity during atrial contraction (E/A) across the mitral valve and the ratio of E to velocity of the E-wave (E’) across the lateral and septal mitral annulus (E/E’) were used as indexes of left ventricular diastolic function. Intra-ventricular septal wall thickness was greater in throwers compared to sprinters (11.9 ± 2.2 vs. 10.3 ± 2.3 mm; p = 0.01). Left ventricular end diastolic diameter/body surface area was higher in endurance athletes and sprinters vs. throwers (25.2 ± 3.0, 24.3 ± 3.1, and 22.0 ± 3.1 mm/m2, respectively, p < 0.01). The E/A was higher in endurance athletes and sprinters vs. throwers (1.35 ± 0.40, 1.37 ± 0.43, and 1.05 ± 0.41, respectively; p < 0.01). The E/E’ was lower in endurance athletes and sprinters vs. throwers (6.9 ± 1.8, 6.6 ± 1.9, and 8.1 ± 1.9, respectively, p < 0.05). Compared to age-matched historical controls (n > 1,000; E/A = 1.06; E/E’ = 7.5), left ventricular diastolic function was not different in throwers, but superior in endurance athletes and sprinters (p < 0.01). Masters throwers have altered left ventricular dimensions and function vs. other athletes, but a lifetime of heavy resistance training does not appear to alter left ventricular function compared to age-matched controls.

Heart failure with reduced ejection fraction is associated with increased exercise intolerance, morbidity, and mortality. Importantly, exercise intolerance in heart failure with reduced ejection fraction is a key factor limiting patient quality of life and survival. Exercise intolerance in heart failure with reduced ejection fraction stems from a multi-organ failure to maintain homeostasis at rest and during exercise, including the heart, skeletal muscle, and autonomic nervous system, lending itself to a system constantly trying to “catch-up”. Hemodynamic control during exercise is regulated primarily by the autonomic nervous system, whose operation, in turn, is partly regulated via reflexive information from exercise-stimulated receptors throughout the body (e.g., arterial baroreflex, central and peripheral chemoreceptors, and the muscle metabo- and mechanoreflexes). Persons with heart failure with reduced ejection fraction exhibit malfunctioning autonomic reflexes, which lead to exaggerated sympathoexcitation and attenuated parasympathetic tone. Chronic elevation of sympathetic activity is associated with increased morbidity and mortality. In this review, we provide an overview of how each main exercise-related autonomic reflex is changed in heart failure with reduced ejection fraction, and the role of exercise training in attenuating or reversing the counterproductive changes.

In the title hydrated salt, [Ni(C21H17F2N3)2](NO3)2·2H2O, the central NiII ion is coordinated by six N atoms from two tridentate chelating 2,6-bis[(E)-(4-fluorobenzylimino)methyl]pyridine ligands. While the central NiII ion is six-coordinate, its environment is distorted from an octahedral structure because of the unequal Ni—N distances. The Ni—N bond lengths vary from 1.8642 (14) to 2.2131 (15) Å, while the N—Ni—N angles range from 79.98 (6) to 104.44 (6)°. Three coordinating sites of each chelating agent are almost coplanar with respect to the pyridine ring, and two pyridine moieties are perpendicular to each other. Two non-coordinating nitrate anions within the asymmetric unit balance the charges of the central metal ion, and are linked with two crystal water molecules, forming a water–nitrate cyclic tetrameric unit [O...O = 2.813 (2) to 3.062 (2) Å]. In an isolated molecule, the fluorophenyl rings of one ligand are stacked with the central ring of the other ligand via π–π interactions, with the closest centroid-to-plane distances being 3.359 (6), 3.408 (5), 3.757 (6) and 3.659 (5) Å.

Summary: Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia. Transcripts whose expression change correlates with the onset of cold allodynia were nociceptor related, whereas those correlating with tactile hypersensitivity were immune cell centric. Ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity, whereas depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain incorporates reactive processes of sensory neurons and immune cells, each leading to distinct forms of hypersensitivity, potentially allowing drug development targeted to each pain type. : Cobos et al. correlated gene expression with behavior after nerve injury and found that two distinct processes contribute to neuropathic pain: one that occurs in neurons, leading to cold allodynia, and another that includes immune cells and neurons, leading to tactile allodynia. Keywords: neuropathic pain, macrophages, T cells, immune system, TrpV1, tactile allodynia, cold allodynia, gene expression, transcript profiling, WCGNA

Type 2 innate lymphoid cells (ILC2) are thought to be a uniform population of effector cells that produce IL-5 and IL-13. Here, the authors shown that, in mice, IL-33 can alternatively activate these cells to generate a molecularly distinct IL-10-producing subset designated ILC210.

Abstract The recognition of anions by designed receptors has attracted much attention in recent days. In particular, the selective binding of sulfate with artificial receptors is important because of its relevance to many biological and environmental applications. However, the development of organized molecular receptors with high-efficiency for sulfate binding still remains a significant challenge. We report a novel para-phenylene-bridged hexafunctional tripodal receptor that contains a urea-based inner cleft and a thiourea-based outer cleft, providing perfect sites for step-wise binding of two anions within a single cavity. The new receptor was synthesized in a three-step process, and was investigated for its anion binding properties by 1H NMR titrations, 2D NOESY experiments and computational studies. As indicated by solution binding studies, the receptor selectively binds sulfate over other oxoanions, forming a 1:2 stoichiometric complex that is stabilized via strong H-bonding interactions. High-level DFT calculations reveal that the receptor, owing to the enhanced H-bonding ability of thiourea groups, initially encapsulates one sulfate in its thiourea-based outer cleft, followed by a second encapsulation in its urea-based inner cleft. Such a functionalized receptor with the unique combination of urea-based cleft and thiourea-based cleft in a single receptor has not been reported previously.

This report describes fibrous cyst lining injection and extracorporeal shock wave therapy (ESWT) of a medial femoral condyle (MFC) subchondral cystic lesion (SCL) resulting in catastrophic MFC fracture in an Arabian mare. The mare was presented for evaluation of a severe hind limb lameness of approximately 4 months duration. On presentation, a non-weight bearing lameness of the left hind limb with severe effusion and soft tissue swelling of the stifle region was noted. Radiographic evaluation of the stifle revealed a large SCL of the MFC with associated osteoarthritis. Arthroscopic guided intra-lesional injection of the SCL with corticosteroids and autologous bone marrow concentrate was performed followed by ESWT of the MFC. The mare was discharged walking comfortably 48-hours post-operatively. An acute increase in lameness was noted 14 days post-operatively. Imaging revealed catastrophic fracture of the left MFC. Possible mechanisms leading to failure of the MFC secondary to the described treatment are discussed.

Abstract Background The tropical gar (Atractosteus tropicus) is the southernmost species of the seven extant species of gar fishes in the world. In Mexico and Central America, the species is an important food source due to its nutritional quality and low price. Despite its regional importance and increasing concerns about overexploitation and habitat degradation, basic genetic information on the tropical gar is lacking. Determining genetic information on the tropical gar is important for the sustainable management of wild populations, implementation of best practices in aquaculture settings, evolutionary studies of ancient lineages, and an understanding of sex-specific gene expression. In this study, the transcriptome of the tropical gar was sequenced and assembled de novo using tissues from three males and three females using Illumina sequencing technology. Sex-specific and highly differentially expressed transcripts in brain and muscle tissues between adult males and females were subsequently identified. Results The transcriptome was assembled de novo resulting in 80,611 transcripts with a contig N50 of 3,355 base pairs and over 168 kilobases in total length. Male muscle, brain, and gonad as well as female muscle and brain were included in the assembly. The assembled transcriptome was annotated to identify the putative function of expressed transcripts using Trinotate and SwissProt, a database of well-annotated proteins. The brain and muscle datasets were then aligned to the assembled transcriptome to identify transcripts that were differentially expressed between males and females. The contrast between male and female brain identified 109 transcripts from 106 genes that were significantly differentially expressed. In the muscle comparison, 82 transcripts from 80 genes were identified with evidence for significant differential expression. Almost all genes identified as differentially expressed were sex-specific. The differentially expressed transcripts were enriched for genes involved in cellular functioning, signaling, immune response, and tissue-specific functions. Conclusions This study identified differentially expressed transcripts between male and female gar in muscle and brain tissue. The majority of differentially expressed transcripts had sex-specific expression. Expanding on these findings to other developmental stages, populations, and species may lead to the identification of genetic factors contributing to the skewed sex ratio seen in the tropical gar and of sex-specific differences in expression in other species. Finally, the transcriptome assembly will open future research avenues on tropical gar development, cell function, environmental resistance, and evolution in the context of other early vertebrates.

Rodent models of l-DOPA-induced dyskinesia (LID) are essential to investigate pathophysiological mechanisms and treatment options. Ratings of abnormal involuntary movements (AIMs) are used to capture both qualitative and quantitative features of dyskinetic behaviors. Thus far, validated rating scales for the mouse have anchored the definition of severity to the time during which AIMs are present. Here we have asked whether the severity of axial, limb, and orolingual AIMs can be objectively assessed with scores based on movement amplitude. Mice sustained 6-OHDA lesions in the medial forebrain bundle and were treated with l-DOPA (3–6 mg/kg/day) until they developed stable AIMs scores. Two independent investigators rated AIM severity using both the validated time-based scale and a novel amplitude scale, evaluating the degree of deviation of dyskinetic body parts relative to their resting position. The amplitude scale yielded a high degree of consistency both within- and between raters. Thus, time-based scores, amplitude scores, and a combination of the two (‘global AIM scores’) were applied to compare antidyskinetic effects produced by amantadine and by the following subtype-specific DA receptor antagonists: SCH23390 (D1/D5), Raclopride (D2/D3), PG01037 (D3), L-745,870 (D4), and VU6004461 (D4). SCH23390 and Raclopride produced similarly robust reductions in both time-based scores and amplitude scores, while PG01037 and L-745,870 had more partial effects. Interestingly, a novel and highly brain penetrable D4 receptor antagonist (VU6004461) markedly attenuated both time-based and amplitude scores without diminishing the general motor stimulant effect of l-DOPA. In summary, our results show that a dyskinesia scale combining a time dimension with an amplitude dimension (‘global AIMs’) is more sensitive than unidimensional scales. Moreover, the antidyskinetic effects produced by two chemically distinct D4 antagonists identify the D4 receptor as a potential future target for the treatment of LID.

We investigated two types of threading dislocations in high Al-composition Al0.55Ga0.45N/AlN multiple quantum well (MQW) structures grown on AlN substrate for electrically injected deep ultraviolet light-emitting diodes (LEDs). The surface morphology and defects electrical characteristics of the MQW LED structures were examined via conductive atomic force microscopy (CAFM). We found that the disparity between photoluminescence (PL) and electroluminescence (EL) spectra in terms of light emission output and wavelength shift are attributed to the existence of the surface hillocks, especially to the ones that have open-core dislocations. The open-core dislocations form current leakage paths through their defect states and the composition inhomogeneity (i.e., Ga rich) at the dislocation sites are responsible for the light emission at longer wavelengths.