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Catherine A Peterson Department of Nutrition and Exercise Physiology, University of Missouri-Columbia, Columbia, MO, USA Abstract: Vitamin D deficiency and childhood obesity have been classified as epidemics throughout the world, and both share some common risk factors including poor diet and inactivity. Observational and clinical studies show that vitamin D status and fat mass are inversely correlated. It is not clear whether vitamin D deficiency contributes to, or is a consequence of obesity, or whether there are regulatory interactions between excess adiposity and vitamin D activity. The effects of this deficiency in childhood obesity appear to have negative influences on overall health, including insulin resistance, inflammation, and impeded bone mineralization, as well as increased future risk of type 2 diabetes, cardiovascular disease, and osteoporosis. The rather ubiquitous distribution of the vitamin D receptor and the 25-hydroxyvitamin D 1a-hydroxylase throughout the body, including evidence for a role of vitamin D in adipogenesis and adipocyte metabolism, may in part explain these widespread effects. Most of the findings to date suggest that the vitamin D needs of obese children are greater than the nonobese. Although ultraviolet B-induced skin synthesis is a main source of vitamin D, its use is neither feasible nor prudent due to limited sun availability for many and concerns for skin cancer. Likewise, obtaining adequate vitamin D from natural food sources alone is generally not achievable, and even in countries that allow fortification, vitamin D intakes are low. Therefore, in obese children, vitamin D supplementation is warranted. Weight loss interventions using energy restriction and physical activity may also improve the poor vitamin D status associated with obesity. More research is needed to define optimal vitamin D status in this vulnerable population, including investigations to determine the efficacy of vitamin D supplementation in attenuating the conditions associated with childhood obesity, and to further elucidate the mechanisms by which vitamin D exerts its effects on health. Keywords: cholecalciferol, childhood overweight, hypovitaminosis D

We present an exquisite 30 minute cadence Kepler (K2) light curve of the Type Ia supernova (SN Ia) 2018oh (ASASSN-18bt), starting weeks before explosion, covering the moment of explosion and the subsequent rise, and continuing past peak brightness. These data are supplemented by multi-color Panoramic Survey Telescope (Pan-STARRS1) and Rapid Response System 1 and Cerro Tololo Inter-American Observatory 4 m Dark Energy Camera (CTIO 4-m DECam) observations obtained within hours of explosion. The K2 light curve has an unusual two-component shape, where the flux rises with a steep linear gradient for the first few days, followed by a quadratic rise as seen for typical supernovae (SNe) Ia. This "flux excess" relative to canonical SN Ia behavior is confirmed in our i-band light curve, and furthermore, SN 2018oh is especially blue during the early epochs. The flux excess peaks 2.14 ± 0.04 days after explosion, has a FWHM of 3.12 ± 0.04 days, a blackbody temperature of K, a peak luminosity of , and a total integrated energy of . We compare SN 2018oh to several models that may provide additional heating at early times, including collision with a companion and a shallow concentration of radioactive nickel. While all of these models generally reproduce the early K2 light curve shape, we slightly favor a companion interaction, at a distance of ∼ based on our early color measurements, although the exact distance depends on the uncertain viewing angle. Additional confirmation of a companion interaction in future modeling and observations of SN 2018oh would provide strong support for a single-degenerate progenitor system.

Agroecosystems are on both the receiving and contributing ends of increasingly demanding climatic and environmental conditions. Maintaining productive systems under resource scarcity and multiplicative stresses requires precise monitoring and systems-scale planning. By incorporating ecological resilience into agroecosystems research we can gain valuable insight into agroecosystem identity, change, responsivity, and performance under stress, but only if we move away from resilience as a mere touchstone concept. Using the productivity, stability, resistance, and recovery of system processes as a basic framework for resilience monitoring, we propose quantitative research approaches to tackle the continuing lack of biophysical, field-scale indicators needed to lend insight into dynamic resilience variables and mechanisms. We emphasize the importance of considering productive functions, sources of system regulation and disturbance, and cross-scale interactions when applying resilience theory to agroecosystems. Agroecosystem resilience research requires understanding of multiple scales and speeds of influence both above and below the focal scale. When these considerations are addressed, resilience theory can add tangible value to agroecosystems research, both for the purposes of monitoring current systems and of planning future systems that can reconcile productivity and sustainability goals.

Glucocorticoids are the cornerstone of therapy in patients with idiopathic inflammatory myopathies (IIM), despite adverse effects and suboptimal therapy success rates. Glucocorticoids are used in patients with IIM to suppress inflammatory and immune responses implicated in the pathogenesis of these diseases. Nevertheless, potential inhibitory effects of glucocorticoids on skeletal muscle mass, myogenesis and immune responses that promote skeletal muscle regeneration after muscle injury warrant attention. Glucocorticoids lead to skeletal muscle catabolism by modulating major pathways involved in regulating muscle mass. Glucocorticoids also inhibit muscle regeneration by decreasing myogenic cell proliferation and differentiation. Finally, glucocorticoids might have inhibitory effects on immune cells that have been shown to be an important component of the muscle regenerative response. Better understanding of the signalling pathways involved in restorative versus adverse effects of glucocorticoids in IIM could yield additional insight into the aetiopathogenesis of persistent muscle weakness in patients with IIM after glucocorticoid treatment, and help in the development of novel, targeted treatment options with fewer adverse effects. [ABSTRACT FROM AUTHOR]

Background: Vitamin D is a key nutrient in bone health and the vitamin D status of individuals with regular exposure to solar or artificial ultraviolet B (UVB) radiation is generally superior to those with limited exposure. Objective: By means of a cross-sectional, observational design, explore the association of serum 25-hydroxy vitamin D (25(OH)D) concentrations and biochemical markers of bone turnover across a spectrum of vitamin D status by comparing women who regularly use tanning beds with women of minimal UVB exposure. Methods: A total of 69 healthy women, ages 25-82 y, were recruited. Serum concentrations of 25(OH)D, intact parathyroid hormone (iPTH), leptin, bone-specific alkaline phosphatase (BAP), osteocalcin (OC), and C-terminal telopeptides of Type I collagen (CTx) were measured. Results: There were no significant differences in age, height, weight, BMI and dietary intakes between groups. Serum 25(OH)D concentrations were significantly higher in tanners (n = 20) compared with non-tanners (n = 49) (p < 0.0001). Serum iPTH concentrations were lower in tanners than in non-tanners (p < 0.0001) and were negatively correlated with serum 25(OH)D concentrations (r = -4571, p < 0.0001). Of the bone turnover markers, only serum OC concentrations were lower in tanners compared with non-tanners (p = 0.0002). After adjusting for age and menopausal status, osteocalcin was negatively correlated (r = -0.0178; p = 0.04) with 25(OH)D and positively correlated with iPTH (r = 0.035; p = 0.05). Conclusions: Our results show healthy women with regular UVB exposure via tanning beds have significantly greater vitamin D status and lower serum osteocalcin concentrations than those without and that there is a significant inverse relationship between serum serum 25(OH)D and osteocalcin concentrations which appears to be PTH-dependent. [ABSTRACT FROM AUTHOR]

To examine the role of adipose-resident macrophages in insulin resistance, we examined the gene expression of CD68, a macrophage marker, along with macrophage chemoattractant protein-1 (MCP-1) in human subcutaneous adipose tissue using real-time RT-PCR. Both CD68 and MCP-1 mRNAs were expressed in human adipose tissue, primarily in the stromal vascular fraction. When measured in the adipose tissue from subjects with normal glucose tolerance, covering a wide range of BMI (21-51 kg/m2) and insulin sensitivity (S(I)) (0.6-8.0 x 10(-4)min(-1).microU(-1).ml(-1)), CD68 mRNA abundance, which correlated with the number of CD68-positive cells by immunohistochemistry, tended to increase with BMI but was not statistically significant. However, there was a significant inverse relation between CD68 mRNA and S(I) (r=-0.55, P=0.02). In addition, there was a strong positive relationship among adipose tissue CD68 mRNA, tumor necrosis factor-alpha (TNF-alpha) secretion in vitro (r=0.79, P<0.005), and plasma interleukin-6 (r=0.67, P < 0.005). To determine whether improving S(I) in subjects with impaired glucose tolerance (IGT) was associated with decreased CD68 expression, IGT subjects were treated for 10 weeks with pioglitazone or metformin. Pioglitazone increased S(I) by 60% and in the same subjects reduced both CD68 and MCP-1 mRNAs by >50%. Furthermore, pioglitazone resulted in a reduction in the number of CD68-positive cells in adipose tissue and reduced plasma TNF-alpha. Metformin had no effect on any of these measures. Thus, treatment with pioglitazone reduces expression of CD68 and MCP-1 in adipose tissue, apparently by reducing macrophage numbers, resulting in reduced inflammatory cytokine production and improvement in S(I). [ABSTRACT FROM AUTHOR]

Proposes a model that shows how composite anatomical structure of roots results in a composite transport of both water and solutes. Function of the root anatomy in the transport processes; Nature of water movement in roots in terms of forces and flows; Water flow within tracheary element lumena and routes of water flow in plant tissue; Role of the endodermis during solute uptake; Composite transport model of the root.

Background: More than 200 different diseases may be transmitted from exposure to blood in the dental setting. The aim of this study is to identify possible faults in the cross-contamination chain control in a dental school clinic searching for traces of blood in the clinical contact surfaces (CCS) through forensic luminol blood test. Methods: Traces of invisible blood where randomly searched in CCS of one dental school clinic. Results: Forty eight surfaces areas in the CCS were tested and the presence of invisible and remnant blood was identified in 28 (58.3%) items. Conclusions: We suggest that the luminol method is suitable for identifying contamination with invisible blood traces and this method may be a useful tool to prevent cross-contamination in the dental care setting.

Abstract Background This pilot randomized controlled trial evaluated the feasibility of conducting a full scale study and compared the efficacy of exercise, spinal manipulation, and a mind-body therapy called Neuro Emotional Technique for the treatment of pregnancy-related low back pain, a common morbidity of pregnancy. Methods Healthy pregnant women with low back pain of insidious onset were eligible to enroll in the study at any point in their pregnancy. Once enrolled, they remained in the study until they had their babies. Women were randomly allocated into one of three treatment groups using opaque envelopes. The treatment schedule paralleled the prenatal care schedule and women received individualized intervention. Our null hypothesis was that spinal manipulation and Neuro Emotional Technique would perform no better than exercise in enhancing function and decreasing pain. Our primary outcome measure was the Roland Morris Disability Questionnaire and our secondary outcome measure was the Numeric Pain Rating Scale. Intention to treat analysis was conducted. For the primary analysis, regression was conducted to compare groups on the outcome measure scores. In a secondary responder analysis, difference in proportions of participants in attaining 30% and 50% improvement were calculated. Feasibility factors for conducting a future larger trial were also evaluated such as recruitment, compliance to study protocols, cost, and adverse events. Results Fifty-seven participants were randomized into the exercise (n = 22), spinal manipulation (n = 15), and Neuro Emotional Technique (n = 20) treatment arms. At least 50% of participants in each treatment group experienced clinically meaningful improvement in symptoms for the Roland Morris Disability Questionnaire. At least 50% of the exercise and spinal manipulation participants also experienced clinically meaningful improvement for the Numeric Pain Rating Scale. There were no clinically meaningful or statistically significant differences between groups in any analysis. Conclusions This pilot study demonstrated feasibility for recruitment, compliance, safety, and affordability for conducting a larger study in the future. Spinal manipulation and exercise generally performed slightly better than did Neuro Emotional Technique for improving function and decreasing pain, but the study was not powered to detect the between-group differences as statistically significant. Trial registration ClinicalTrials.gov (Identifier: NCT00937365).

Abstract Background Circulating 25 hydroxyvitamin D (25 (OH)D), an accurate measure of vitamin D status, is markedly greater in individuals with increased exposure to ultraviolet B (UVB) light via sunlight or the use of artificial UV light. Aside from the known relationship between vitamin D and bone, vitamin D has also been implicated in immune function and inflammation. Furthermore, a mass of evidence is accumulating that vitamin D deficiency could lead to immune malfunction. Our overall objective was to study the relationship between vitamin D status (as determined by serum 25(OH) D concentrations) and inflammatory markers in healthy women. Methods This observational study included 69 healthy women, age 25–82 years. Women with high UVB exposure and women with minimal UVB exposure were specifically recruited to obtain a wide-range of serum 25(OH)D concentrations. Health, sun exposure and habitual dietary intake information were obtained from all subjects. Body composition was determined by dual-energy-x-ray absorptiometry. A fasting blood sample was collected in the morning and analyzed for serum 25(OH)D, parathyroid hormone (iPTH), estradiol (E2), cortisol, and inflammatory markers [tumor necrosis factor -alpha (TNF-α), interleukin-6 and -10 (IL-6, IL-10), and C-reactive protein (CRP)]. Results Women with regular UVB exposure (Hi-D) had serum 25(OH)D concentrations that were significantly higher (p < 0.0001) and iPTH concentrations that were significantly lower (p < 0.0001) than women without regular UVB exposure (Lo-D). Although IL-6, IL-10, and CRP did not have a statistically significant relationship with 25(OH)D concentrations, linear regression models revealed a significant inverse relationship between serum 25(OH)D and TNF-α concentrations. This relationship remained significant after controlling for potential covariates such as body fat mass, menopausal status, age, or hormonal contraceptive use. Conclusion Serum 25(OH)D status is inversely related to TNF-α concentrations in healthy women, which may in part explain this vitamin's role in the prevention and treatment of inflammatory diseases. Results gleaned from this investigation also support the need to re-examine the biological basis for determining optimal vitamin D status.

Abstract Background Signal transduction pathways convey information from the outside of the cell to transcription factors, which in turn regulate gene expression. Our objective is to analyze tumor gene expression data from microarrays in the context of such pathways. Results We use pathways compiled from the TRANSPATH/TRANSFAC databases and the literature, and three publicly available cancer microarray data sets. Variation in pathway activity, across the samples, is gauged by the degree of correlation between downstream targets of a pathway. Two correlation scores are applied; one considers all pairs of downstream targets, and the other considers only pairs without common transcription factors. Several pathways are found to be differentially active in the data sets using these scores. Moreover, we devise a score for pathway activity in individual samples, based on the average expression value of the downstream targets. Statistical significance is assigned to the scores using permutation of genes as null model. Hence, for individual samples, the status of a pathway is given as a sign, + or -, and a p-value. This approach defines a projection of high-dimensional gene expression data onto low-dimensional pathway activity scores. For each dataset and many pathways we find a much larger number of significant samples than expected by chance. Finally, we find that several sample-wise pathway activities are significantly associated with clinical classifications of the samples. Conclusion This study shows that it is feasible to infer signal transduction pathway activity, in individual samples, from gene expression data. Furthermore, these pathway activities are biologically relevant in the three cancer data sets.

Following the September 11, 2001, incident in the United States (US) and subsequent natural disasters, the US, like other countries, has focused on improving its overall disaster response capabilities. One mechanism that is under development to improve the country's surge capacity, i.e., its ability to substantially increase the number of volunteer health care professionals available to respond during a disaster, is the Emergency System for Advance Registration of Volunteer Health Professionals (ESAR-VHP). Registries, like ESAR-VHP, are significant tools for disaster planning and deployment. The goal of ESAR-VHP is to create a state-based registry of volunteer health professionals, verify their credentials prior to a disaster, and provide opportunities for education and training in disaster response. Each of these steps is necessary in ensuring access to patient services during an emergency, while also providing for the safety of the volunteer health professional. This article speaks to the registered nurse as a volunteer acting within these types of registries. Specifically, it addresses the development of a personal and professional response plan, and registration programs that provide the preparation needed to enable a nurse responder to work effectively within a disaster response team and facilitate preregistration with one and only one registry. The legal implications of responding are also discussed. © 2006 OJIN: The Online Journal of Issues in Nursing. Article published September 30, 2006 [ABSTRACT FROM AUTHOR]

Power toothbrushes (PTBs), in combination with abrasive dentifrices, may encourage wear of dental cements at crown margins. PURPOSE: The objective of this in vitro simulation was to control the clinical variables associated with PTB use and measure the potential side effects of PTBs with mild and abrasive dentifrices. METHODS AND MATERIALS: Four PTBs ( Braun-Oral-B-Professional Care at 150 g brushing force, Sonicare-Elite at 90 g, Colgate-Actibrush at 200 g and Crest-Spinbrush-Pro at 250 g) and 2 dentifrices mixed 1:1 with tap water (Mild= Colgate-Total, Colgate-Palmolive; Abrasive= Close-up, Chesebrough-Ponds) versus tap water alone (control) were used to abrade 2 cements (Fleck's Mizzy Zinc Phosphate [ZP]; 3M-ESPE Unicem universal cement [UC]) using cement-filled slots (160 m wide) cut into wear-resistant ceramic blocks. A custom fixture controlled PTB/block alignment, PTB loads, and other testing variables. Wear was measured (3 profilometer traces/slot, 5 slots/block/group, baseline to 5-year differences) and analyzed (3-way ANOVA, p < or = 0.05, Bonferroni). RESULTS: Wear for ZP was much greater than UC (p<0.05) for all 4 PTBs and both dentifrices. Brushing with water showed no effects (p<0.05). Cement-PTB-dentifrice interactions did occur. Only minor differences occurred among PTBs. Pooled 5y-wear levels for ZP for both dentifrices approximately 21 microm /5y) were similar to values for current-day posterior composite materials. CONCLUSIONS: Combinations of PTBs with mild and abrasive dentifrices produced significant wear with ZP but not UC; thus, resin-composite cements seem to represent a better choice for wear resistance. [ABSTRACT FROM AUTHOR]

PURPOSE: This study tested an infection control protocol for photostimulable phosphor (PSP) sensors while simulating multiple uses. METHODS: Dental hygiene students (n=36) were randomly assigned to a control group (dry wipe) or test group (disinfectant wipe). A sterile, barriered sensor was placed in a peer patient's mouth to simulate an exposure. After simulation, the barriered sensors were disinfected, placed into a new barrier, and inserted into the same peer patient's mouth. Following the fourth placement and treatment, sensors were vortexed in specimen cups containing trypticase soy broth (TSB) and incubated at 37 degrees C to detect contamination by oral bacteria. RESULTS: Bacterial growth in TSB was monitored as a change in optical density and by quantitation of oral streptococci on Mitis-salivarius agar. The barrier-protected sensors were minimally contaminated (<10(5) colony forming units/ml at baseline) regardless of treatment. After culture amplification, the control TSB had more samples that remained negative through 48 hours (5/18 vs. 0/18 for test group, p<0.05). CONCLUSION: Barrier envelopes used with the PSP sensors appeared to be an effective way of reducing microbial contamination. [ABSTRACT FROM AUTHOR]

Introduction: VM202 is a plasmid encoding two isoforms of hepatocyte growth factor (HGF). In preclinical studies, HGF stimulated angiogenesis and muscle regeneration. This preliminary clinical trial tested the hypothesis that VM202 injections in gastrocnemius muscle would improve walking performance in people with mild to moderate and symptomatic lower extremity peripheral artery disease (PAD)., Methods: In a double-blind clinical trial, people with PAD were randomized to gastrocnemius muscle injections of either 4 mgs of VM202 or placebo every 14 days for four doses. The primary outcome was 6-month change in 6-minute walk distance. Secondary outcomes included 3-month change in treadmill walking time and gastrocnemius muscle biopsy measures. In this preliminary trial, statistical significance was pre-specified as a one-sided P value <0.10., Results: 39 participants with PAD (64.1% Black, 28.2% female) were randomized. Adjusting for age, race, smoking, and baseline performance, VM202 did not improve 6-minute walk at 6-month follow-up, compared to placebo (-13.5 meters, 90% confidence interval (CI): -38.5,+∞). At 3-month follow-up, VM202 improved maximum treadmill walking time (+2.38 minutes (90% CI: +1.08, +∞), P=0.014) and increased central nuclei abundance in gastrocnemius muscle (+5.86, 90% CI: +0.37,+∞, P=0.088), compared to placebo. VM202 did not significantly improve pain-free walking distance (difference: +0.30 minutes, 90% CI:-1.10,+∞, P=0.39), calf muscle perfusion (difference: +1.80 ml/minute per 100 g tissue, 90% CI: -3.80,+∞, P=0.33), or the WIQ distance score (difference: +2.02, 90% CI: -8.11,+∞, P=0.40). In post-hoc analyses, VM202 significantly improved 6-minute walk in PAD participants with diabetes mellitus at 6-month follow-up (+34.19 (90% CI: 4.04,+∞), P=0.075), but had no effect in people without diabetes (interaction P value=0.079)., Conclusions: These data do not support gastrocnemius injections of VM202 to improve 6-minute walk in PAD. Secondary outcomes suggested potential benefit of VM202 on skeletal muscle measures and treadmill walking, while post-hoc analyses suggested benefit in PAD participants with diabetes., (Copyright © 2025 Society for Vascular Surgery. All rights reserved.)

Background: Mitochondrial abnormalities exist in lower-extremity peripheral artery disease (PAD), yet the association of the ankle-brachial index (ABI) with mitochondrial respiration in gastrocnemius muscle is unknown. The association of gastrocnemius mitochondrial respiration with 6-minute walk distance in PAD is unknown. This objective of this study was to describe associations of the ABI with mitochondrial respiratory function in gastrocnemius muscle biopsies and associations of gastrocnemius mitochondrial respirometry with 6-minute walk distance in people with and without PAD., Methods: People with (ABI ⩽ 0.90) and without (ABI 1.00-1.40) PAD were enrolled. ABI and 6-minute walk distance were measured. Mitochondrial function of permeabilized myofibers from gastrocnemius biopsies was measured with high-resolution respirometry., Results: A total of 30 people with PAD (71.7 years, mean ABI: 0.64) and 68 without PAD (71.8 years, ABI: 1.17) participated. In non-PAD participants, higher ABI values were associated significantly with better mitochondrial respiration (Pearson correlation for maximal oxidative phosphorylation P CI+II : +0.29, p = 0.016). In PAD, the ABI correlated negatively and not significantly with mitochondrial respiration (Pearson correlation for P CI+II : -0.17, p = 0.38). In people without PAD, better mitochondrial respiration was associated with better 6-minute walk distance (Pearson correlation: +0.51, p < 0.001), but this association was not present in PAD (Pearson correlation: +0.10, p = 0.59)., Conclusions: Major differences exist between people with and without PAD in the association of gastrocnemius mitochondrial respiration with ABI and 6-minute walk distance. Among people without PAD, ABI and walking performance were positively associated with mitochondrial respiratory function. These associations were not observed in PAD., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. McDermott has received research support from Helixmith, Mars, and ArtAssist. The other authors have no conflicts of interest.

Extracellular vesicles (EVs) have emerged as important mediators of intertissue signaling and exercise adaptations. In this human study, we provide evidence that muscle-specific microRNA-1 (miR-1) was transferred to adipose tissue via EVs following an acute bout of resistance exercise. Using a multimodel machine learning automation tool, we discovered muscle primary miR-1 transcript and CD63+ EV count in circulation as top explanatory features for changes in adipose miR-1 levels in response to resistance exercise. RNA-Seq and in-silico prediction of miR-1 target genes identified caveolin 2 (CAV2) and tripartite motif containing 6 (TRIM6) as miR-1 target genes downregulated in the adipose tissue of a subset of participants with the highest increases in miR-1 levels following resistance exercise. Overexpression of miR-1 in differentiated human adipocyte-derived stem cells downregulated these miR-1 targets and enhanced catecholamine-induced lipolysis. These data identify a potential EV-mediated mechanism by which skeletal muscle communicates with adipose tissue and modulates lipolysis via miR-1.

MicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and in C. elegans, the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice causes a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.

People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. -10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed., (© 2024. The Author(s).)

Skeletal muscle adaptation to external stimuli, such as regeneration following injury and hypertrophy in response to resistance exercise, are blunted with advanced age. The accumulation of senescent cells, along with defects in myogenic progenitor cell (MPC) proliferation, have been strongly linked as contributing factors to age-associated impairment in muscle adaptation. p53 plays an integral role in all these processes, as upregulation of p53 causes apoptosis in senescent cells and prevents mitotic catastrophe in MPCs from old mice. The goal of this study was to determine if a novel pharmaceutical agent (BI01), which functions by upregulating p53 through inhibition of binding to MDM2, the primary p53 regulatory protein, improves muscle regeneration and hypertrophy in old mice. BI01 effectively reduced the number of senescent cells in vitro but had no effect on MPC survival or proliferation at a comparable dose. Following repeated oral gavage with 2 mg/kg of BI01 (OS) or vehicle (OV), old mice (24 months) underwent unilateral BaCl 2 injury in the tibialis anterior (TA) muscle, with PBS injections serving as controls. After 7 days, satellite cell number was higher in the TA of OS compared to OV mice, as was the expression of genes involved in ATP production. By 35 days, old mice treated with BI01 displayed reduced senescent cell burden, enhanced regeneration (higher muscle mass and fiber cross-sectional area) and restoration of muscle function relative to OV mice. To examine the impact of 2 mg/kg BI01 on muscle hypertrophy, the plantaris muscle was subjected to 28 days of mechanical overload (MOV) in OS and OV mice. In response to MOV, OS mice had larger plantaris muscles and muscle fibers than OV mice, particularly type 2b + x fibers, associated with reduced senescent cells. Together our data show that BI01 is an effective senolytic agent that may also augment muscle metabolism to enhance muscle regeneration and hypertrophy in old mice., (© 2023. The Author(s).)

Adult muscle stem cells (MuSCs) are known to replicate upon activation before differentiating and fusing to regenerate myofibers. It is unclear whether MuSC differentiation is intrinsically linked to cell division, which has implications for stem cell population maintenance. We use single-cell RNA-sequencing to identify transcriptionally diverse subpopulations of MuSCs after 5 days of a growth stimulus in adult muscle. Trajectory inference in combination with a novel mouse model for tracking MuSC-derived myonuclei and in vivo labeling of DNA replication revealed an MuSC population that exhibited division-independent differentiation and fusion. These findings demonstrate that in response to a growth stimulus in the presence of intact myofibers, MuSC division is not obligatory., (© The Author(s) 2023. Published by Oxford University Press.)

In large-volume muscle injuries, widespread damage to muscle fibers and the surrounding connective tissue prevents myogenic progenitor cells (MPCs) from initiating repair. There is a clinical need to rapidly fabricate large muscle tissue constructs for integration at the site of large volume muscle injuries. Most strategies for myotube alignment require microfabricated structures or prolonged orientation times. We utilize the MPC's natural propensity to close gaps across an injury site to guide alignment on collagen I. When MPCs are exposed to an open boundary free of cells, they migrate unidirectionally into the cell-free region and align perpendicular to the original boundary direction. We study the utility of this phenomenon with biotin-streptavidin adhesion to position the cells on the substrate, and then demonstrate the robustness of this strategy with unmodified cells, creating a promising tool for MPC patterning without interrupting their natural function. We preposition MPCs in straight-line patterns separated with small gaps. This temporary positioning initiates the migratory nature of the MPCs to align and form myotubes across the gaps, similar to how they migrate and align with a single open boundary. There is a directional component to the MPC migration perpendicular (90°) to the original biotin-streptavidin surface patterns. The expression of myosin heavy chain, the motor protein of muscle thick filaments, is confirmed through immunocytochemistry in myotubes generated from MPCs in our patterning process, acting as a marker of skeletal muscle differentiation. The rapid and highly specific binding of biotin-streptavidin allows for quick formation of temporary patterns, with MPC alignment based on natural regenerative behavior rather than complex fabrication techniques.

Given the importance of health to educational outcomes, and education to concurrent and future health, cross-systems approaches, such as the Whole School, Whole Community, Whole Child (WSCC) framework, seek to enhance services typically in K-12 settings. A major gap exists in cross-systems links with early care and education serving children birth to age 5. Both pediatric health systems and early family and child support programs, such as Early Head Start (EHS) and Head Start (HS), seek to promote and optimize the health and wellbeing of infants, toddlers, preschoolers, and their families. Despite shared goals, both EHS/HS and pediatric health providers often experience challenges in reaching and serving the children most in need, and in addressing existing disparities and inequities in services. This paper focuses on infant/toddler services because high-quality services in the earliest years yield large and lasting developmental impacts. Stronger partnerships among pedicatric health systems and EHS programs serving infants and toddlers could better facilitate the health and wellbeing of young children and enhance family strengths and resilience through increased, more intentional collaboration. Specific strategies recommended include strengthening training and professional development across service platforms to increase shared knowledge and terminology, increasing access to screening and services, strengthening infrastructure and shared information, enhancing integration of services, acknowledging and disrupting racism, and accessing available funding and resources. Recommendations, including research-based examples, are offered to prompt innovations best fitting community needs and resources., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Horm, Brophy-Herb and Peterson.)

The pathophysiology of muscle damage in peripheral artery disease (PAD) includes increased oxidant production and impaired antioxidant defenses. Epicatechin (EPI), a naturally occurring flavanol, has antioxidant properties that may mediate the beneficial effects of natural products such as cocoa. In a phase II randomized trial, a cocoa-flavanol-rich beverage significantly improved walking performance compared with a placebo in people with PAD. In the present work, the molecular mechanisms underlying the therapeutic effect of cocoa flavanols were investigated by analyzing baseline and follow-up muscle biopsies from participants. Increases in nuclear factor erythroid 2-related factor 2 (Nrf2) target antioxidants heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) in the cocoa group were significantly associated with reduced accumulation of central nuclei, a myopathy indicator, in type II muscle fibers ( P = 0.017 and P = 0.023, respectively). Protein levels of the mitochondrial respiratory complex III subunit, cytochrome b-c1 complex subunit 2 (UQCRC2), were significantly higher in the cocoa group than in the placebo group ( P = 0.032), and increases in UQCRC2 were significantly associated with increased levels of Nrf2 target antioxidants HO-1 and NQO1 ( P = 0.001 and P = 0.035, respectively). Exposure of non-PAD human myotubes to ex vivo serum from patients with PAD reduced Nrf2 phosphorylation, an indicator of activation, increased hydrogen peroxide production and oxidative stress, and reduced mitochondrial respiration. Treatment of myotubes with EPI in the presence of serum from patients with PAD increased Nrf2 phosphorylation and protected against PAD serum-induced oxidative stress and mitochondrial dysfunction. Overall, these findings suggest that cocoa flavanols may enhance antioxidant capacity in PAD via Nrf2 activation. NEW & NOTEWORTHY The current study supports the hypothesis that in people with PAD, cocoa flavanols activate Nrf2, thereby increasing antioxidant protein levels, protecting against skeletal muscle damage, and increasing mitochondrial protein abundance. These results suggest that Nrf2 activation may be an important therapeutic target for improving walking performance in people with PAD.

Background: A fixed-dose combination of phentermine and extended-release topiramate (PHEN/TPM - approved for weight management) has demonstrated in-clinic reduction of blood pressure (BP). Ambulatory BP monitoring (ABPM) may be a better predictor of cardiovascular disease risk than in-clinic BP., Methods: This randomized, multicenter, double-blind study enrolled 565 adults with overweight/obesity. Inclusion criteria included participants willing to wear ABPM device for 24 h. Exclusion criteria included screening blood pressure >140/90 mmHg and antihypertensive medications not stable for 3 months prior to randomization. Participants received placebo (n = 184), phentermine 30 mg; (n = 191), or PHEN 15 mg/TPM 92 mg; (n = 190). 24-hour ABPM was performed at baseline and at week 8. The primary endpoint was mean 24-h systolic BP (SBP) as measured by ABPM, in the per protocol population., Results: Participants were mostly female (73.5 ​%) and White (81.6 ​%), with a mean age of 53.4 years; 32.4 ​% had no hypertension diagnosis or treatment, 62.5 ​% had hypertension using 0 to 2 antihypertensive medications, and 5.1 ​% had hypertension using ≥ 3 antihypertensive medications. Baseline mean SBP/diastolic BP (DBP) was 123.9/77.6 ​mmHg. At week 8, mean SBP change was -0.1 ​mmHg (placebo), +1.4 ​mmHg (phentermine 30 ​mg), and -3.3 ​mmHg (PHEN/TPM). Between-group difference for PHEN/TPM versus placebo was -3.2 ​mmHg (95 ​% CI: -5.48, -0.93 ​mmHg; p ​= ​0.0059). The between-group difference for PHEN/TPM versus phentermine 30 ​mg was -4.7 ​mmHg (95 ​% CI: -6.96, -2.45 ​mmHg; p ​< ​0.0001). Common (>2 ​% in any treatment group) adverse events (i.e., dry mouth, constipation, nausea, dizziness, paresthesia, dysgeusia, headache, COVID-19, urinary tract infection, insomnia, and anxiety) were mostly mild or moderate., Conclusions: In this randomized, multicenter, double-blind ABPM study, PHEN/ TPM reduced SBP compared to either placebo or phentermine 30 mg (Funding: Vivus LLC; ClinicalTrials.gov: NCT05215418)., Competing Interests: HEB's research site institution has received research grants from 89Bio, Alon Medtech/Epitomee, Altimmune, Amgen, Boehringer Ingelheim, Eli Lilly, Kallyope, Novartis, NovoNordisk, Pfizer, Shionogi, Viking, and Vivus. HEB has served as a consultant/advisor for 89Bio, Altimmune, Amgen, Boehringer Ingelheim, and Lilly. DSH served as a site principal investigator for this study, which was conducted through a contract with his institution. DSH did not receive any funds directly from the sponsor. LTN is a full-time employee of VIVUS LLC, which markets the PHEN/TPM product evaluated in this study. At the time of this study her work on this study was done as part of her employment. CAP is a full-time employee of VIVUS LLC, which markets the PHEN/TPM product evaluated in this study. At the time of this study, his work on this study was done as part of his employment. STV is a full-time employee of VIVUS LLC, which markets the PHEN/TPM product evaluated in this study. At the time of this study, his work on this study was done as part of his employment and role as an officer in the company., (© 2024 The Authors.)