bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repression but not deletion of β‐catenin contributes to heart failure
Authors: Kararigas Georgios , Zelarayan Laura C , Toischer Karl , Summer Holger , Baczko Istvan , Golz Stefan , Hasenfuss Gerd , Jarry Hubertus , Regitz‐Zagrosek Vera 
Published: November 2023

The role of β‐catenin and the actions of 17β‐estradiol (E2) in cardiovascular (patho)physiology are not fully understood. We aimed at the characterization of the effects of the E2/β‐catenin axis in the healthy C57Bl/6N heart. Two‐month‐old female C57Bl/6N wild‐type (WT) and cardiac‐specific β‐catenin‐deleted (β‐catΔex2–6) mice were ovariectomized and randomized to an E2‐containing or soy‐free (control, CON) diet (n = 7–13/group). All mice underwent transthoracic two‐dimensional echocardiography under volatile anesthesia (isoflurane 2%) following established procedures. The three‐month physiological dose of E2 led to a significant repression of nuclear β‐catenin levels compared with CON (P < 0.001) in WT mice. This was underlain by a significant decrease in the heart‐weight‐to‐tibia‐length ratio and cardiomyocyte cross‐sectional area (E2 vs. CON WT mice P < 0.001). Furthermore, echocardiographic measurements revealed a significant decrease in septum width (P < 0.001), posterior wall thickness (P < 0.01) and fractional shortening (P < 0.05) in E2‐treated WT mice compared with CON. Deletion of β‐catenin abrogated these E2‐dependent detrimental effects on cardiac structure and function. Mechanistically, we found a significant increase in the levels of the ubiquitin ligase and key regulator of proteasome‐dependent protein degradation muscle‐specific RING finger protein 1 (MuRF1) by E2 compared with CON in WT mice (P < 0.05), while there was no significant effect in β‐catΔex2–6 mice. In a translational approach, we profiled the transcriptome of left ventricles of female patients (n = 5) with end‐stage non‐ischemic dilated cardiomyopathy (DCM) vs. women (n = 8) with no apparent cardiovascular disorder. We found a significant induction in the expression of the genes coding for SFRP5, a negative regulator of Wnt signaling, DACT2, an antagonist of beta‐catenin, and APC2, which is required for targeted degradation of beta‐catenin (P < 0.01), in DCM samples. Our mouse data indicate that repression of β‐catenin contributes to heart failure and our human data suggest that targeting Wnt/beta‐catenin signaling in heart failure may be of therapeutic value.Support or Funding InformationDZHK (German Centre for Cardiovascular Research)
Colonic Dysfunction Following Acute Spinal Cord Injury: Oxidative Damage to Interstitial Cells of Cajal?
Authors: White Amanda R , Holmes Gregory M 
Published: November 2023

Over 250,000 Americans are spinal cord injured with approximately 12,000 new injuries occurring annually. Colonic dysregulation is widely acknowledged as a common co‐morbidity associated with spinal cord injury (SCI). SCI‐induced colonic dysregulation is recognized as a lifelong physical and psychological challenge for SCI patients and gravely impacts quality of life. The combined actions of the enteric nervous system (ENS) and interstitial cells of Cajal (ICC) contribute to slow‐wave propagation along much of the gastrointestinal (GI) tract including the colon. Mechanisms leading to colonic dysmotility following SCI remain largely understudied and, therefore, poorly understood, however, studies focusing on colitis, aging, and slow transit constipation suggest that ICCs are dramatically reduced and may reflect a similar mechanism of dysfunction following SCI.AimWe hypothesized that acute spinal cord injury results in colonic inflammation, elevated reactive oxygen species (ROS) thereby provoking a reduction of colonic ICCs.MethodsMale Wistar rats received a contusion spinal cord injury at 3 days and 1 week prior to in vivo experimentation and tissue harvest for histological evaluation. In vivo colonic contractility was measured via a Mikro‐Tip® catheter pressure transducer that was intra‐luminally inserted within the descending colon. Whole tissue colonic samples from SCI or surgical controls were processed with DHE to visualize oxidative stress. In addition, c‐Kit immunofluorescence was performed to evaluate the colonic ICC populations within the myenteric plexus of both surgical control and SCI rats.ResultsSimilar to previous reports of anorectal dysmotility, contraction within the descending colon were reduced following acute SCI. Preliminary data collected from DHE staining suggested an increase in ROS within the myenteric plexus of the SCI colon when compared to the surgical control. Immunofluorescent c‐Kit labeling displayed well‐structured and intact ICC networks throughout the myenteric plexus and circular muscle of the sham colon. Conversely, the 3 day SCI samples displayed ICC networks that appeared structurally normal but not completely intact and by 1 week the networks were disorganized and fragmented. With increased ROS and ICC networks progressively worsening over time, this data suggests possible prolonged inflammatory damage.ConlusionIn the acute (3 day) phase of experimental SCI, diminished blood flow to the visceral tissues has been associated with increased inflammatory markers and vagally‐mediated dysmotility in the upper GI tract. Our preliminary data suggests that post‐SCI inflammation and oxidative stress may be prolonged and provoke diminished colonic motility, possibly through the disruption of intrinsic ICCs generating intrinsic pacemaker activity of smooth muscle.Support or Funding InformationSupport: NINDS #049177
Exosomes and their RNA contents as mediators of therapeutic regeneration
Authors: Marban Eduardo 
Published: November 2023

The heart is a terminally‐differentiated organ with a low rate of cellular turnover. Patients who suffer a myocardial infarction (commonly known as a “heart attack”) can lose up to 40% of their functional heart muscle within hours, leaving them prone to death and disability. Once formed, scar does not resolve spontaneously, and, once lost, living heart muscle does not regrow on its own. We challenged that pessimistic dogma using a novel approach: growing regenerative cells from a patient's heart and transplanting those cells back into the zone of injury. In the first‐in‐human CADUCEUS trial, we used magnetic resonance imaging to quantify scar and living heart muscle before and after cardiosphere‐derived cell (CDC) therapy in patients who had suffered moderately large heart attacks. Control subjects randomized to receive standard care behaved according to dogma: scar did not shrink, and living heart muscle did not regrow, over the one‐year period of follow up. In contrast, patients who had received CDCs experienced reduction of scar by about half, and regrowth of substantial amounts (>20 g) of viable myocardium. CADUCEUS was the first controlled study to show evidence of therapeutic regeneration in humans (Lancet 379:895–904, 2012). We have since discovered that allogeneic CDCs are safe and effective in preclinical models, prompting initiation of the ongoing ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) clinical trial. Current mechanistic studies focus on the role of exosomes, and their RNA contents, as mediators of the therapeutic benefits, and on macrophages as important effector cells.Support or Funding InformationFunded by NIH and by the California Institute for Regenerative Medicine
O‐GlcNAc occurs cotranslationally to stabilize nascent polypeptides
Authors: Vocadlo David , Zhu Yanping , Liu Ta‐Wei , Cecioni Samy , Eskandari Raieh , Zandberg Wesley , Willems Lianne 
Published: November 2023

Nucleocytoplasmic glycosylation of proteins with O‐linked N‐acetylglucosamine residues (O‐GlcNAc) is mediated by the glycosyltransferase O‐GlcNAc transferase (OGT). O‐GlcNAc is recognized as a common post‐translational modification and is found on hundreds of proteins within all metazoans studied to date. O‐GlcNAc has emerged as a regulator of diverse cellular processes ranging from gene expression through to circadian rhythm. Notably, impairments in cellular O‐GlcNAcylation have been found to lead to decreases in the levels of various proteins and this is one mechanism by which O‐GlcNAc seems to exert its varied physiological effects. Here we use a chemical biology approach in combination with biochemical fractionation to show that O‐GlcNAcylation also occurs on polypeptides that are emerging from the ribosome. Using both chemical and genetic blockade of OGT we show that this cotranslational O‐GlcNAcylation protects nascent polypeptide chains from premature degradation by decreasing their cotranslational ubiquitylation. Given that hundreds of proteins are O‐GlcNAcylated within cells, our findings suggest that cotranslational O‐GlcNAcylation may be a phenomenon regulating proteostasis of an array of nucleocytoplasmic proteins. We describe our recent findings and discuss the similarities between cotranslational O‐GlcNAcylation and the roles played by cotranslational N‐glycosylation occurring within the secretory pathway.Support or Funding InformationFinancial support through a Discovery Grant (Grant number: RGPIN/298406‐2010) the Natural Sciences and Engineering Research (NSERC) and the Canadian Institutes of Health Research (CIHR) (Grant number: MOP‐102756) is gratefully acknowledged. Y.Z. thanks the CIHR for support through a postdoctoral fellowship. D.J.V. acknowledges the kind support of the Canada Research Chairs program for a Tier I Canada Research Chair in Chemical Glycobiology and NSERC for support as an E.W.R. Steacie Memorial Fellow.
Dynamic Regulation Of The Signaling Lipid Phosphatidylinositol 3,5‐Bisphosphate
Authors: Weisman Lois S , Jin Natsuko 
Published: November 2023

Cyclin dependent kinases (CDKs) are key regulators of the cell cycle, nutrient homeostasis, cell polarity and gene expression. Here we show an unexpected link between a CDK and the signaling lipid, phosphatidylinositol 3,5 bis phosphate (PI(3,5)P2). PI(3,5)P2 is required for the growth and development of fungi, plants and animals. Minor defects in the levels of this lipid underlie some neurological diseases. Moreover, PI(3,5)P2 plays essential roles in several organs. PI(3,5)P2 is generated by a protein complex that includes the PI3P‐5‐kinase Fab1 (called PIKfyve in mammals), the PI(3,5)P2 lipid phosphatase, Fig4, and the scaffold protein Vac14. PI(3,5)P2 levels are dynamic, and in response to selected signals transiently rise in both yeast and in cultured neurons. However, the upstream signaling pathways that regulate PI(3,5)P2 were unknown. We performed screens in yeast to determine upstream regulators of PI(3,5)P2. Here, we show that the yeast cyclin‐dependent kinase, Pho85 and the cyclin, Pho80 are required for the transient elevation of PI(3,5)P2. Pho85‐Pho80 directly phosphorylates Fab1 and positively regulates the synthesis of PI(3,5)P2. Furthermore, we find that Pho85‐Pho80 phosphorylation of Fab1 likely generates a conformation change that regulates Fab1. We found that in neurons, PIKfyve is a negative regulator of synaptic function. Notably, the mammalian homologue of Pho85‐Pho80, Cdk5‐ p35, is similarly a negative regulator of synaptic function. This raises the possibility that Cdk5 and PIKfyve could function in the same pathway. Indeed, we find that mammalian Cdk5‐p35 directly phosphorylates peptides of mammalian Fab1/PIKfyve, and is required for the synthesis of PI(3,5)P2 in mouse fibroblasts. These studies reveal a conserved, upstream regulator of Fab1/PIKfyve, and provide insights into how PI(3,5)P2 is regulated.Support or Funding InformationSupported by R01 GM50403 and R01 NS064015 to LSW.
The Role of Grit in Body Weight Regulation over Time
Authors: Metzgar Catherine J , Nickols‐Richardson Sharon M 
Published: November 2023

Management of body weight (BW) over time remains a challenge for most individuals, specifically women during young adulthood. Grit, the perseverance and passion for sustaining efforts to pursue goals over time, and other personality traits may play a role in BW regulation. This prospective study explored the association of grit, cognitive eating restraint (CER), disinhibition and hunger in predicting BW and BW change over 12 months in a sample of healthy premenopausal women. The Short Grit Scale (Grit‐S) and Eating Inventory (EI) were completed by 79 women [mean±SD, age: 31.5±8.2 y, BW: 76.3±19.2 kg, body mass index (BMI): 28.0±6.9 kg/m2] upon enrollment (baseline) and after completion of a 1‐year weight gain prevention intervention; BW and BMI were assessed at the same time intervals. Paired t‐tests were used to evaluate changes over time and independent t‐tests were used to compare women who met weight gain prevention criteria with those who did not. The relationship between baseline Grit‐S score and month 12 BW, BMI and percent BW change were examined using Pearson's correlation coefficients. Backward elimination regression was used to further evaluate predictors of month 12 BW, BMI and percent BW change. All analyses were conducted using SPSS (version 22.0); significance was set at P<0.05. Average Grit‐S, CER, disinhibition and hunger scores did not significantly change over 12 months. Body weight and BMI, respectively, at baseline and month 12 were negatively associated with baseline grit (baseline: r=−0.24, P<0.05; r=−0.23, P<0.05; month 12: r=−0.25, P<0.05; r=−0.23, P<0.05) and positively associated with disinhibition (baseline: r=0.31, P<0.01; r=0.29, P<0.01; month 12: r=0.34, P<0.01; r=0.31, P<0.01). Lower baseline disinhibition and greater increases in CER over time were related to successful weight gain prevention (both P<0.05). Change in BW was not associated with any measures. Disinhibition predicted month 12 BW (F=9.80, P<0.01) and BMI (F=8.08. P<0.01). No measures significantly predicted BW change. Successful body weight regulation over 12 months was characterized by low disinhibition at baseline and an increase in CER over time. Additionally, high levels of grit and low levels of disinhibition at baseline were related to lower BW and BMI at the end of the 1‐year intervention. Future interventions should consider strategies that manage disinhibition and increase CER over time.Support or Funding InformationFunded by an Illinois Agricultural Experiment Station/National Institute of Food and Agriculture research grant (#1001251).
Mechanisms of appetite suppression after high intensity exercise in lean and obese boys
Authors: Hunschede Sascha , Schwartz Alexander , Kubant Ruslan , Akilen Rajadurai , Thomas Scott , Anderson G. Harvey 
Published: November 2023

BackgroundHigh intensity exercise (HIE) suppresses appetite in adults and is thought to be mediated by appetite regulating hormones. It also affects a variety of other appetite controlling mechanism, such as inflammation and stress.RationaleAlthough the role of appetite hormones in HIE suppression of appetite has received much attention, their role remains unclear.HypothesisHIE exercise induces a reduction of appetite due to an increase in inflammation and stress related responses.ObjectiveTo investigate and compare the underlying mechanisms contributing to the suppression of appetite with HIE in obese and lean children.MethodsCrossover design of 11 lean and 11 obese boys (aged 10–18y) randomly assigned to rest or 30 min of HIE at 70% peak oxygen consumption (VO2peak). Subjective appetite was assessed before and after HIE with visual analog scales. Blood samples were collected at baseline (0 min), immediately after exercise at 50 min, 80 min and 110 min. Plasma biomarkers of appetite were measured by leptin, active ghrelin, glucagon‐like‐peptide‐1 (GLP‐1), peptide YY (PYY) and biomarkers of stress and inflammation were assessed by c‐reactive protein (CRP), Interleukin‐6 (IL‐6), tumor necrosis factor alpha (TNF‐α) and cortisol.ResultsAt baseline, appetite was significantly increased (p=0.026) in obese compared to lean children. Appetite increased over time (p<0.001) but was suppressed by HIE (p=0.006) with no differences in lean and obese. Leptin (p<0.001), glucose (p=0.011) and insulin (p<0.001) were also increased more in obese children. At baseline there was no difference in active ghrelin, GLP‐1, PYY, CRP, IL‐6, TNF‐α and cortisol between lean and obese children. HIE suppressed active ghrelin (p<0.001) and increased inflammation as measured by interleukin‐6 (p<0.001), tumor‐necrosis‐factor‐alpha (p<0.001) and stress as measured by cortisol (p<0.001), with no differences in lean or obese. Blood glucose (p=0.002) and Insulin (p=0.028) increased with HIE. Interaction analysis for bodyweight and HIE revealed an increase in blood glucose (p=0.032) and insulin (p=0.042) in lean when compared to obese. The anorectic hormones, leptin, GLP‐1, PYY and CRP and biomarkers of inflammation and stress, CRP and cortisol, were not affected by HIE.ConclusionThe suppression of appetite with HIE was similar in lean and obese boys and accompanied by a decrease of the orexigenic hormone active ghrelin and increased inflammation and stress responses. The relative role of each of these signals in the suppression of appetite with HIE remains to be determined.Support or Funding InformationThis project was funded by the Canadian Institutes of Health Research (CIHR).
The Breath Carbon Isotope Ratio is a Promising Biomarker of Added Sugar Intake
Authors: O'Brien Diane M , Black Jynene A , Niles Kristine , Schoeller Dale 
Published: November 2023

High consumption of added sugars in the US is a significant public health concern. Added sugar intake is widely misreported, hampering efforts to understand its association with health. The carbon stable isotope ratio has been proposed as a biomarker of added sugar intake, because it is elevated in corn and sugar cane, the source of most added sugars consumed in the US. The objective of this study was to investigate the carbon isotope ratio of breath as a biomarker of short term (same day) added sugar consumption. Breath can be collected quickly and non‐invasively, and breath carbon isotope ratios can be rapidly measured using cavity ring‐down spectroscopy (CRDS). If shown to be a valid measure of short term added sugar intake, the breath carbon isotope ratio could be feasibly collected and measured multiple times, then averaged to estimate usual intake. Our objective was to test whether breath carbon isotope ratios could distinguish low (0 g/day), medium (75 g/day) and high (150 g/day) added sugar intakes, using a randomized cross‐over study of 12 adults (6 female, 6 male). Diets were 50% carbohydrate, 30% fat, and 20% protein, and included breakfast and lunch only (delivering 60% of daily energy and added sugar target values). On each study day, participants provided breath samples by blowing into a gas sampling bag at 8 am (fasted), 10 am, 12 pm, 2 pm and 4 pm, and were served breakfast and lunch following the 8 am and 12 pm sampling times, respectively. There were 1–2 weeks between each treatment day. The effect of added sugar level on breath carbon isotope ratios was analyzed for each sampling time point using Analysis of Covariance, including sex, age, and fasting breath isotope ratios as covariates. Breath carbon isotope ratios increased significantly with added sugar intake, and differed significantly between all three treatments (low, medium and high added sugar, all P < 0.0001) at all four post‐feeding time points (10 am, 12 pm, 2 pm and 4 pm). Fasting breath carbon isotope ratios were a significant covariate, especially for the 10 am and 12 pm measurements. This preliminary work shows that breath carbon isotope ratios are promising measures of short term sugar intake that are non‐invasive and easily‐collected. If collected over multiple days and averaged, these measures could potentially provide objective biomarkers of usual added sugar intake for epidemiological research.Support or Funding InformationP30 GM 103325‐03
Energy Deficiency, but not Aerobic Exercise, is Associated with Increased Stable Nitrogen Isotope Ratio of Urinary Urea
Authors: Koehler Karsten , Flenker Ulrich , Schaenzer Wilhelm , Huelsemann Frank 
Published: November 2023

Energy deficiency (ED) is typically associated with the loss of lean mass, which occurs secondary to increased body protein breakdown. Exercise, which stimulates both protein synthesis and breakdown, has the capacity to attenuate the loss of lean mass during ED, but the contribution of protein sources, i.e. body protein vs. dietary protein, to protein turnover during ED and/or exercise remains only poorly understood. Analysis of the stable nitrogen isotope ratio (δ15N) of urea, the primary end‐product of protein metabolism, could provide useful information about the source of protein breakdown and, subsequently, for dietary protein requirements to preserve lean mass during ED.PURPOSETo determine the effects of ED with and without exercise on the stable nitrogen ratio of urinary urea (δ15Nurea).METHODSHealthy, trained, young men (n=6, 25.2 ± 2.4 y, 79.7 ± 7.7 kg; 9.6 ± 1.5% body fat) were included in this 4‐way crossover study. Participants underwent two 4‐day ED conditions during which energy availability (EA) was reduced to 15 kcal/kg fat free mass (FFM) per day, once while conducting exercise to expend 15 kcal/kg FFM (ED+EX) and once while not exercising (ED‐EX). Participants also underwent two 4‐day control conditions in energy balance (EA of 40 kcal/kg FFM), once with exercise (C+EX) and once without exercise (C‐EX). δ15Nurea was assessed from urine samples using elemental analysis‐isotope ratio mass spectrometry (EA‐IRMS, Eurovektor EA 3000) and was adjusted for dietary nitrogen isotope ratio (δ15Ndiet), which was computed as previously described [1].RESULTSWeight loss was similar in both ED conditions (ED‐EX: −2.4±0.7 kg, p<0.001; ED+EX: −1.8±1.0 kg, p=0.004). δ15Nurea adjusted for δ15Ndiet (δ15Nurea ‐δ15Ndiet) was significantly elevated in ED‐EX when compared with C‐EX (0.3±0.4‰ vs. −1.1±0.4‰, p=0.01) and in ED+EX when compared with C+EX (−0.6±1.0‰ vs. −1.1±0.4‰, p=0.01); whereas, there was no significant difference in δ15Nurea ‐δ15Ndiet between ED‐EX and ED+EX and between C‐EX and C+EX. Multiple linear regression identified EA (p=0.015), dietary protein intake (p=0.001), and the interaction between EA and protein intake (p=0.03) as significant predictors of δ15Nurea ‐δ15Ndiet.CONCLUSIONThe increase in δ15Nurea during both ED conditions confirms that endogenous protein breakdown is increased in the energy‐deficient state. However, our results do not indicate that exercise per se is associated with changes in endogenous protein breakdown. Future studies with controlled dietary protein intake are needed to verify that changes in δ15Nurea are reflective of increased body protein breakdown during ED.Support or Funding InformationThe study was supported by a University seed grant.