bluuebunny/crossref_metadata_2025 huggingface dataset:
Tuberculosis treatment modifies iron status without iron intervention (389.8)
Authors: Minchella Peter , Donkor Simon , Sutherland Jayne , McDermid Joann
Published: June 2021

Iron biomarker patterns identify tuberculosis (TB) risk, but evidence of the evolution of iron biomarkers from treatment initiation to disease resolution is limited. Plasma/serum ferritin, hepcidin and soluble transferrin receptor (sTfR) were measured in 45 Gambians diagnosed with TB (active disease) at treatment initiation, 2 and 6 months and compared to 42 tuberculin skin test (TST)+ (infection only, no disease) and 44 TST‐ (uninfected) controls. At treatment initiation, median ferritin (164.5 ng/ml), hepcidin (84.0 ng/ml), and sTfR (29.4 nM) identified active disease compared to infected (ferritin 29.3 ng/ml, P<0.001; hepcidin 19.8 ng/ml, P<0.001; sTfR 23.0 nM, P=0.005) and uninfected (ferritin 23.3 ng/ml, P<0.001; hepcidin 24.2 ng/ml P<0.001; sTfR 18.6 nM, P<0.001) levels, which were similar. Ferritin, hepcidin and sTfR decreased significantly during the first two months of treatment and remained at these levels until treatment completion. Understanding fluctuations in iron distribution driven by infection and immune activation will inform the clinical management of TB, particularly in global regions with high burdens of iron malnutrition. Additionally, nutritional iron interventions to alleviate co‐existing iron insufficiency and iron deficiency anemia may be most effective if targeted after immune or infection‐driven iron redistribution stabilizes after 2 months of TB treatment.

Grant Funding Source: ILSI North America, National Science Foundation Graduate Research Fellowship Program
Testosterone influences the accumulation of carotenoids in the retina of a wild bird (39.4)
Authors: Toomey Matthew , Daniel Chelsie , Davies Scott , McGraw Kevin
Published: June 2021

Carotenoids accumulate at high concentrations in the avian retina, where they filter incoming light, tune spectral sensitivity, and provide protection from damaging UV light. Among wild house finches (Haemorhous mexicanus), we have observed significant seasonal variation in retinal carotenoid levels, with a peak during the non‐reproductive winter period and lowest levels during the spring/summer breeding season. We hypothesized that these seasonal patterns of accumulation could be driven by the direct influence of photoperiod and/or indirectly through the influence of seasonally sensitive sex steroid hormones (testosterone) on retinal carotenoid physiology. To test these hypotheses, we brought wild caught male and female adult house finches into captivity, gonadectomized a subset of the male birds, and maintained groups on long (16:8 light:dark) or short (8:16) photoperiods for two months. At the conclusion of the study, gonadectomized males had significantly higher carotenoid levels in their retinas and much lower circulating testosterone levels than males that were sham‐treated, but did not differ significantly from intact females. Photoperiod alone had no significant effect on retinal carotenoid levels; however there was a significant interactive effect of gonad status, photoperiod, and time on plasma carotenoid levels. Sham‐treated males on the long photoperiod showed a significant decline in plasma carotenoid levels in the first month of the experiment, but recovered in the second month. These results suggest that testosterone maybe influencing the uptake, transport, and/or accumulation of carotenoids in the avian retina and driving seasonal patterns of accumulation. These shifts in retinal carotenoid accumulation represent a previously unrecognized cost of testosterone‐mediate traits (e.g. song, territoriality).

Grant Funding Source: Supported by NSF‐IOS‐0910357, 0923694 and DBI‐1202776
Vitamin A supplementation and ontogeny affect maturation‐related gene expression in neonatal rat lung (39.7)
Authors: Owusu Sarah , Ross A
Published: June 2021

Background: Vitamin A (VA) is necessary for proper lung development in early life. Previously, the combination of VA and 10% all‐trans‐retinoic acid (VARA) synergistically increased total retinol uptake and storage in neonatal rat lung. In this study, we investigated whether periodic VARA supplementation during postnatal development and in adulthood alters the expression of genes essential for proper lung alveolarization (proliferation) and septation. Methods: Rat dams and their post‐weaning offspring were fed a VA‐marginal diet, while pups received an oral dose of oil (placebo) or VARA on post‐natal day (P) P0/1, P4, P7, P10, and 2 months (adult). Tissues were collected 6 h after the final dose and qPCR was used to determine gene expression. Results: Ontogenic expression of PDGFRα (secondary septation) increased linearly with significant attenuation by VARA. VARA decreased EGFR (epithelial maturation) and surfactant protein expression at P14 and adult while increasing VEGF (vascularization) expression in adult lung. Ontogenic expression of αSMA was highest during alveolarization (P4‐P14); however, VARA reduced expression pre‐ and postalveolarization (P0/1 and adult). Elastin expression was not effected by VARA. Impact: Our results advance understanding of the ontogenic pattern of proliferative genes during neonatal lung development and show that expression is also regulated by VA supplementation.

Grant Funding Source: Supported by Alfred P. Sloan Scholarship and NIH HD006892
Providing flexible food portions in a restaurant setting: impact on business operations, food consumption and food waste (390.3)
Authors: Berkowitz Sarah , Marquart Leonard , Reicks Marla , Mykerezi Elton , Degeneffe Dennis
Published: June 2021

Large portion sizes in restaurants have been identified as a public health risk. A field experiment was conducted to examine the impact of offering flexible portion sizes in a sit‐down restaurant setting in St. Paul MN on business operations, food consumption and waste. Patrons were surveyed online at the beginning and end of the study to determine their likelihood of purchasing reduced portion size menu items. Purchasing, consumption and food waste data were collected throughout the study. Reduced sized portions were added to the menus halfway through the study in the spring of 2013. The management team was interviewed at the completion of the study. Patron survey data and observational data on actual customer choices showed that a large proportion of customers (>25%) were willing to purchase the reduced portion items. Analyses of choice and plate waste data show that food consumed per seating decreased 29% and share of food wasted decreased >30% with the addition of reduced portion items. The management team reported the added items provided higher profit margins and improved customer satisfaction and has implemented the menu changes indefinitely. Promoting voluntary introductions of flexible portions may be a viable policy alternative to more restrictive regulation options.

Grant Funding Source: Supported by the Food Policy Research Center, University of Minnesota, supported through USDA NIFA
Why are associations with health risks better for waist circumference than for visceral adipose tissue? A mechanistic explanation (391.5)
Authors: Shen Wei , Bosy‐Westphal Anja , Thomas Diana , Heymsfield Steven , Mueller Manfred
Published: June 2021

Visceral adipose tissue (VAT) is strongly associated with health risks, although an anomalous finding is that VAT‐surrogate waist circumference (WC) is often an even better risk predictor. This led us to hypothesize that other compartments might in‐part account for the stronger WC‐health risk relationship. We tested this hypothesis by conducting whole‐body MRI in 314 adults with additional measures including WC and cardiovascular disease risk markers. Regression models were developed with health risk factors as dependent variables and abdominal compartments (VAT and liver, spleen, kidney, skeletal muscle, and total adipose tissue [TAT] volumes) as independent variables. Liver volume (LV, P=0.002), VAT (P<0.001), TAT (P<0.001), and skeletal muscle (P=0.048) all independently contributed to WC in regression models. LV independently contributed to fasting plasma triglyceride levels, HDL‐cholesterol, insulin, and systolic‐diastolic BP (all P<0.001 except HDL P=0.005) after VAT and TAT adjustment. LV, in turn, was borderline significantly correlated with spectroscopy‐measured liver fat (r=0.33, p=0.08) in a 30 subject subsample. LV changes with 3‐month dieting were significantly correlated with liver fat changes (r=0.44, P=0.03). WC as a phenotypic measure thus detects risk factor effects beyond that produced by VAT, notably the well‐characterized metabolic effects of hepatic steatosis.
Mid‐arm circumference is a reliable predictor of adiposity in preterm and term infants (391.6)
Authors: Daly‐Wolfe Kelly , Jordan Kristine , Slater Hillarie , Beachy Joanna , Moyer‐Mileur Laurie
Published: June 2021

Premature birth is associated with poor growth quality due to increased fat deposition. Standard anthropometry (body weight, length, and head circumference) may not adequately assess fat deposition. Validated, low‐risk methods to assess body fat deposition are needed to assist clinicians with optimizing growth quality in preterm infants.

The purpose of this study was to identify predictors of infant body fat (%BF). Air displacement plethysmography (ADP), standard anthropometry, and body circumferences were measured at hospital discharge in preterm (n=28; 32‐36 weeks post‐menstrual age, PMA) and term (n=28; 38‐41 weeks PMA) infants.

Body weight, length, and head circumference were significantly lower for preterm infants (p<0.05) at hospital discharge compared to term infants. Despite the smaller body size and younger PMA, preterm infant %BF by ADP was 12.33% (SD±4.15%) versus 9.64% (SD±4.01%) in term infants (p=0.01). Mid‐arm circumference (MAC) and suprailiac skinfold were significant predictors of %BF in both preterm and term infants (adj‐R2=0.49 vs. adj‐R2=0.41, p<0.001). In preterm infants alone, MAC predicted 60.4% of the variability of %BF by ADP (p<0.01).

Our results confirm a greater rate of body fat deposition in preterm infants as they approach term‐corrected age. Importantly, MAC appears to be a reliable, low‐cost measure for monitoring infant body fat deposition in preterm and term infants.

Grant Funding Source: Supported by the Division of Neonatology and the Department of Pediatrics, University of Utah
Relationship between body composition and arterial stiffness in postmenopausal women (391.8)
Authors: Feresin Rafaela , Figueroa Arturo , Johnson Sarah , Elam Marcus , Kalfon Roy , Wong Alexei , Navai Negin , Pourafshar Shirin , Arjmandi Bahram
Published: June 2021

Menopause is associated with age‐related increases in blood pressure (BP) and arterial stiffness and has also been linked to increased fat mass (FM), decreased bone mineral density (BMD) and content (BMC) and decreased lean body mass (LBM). Thus, the goal of this cross‐sectional study was to investigate the relationship between body composition and arterial stiffness. In 81 pre‐ and stage 1‐hypertensive postmenopausal women (age: 59 ± 5 years; BMI: 31 ± 6; SBP: 140 ± 15 mmHg) BMD, BMC, LBM, and FM were assessed by dual X‐ray absorptiometry and arterial stiffness was evaluated by brachial pulse wave velocity (baPWV) using applanation tonometry. No significant correlations were found between BMD, LBM, or FM and baPWV yet BMC tended to negatively correlate with baPWV (p = 0.07, r = ‐ 0.202) which remained true after adjusting for systolic BP and treatment for hypertension or with statins. However, a significant correlation between BMC and baPWV was observed after adjusting for mean arterial pressure (MAP; p = 0.04, r = ‐ 0.227). Multiple regression analysis showed that baPWV was significantly and independently associated with age, MAP, and weight (p = 0.000, R² = 0.270) which was unchanged after exclusion of statins users (p = 0.000, R² = 0.251). Nonetheless, a subsequent multiple regression analysis in which women on anti‐hypertensive medications were excluded revealed that MAP, age, and BMD are independent predictors of baPWV (p = 0.001, R² = 0.433). Our findings suggest that lower BMD and BMC may be related to increased arterial stiffness and a greater risk of cardiovascular diseases and osteoporosis in postmenopausal women.
Granulocyte/monocyte phagocytosis is related to inflammation and disease risk factors in overweight/obese women (392.2)
Authors: Nieman David , Dréau Didier , Henson Dru , Luo Beibei , Meaney Mary Pat , Shanely R. Andrew , Dew Dustin
Published: June 2021

Correlates of granulocyte (GPHAG) and monocyte (MPHAG) phagocytosis and oxidative burst activity (GOBA, MOBA) were investigated during a 12‐week period in overweight/obese women (N=106, 18‐75 years, BMI 蠅 25 kg/m2). Blood samples were collected pre‐ and post‐study, and analyzed for oxidative stress/capacity (oxidized LDL, RBC glutathione, 8 hydroxy‐2‐deoxyguanosine, FRAP, ORAC), inflammation (CRP, WBC differential), and metabolic factors (insulin, hemoglobin A1C, human growth hormone, epinephrine, cortisol, lipid/diagnostic chemistry panel). GPHAG, MPHAG, GOBA, and MOBA were measured using flow cytometric methods and Staphylococcus aureus as the target pathogen (bacteria‐to‐phagocyte ratio of 8:1). The Wisconsin Upper Respiratory Symptom Survey was used to assess acute respiratory illness (ARI). Pre‐ and post‐study blood sample outcomes were averaged and correlated with GPHA, MPHAG, GOBA, and MOBA. GPHAG and MPHAG (but not GOBA or MOBA) were significantly related with the neutrophil/lymphocyte ratio (NE/LY) (r=0.62, 0.61, respectively, P<0.001), BMI (r=0.50, 0.40, P<0.001), CRP (r=0.44, 0.30, P<0.01), insulin (r=0.30, 0.23, P<0.03), and A1C (r=0.28, 0.21, P<0.04), but not with ARI, oxidative stress/capacity, or other metabolic factors. In summary, GPHAG and MPHAG were related to NE/LY, BMI, and CRP in overweight/obese women and can be regarded as biomarkers of systemic inflammation.
Metabolic profiling uncovers differential metabolic signatures and biomarkers in influenza‐infected obese mice (392.3)
Authors: Milner J , Wang Jue , Paich Heather , Sheridan Patricia , Ebbels Tim , Saric Jasmina , Beck Melinda
Published: June 2021

Obese individuals are at greater risk for hospitalization and death from influenza virus infection. Paralleling human evidence, obese mice also exhibit greater mortality to influenza compared with lean mice. Although obesity is known to impair immunity, the mechanisms driving greater influenza severity in the obese remain unclear. Therefore, we have taken a novel approach for elucidating the underlying mechanisms contributing to altered infection responses. We conducted metabolic profiling to identify differential metabolic signatures in infected lean and obese mice, and integrated metabolite data with immune parameters to identify significant immune‐metabolic interactions. Urine, feces, serum, bronchoalveolar lavage fluid, lungs, mesenteric white adipose tissue, and livers were harvested from uninfected or influenza infected mice for subsequent 1H NMR‐based metabolic profiling. Multivariate statistical analysis revealed distinct metabolic signatures between lean and obese mice, both locally at the site of infection and systemically. Obesity caused perturbations in lipid, choline, nucleotide and carbohydrate metabolic pathways during infection. Further, activated T cells negatively correlated with 3‐hydroxybutyrate and creatine in the lungs of obese mice, possibly suggesting regulatory functions for these metabolites. Of interest, urine samples obtained from obese mice as early as two days post‐infection had a distinct metabolic signature compared with urine samples from lean infected mice. Given the rapidity of influenza transmission and the sudden onset of symptoms during infection, identification of an early infection metabolic signature and unique biomarkers in a non‐invasive biofluid, such as urine, has widespread prognostic and diagnostic implications. Further, identification of altered metabolic pathways in obese mice will facilitate better understanding of the determinants of greater influenza mortality observed in obese mice and humans.

Grant Funding Source: Supported by NORC DK56350
Vitamin E boosts resistance to Streptococcus pneumoniae infection in aged mice by inhibiting hepoxilin A3‐mediated neutrophil recruitment across the lung epithelium (392.4)
Authors: Bou Ghanem Elsa , Wu Dayong , Camilli Andrew , Leong John , Meydani Simin
Published: June 2021

Streptococcus pneumoniae (Sp) infections in the elderly are a significant health and economic burden. We showed that vitamin E (VE) supplementation reverses the age‐associated decline in resistance to Sp in mice. To identify mechanisms of VE‐mediated protection, young and old (2 and 22 mo, respectively) mice were fed a control (30 PPM VE) or supplemented (500 PPM VE) diet for 1 mo and then intratracheally challenged with Sp. Aged mice fed the control diet suffered excessive pulmonary inflammation relative to young mice, with almost two‐fold higher levels of neutrophil infiltration (PMNs; p= 0.0157), a feature associated with pulmonary damage and poor disease outcome. VE supplementation reduced pulmonary inflammation in old mice to levels found in young mice. VE also inhibited Sp‐induced PMN egress across polarized lung epithelial monolayers. PMN trans‐epithelial migration in response to Sp infection requires 12‐lipoxygenase‐ (12‐LO‐) dependent production of the eicosanoid hepoxilin A3 (HXA3) but VE had no effect on 12‐LO levels or activity. Rather, VE decreased the responsiveness of PMNs to HXA3. These results indicate that VE dramatically reduces age‐associated susceptibility to Sp in a murine infection model and identify HXA3 responsiveness as a key target for VE‐mediated reduction of PMN migration in aged mice.

Grant Funding Source: Supported by Tufts Collaborates, ASPEN ‘13 Abbott Nutrition Grant and USDA Contract #58‐1950‐0‐014
Ferritin, when corrected for inflammation, is associated with increased malaria incidence in rural Zambian children (392.6)
Authors: Barffour Maxwell , Schulze Kerry , Palmer Amanda , Klemm Rolf , Coles Christian , Arguello Margia , Chileshe Justin , Kalungwana Ngandwe , Moss William , West Keith
Published: June 2021

Poor iron status, assessed by low serum ferritin (SF), may protect against malaria. We evaluated the association of SF, and SF corrected for inflammation and malaria status (SFcorr), with microscopy‐confirmed incident malaria in a cohort of 954 4‐8 y old Zambian children participating in a 6 mo trial to improve vitamin A status (August 2012 to March 2013). Analyses were stratified by age (<5 y and >5 y) to account for the age‐specific risk of malaria. Baseline SFcorr was determined by proportionately reducing SF based on categories of inflammation defined by AGP > 1g/L, CRP > 5 mg/L, and by concurrent malaria status assessed by microscopy, relative to SF observed in unaffected children. SF and SFcorr levels were classified as deficient, medium, and high using cutoffs of <12 or 15 ug/L (depending on age), up to 60 ug/L (but not deficient), and >60 ug/L, respectively. Malaria‐infected children were treated at baseline. Among children <5 y, having medium or high SFcorr resulted in relative risks for incident malaria after 6 mo of 1.61 (95%CI: 1.05‐2.50) and 1.67 (95%CI: 1.06‐2.61), respectively. This pattern was not observed with uncorrected SF. Our findings demonstrate the necessity of adjusting for inflammation and concurrent malaria infection when assessing the relationship between iron status and malaria, and are consistent with evidence that iron status modifies malaria risk, particularly in young children.

Grant Funding Source: Supported by HarvestPlus and Canadian International Development Agency
Lactobacillus gasseri KS‐13, Bifidobacterium bifidum G9‐1, and Bifidobacterium longum MM‐2 ingestion induces a potentially beneficial shift in gut microbiota and impacts cell‐mediated immunity in older adults: a randomized, double‐bli (392.7)
Authors: Culpepper Tyler , Spaiser Samuel , Nieves Carmelo , ElAyouty Nada , Ukhanova Maria , Mai Volker , Percival Susan , Christman Mary , Langkamp‐Henken Bobbi
Published: June 2021

Aging is associated with dysregulated immune function. It was hypothesized that ingestion of a probiotic would induce a beneficial shift in gut microbiota composition resulting in a greater proportion of T helper (Th) cells, increased Th1 cytokine production, and decreased inflammation. In a 13‐wk study, older adults (70±1 y; n=32) consumed a probiotic mix or a placebo twice daily for 3 wks with a 5‐wk washout. Blood and stools were collected at baseline and post intervention. After the intervention, several bacterial groups matching Faeacalibactierium prausnitzii, a species inversely associated with inflammatory GI disease, were more prevalent in stool samples with the probiotic vs. placebo. Percentages of peripheral Th cells were higher after probiotic (41% ± 2%, mean ± SEM) vs. placebo (35% ± 3%). After in vitro mitogen stimulation of T cells, IFN‐γ (6.9 ± 0.2 vs. 5.5 ± 0.4, probiotic vs. placebo, log transformed means ± SEM, pg/mL), IL‐10 (4.2 ± 0.2 vs. 2.9 ± 0.3), and IL‐2 (4.7 ± 0.2 vs. 3.7 ± 0.4) concentrations were higher with ingestion of the probiotic. These data suggest that ingestion of this probiotic mix results in a potentially beneficial shift in gut microbiota composition at the individual species level and may impact cell‐mediated immunity in older adults.

Grant Funding Source: Wakunaga of America Co. Ltd.
Participation of NF‐κB in cell survival or proliferation is regulated by interaction with β‐catenin (398.7)
Authors: Nejak‐Bowen Kari , Monga Satdarshan
Published: June 2021

Understanding the signaling pathways involved in liver regeneration (LR) has important therapeutic implications. We have previously shown that β‐catenin sequestration of p65 in cytosol prevents it from translocating to the nucleus, and that lack of p65/β‐catenin complex in hepatocyte‐specific β‐catenin knockout (KO) mice enhances survival. To determine whether this association regulates cell proliferation, wild‐type (WT) and KO mice were treated with GalN/LPS to induce liver injury. Proliferation in WT liver occurs during the early phase of injury, but is absent at time of morbidity. Conversely KO display scant proliferation until the “recovery” phase, and an increase in pro‐survival target genes. We then characterized the association and expression of NF‐κB and β‐catenin after LR by immunoprecipitation and demonstrated translocation and interaction of these two proteins in the nucleus within hours after partial hepatectomy (PH), which preceded a 2.5‐fold increase in cyclin‐D1 mRNA. Finally, Hep3B hepatoma cells demonstrated a significant decrease in cyclin‐D1 reporter activity when treated with β‐catenin siRNA but not with p65 siRNA, indicating that while β‐catenin is required for proliferation, p65 may be dispensable. Thus, β‐catenin is an important component of balancing the context‐dependent pro‐proliferation versus pro‐survival function of NF‐κB.
Elevated iron stores in the first trimester of pregnancy are associated with subsequent gestational diabetes in absence of inflammation (40.7)
Authors: Khambalia Amina , Roberts Christine , McElduff Aidan , Shand Antonia , Morris Jonathan , Tasevki Vitomir , Nassar Natasha
Published: June 2021

Background: Increasing gestational diabetes (GDM) places greater demand on resources to manage high‐risk pregnancies and prevent adverse perinatal outcomes. High levels of serum ferritin (SF) have been associated with type 2 diabetes; however it is uncertain whether elevated SF are associated with GDM and reflect increased iron stores or inflammation.

Aim: To determine whether first trimester SF is associated with subsequent GDM in absence of inflammation.

Methods: Serum samples for women with first trimester screening were linked to birth and hospital discharge records for data on maternal characteristics and GDM diagnosis. Blood was analysed for iron stores (SF; µg/L), tissue iron (transferrin receptor, TfR; nmol/L) and inflammation (C‐reactive protein, CRP; mg/L). Women with CRP >5 or pre‐existing diabetes were excluded. Odds ratios for GDM adjusted for age, parity, plurality, country of birth, smoking, private vs. public hospital, low SES, gestational age, and maternal weight.

Results: Of 3, 143 pregnancies, 3.6% developed GDM. Compared to no GDM, GDM pregnancies had higher median SF (25.9 vs. 33.9, p= 0.0007); but not TfR (14.7 vs. 15.7, p=0.14) levels. Adjusted model found increased odds of GDM by SF (OR: 1.47; 95% CI: 1.12, 1.94).

Conclusions: Elevated iron stores are associated with GDM and may be important for early identification of high‐risk pregnancies.

Grant Funding Source: Sydney Medical School Early Career Researcher Scheme 2011, University of Sydney; NHMRC project grant
The COP9 signalosome as a novel mediator of arrhythmogenic cardiomyopathy (404.1)
Authors: Lyon Robert , Mezzano Valeria , Pellman Jason , Lim Byung‐Kwan , Iwakuma Tomoo , Lee Mong‐Hong , Nigam Vishal , Scheinman Melvin , Sheikh Farah
Published: June 2021

Arrhythmogenic cardiomyopathy (AC) is a genetic‐based heart disease characterized by a high frequency of ventricular arrhythmias leading to sudden cardiac death in young people. AC is termed a cardiac disease of the desmosome; however, only 40% of AC patients carry genetic mutations in known desmosomal cell‐cell junction genes, suggesting that novel mechanisms remain to be uncovered. To address this challenge, we set out to identify novel desmosomal associated proteins by performing a yeast‐two‐hybrid screen with the desmosomal gene, desmoplakin (DSP), as bait in an adult human heart cDNA library. We identified COP9 signalosome subunit 6 (CSN6), a protein traditionally linked to mediating ubiquitin‐mediated protein degradation, as a novel desmosomal (DSP)‐interacting protein, which localizes at the intercalated disc in both adult mouse and human heart. We show that CSN6 levels are dramatically reduced at the intercalated disc in hearts of a mouse model of AC (cardiac‐specific DSP knockout mice (DSP‐cKO)) and human AC patient harboring desmosomal mutations in DSP and plakophilin‐2 (PKP2). Yeast‐two‐hybrid assays revealed that the DSP mutation in the human AC patient abrogates the binding of DSP with CSN6. We further show that DSP‐cKO hearts display underlying defects in protein degradation associated with loss of CSN6 function including increased neddylation, ubiquitination, and ubiquitin‐mediated autophagy profiles. A striking increase in markers for the autophagy/lysosome degradation system could also be detected specifically at the intercalated disc in DSP‐cKO mouse hearts. Most importantly, analysis of CSN6 heterozygous knockout mouse hearts and CSN6 knockdown in neonatal ventricular cardiomyocytes in vitro revealed that loss of CSN6 is sufficient to trigger and recapitulate the desmosomal and protein turnover defects observed in our mouse model of AC. Our studies highlight the importance of CSN6 at the cardiac desmosome and reveal new mechanisms underlying AC.

Grant Funding Source: Supported by American Heart Association
Cross‐talk between Toll‐like receptors and renin angiotensin system in a cardiac hypertrophy model induced by renal ischemia/reperfusion (404.5)
Authors: Abrahão Mariana , Carneiro‐Ramos Marcela
Published: June 2021

Objectives: The cardio‐renal syndrome comprises a set of pathophysiological kidney‐heart interactions. Renal inflammatory conditions are able to promote the release of inflammatory cytokines, which may act through cardiac TLR, promoting cardiovascular diseases such as cardiac hypertrophy (CH), as well as angiotensin II. This study aims to investigate a possible interaction between TLR and RAS in a model of CH induced by ischemic renal injury. Methods: C57BL/6 male mice (n=85) were subjected to surgical occlusion of left renal pedicle. Mice were treated with Los (10 mg/kg/day) or Ena (40 mg/kg/day) and kept under observation for 12, 15 or 20 days of reperfusion (REP). Kidney injury and CH were assessed by morphologic and molecular parameters. Cardiac and serum cytokines and protein and mRNA levels of cardiac RAS components and TLR2 and TLR4 were evaluated. Results: The succesfully‐performed ischemic protocol induced CH after 12d of REP, which was accompanied by enhanced IL‐6 levels in serum. CH were completely reversed by Los and Ena treatment. At the same time point, cardiac AT1, ACE2, TLR2 and TLR4 levels were increased (p<0.001). Treatment with RAS inhibitors abolished this increase to levels similar to control group. Conclusion: RAS may modulate CH through regulation of TLRs levels in the heart, suggesting the existence of a important cross‐talk between TLR and RAS in CH induced by renal ischemia/reperfusion.
Investigating the cell death mechanism(s) of 4‐hydroxy‐tamoxifen in glioblastoma (411.1)
Authors: Graham Christopher , Kaza Niroop , Taylor Barbara , Roth Kevin
Published: June 2021

Tamoxifen (TMX) is widely used as a chemotherapeutic agent in the treatment of estrogen receptor (ER)‐positive breast cancer. Recent studies have demonstrated that TMX inhibits the growth of malignant peripheral nerve sheath tumors (MPNSTs) through an ER‐independent mechanism associated with the induction of autophagy. We hypothesize that TMX could induce autophagic cell death in glioblastoma (GBM), the most common and aggressive malignant astrocytic glioma. In an established human GBM cell line and xenografts, TMX caused a concentration‐dependent decrease in cell viability that was not mediated by caspase 3‐like enzymatic activity. We observed a concentration‐dependent decrease in KRAS protein levels and an accumulation of LC3‐II, a surrogate marker of autophagic vacuoles. Finally, because epidermal growth factor receptor (EGFR) amplification is frequently associated with GBM and elevated EGFR signaling is known to contribute to the malignant properties of GBM, we examined the effects of TMX on EGFR and found a decrease in EGFR protein and Akt signaling. These data suggest that TMX induces GBM cell death through a caspase‐independent, autophagy‐related mechanism and should be considered as a potential therapeutic agent in GBMs and other malignancies that are not amenable to apoptotic‐targeting therapies.

Grant Funding Source: NINDS
PAR4 Mediates an Elevated Risk for Thrombosis in Blacks Relative to Whites (425.1)
Authors: Tourdot Benjamin , Niisuke Katrin , Holinstat Michael
Published: June 2021

Coronary heart disease (CHD) is the leading cause of mortality in the US amongst all races. CHD disproportionality burdens blacks relative to whites and even after adjusting for other demographic parameters, blacks have a two‐fold increase in incidence of CHD and a decrease in long‐term survival. Occlusive thrombus formation is the underlying cause of mortality associated with CHD. Due to the importance of platelets in CHD and formation of occlusive thrombi, the response of platelets from blacks and whites to thrombin and its protease‐activated receptors (PAR1 and PAR4) was characterized. Platelets isolated from blacks and whites differentially responded to PAR4 but not PAR1. Specifically, platelets from blacks were hyperaggregable to low and intermediate doses of PAR4‐activating peptide (PAR4‐AP) compared to platelets from whites. The mechanism responsible for the racial difference in PAR4 mediated platelet reactivity however is still unknown. We hypothesize that changes in expression or activity of proteins known to participate in the PAR4 pathway are responsible for the racial difference in platelet PAR4 reactivity. To test this hypothesis, the PAR4 pathway in platelets from blacks and whites was characterized. No measurable difference was observed in the surface expression of PAR4 on platelets from blacks or whites however following stimulation with low dose PAR4‐AP (50uM), platelets from blacks had an increase in PAR4 signaling components compared to whites including intracellular Ca2+ release, RAP1 activation, and integrin αIIbβ3 activation. This data suggest that the kinetics of platelet activation through PAR4‐AP is hyper‐responsive in blacks compared to whites due to a shift in threshold downstream of the receptor. As PAR1 antagonists are currently in clinical trials and PAR4 antagonists are in pre‐clinical development, this work has important clinical implication as to which patients may benefit the most from selective PAR inhibition and is the first to suggest a racial component in the prevention of occlusive thrombus formation and stroke.

Grant Funding Source: RO1 MD007880
High multivitamin intake during pregnancy leads to dopamine dysregulation in the nucleus accumbens of Wistar rat dams post‐weaning (47.6)
Authors: Pannia Emanuela , Cho Clara , Sanchez‐Hernandez Diana , Huot Pedro , Kubant Ruslan , Anderson G
Published: June 2021

Diet‐induced obesity is known to alter dopamine neurochemistry within central reward circuitry essential for coding the rewarding properties of palatable foods. Our objective was to investigate whether high multivitamin (10‐fold, HV) intake during pregnancy alone, which increases post‐weaning (PW) weight gain in Wistar rat dams, affects their dopamine (DA) metabolism and related gene expression in the nucleus accumbens (NAc) when exposed to an obesogenic environment. Pregnant Wistar rats were fed an AIN‐93G diet with either the recommended vitamin (1‐fold, RV) or HV mix (n=15/group). During lactation, dams were fed a RV diet until weaning and then a high fat (RV with 60% fat) diet for 16 weeks. Dams fed the HV diet gained 30% (p<0.05) more weight after weaning than RV dams. Although differences in food intake were not detected, HV dams had a 10% (p<0.05) reduced preference for sucrose when exposed to a two‐bottle preference test (4% sucrose vs. water) at 12 weeks PW suggesting a state of reward hypofunction. Total DA, DA receptor 1a/2, catechol‐O‐methyl transferase and monoamine‐oxidase A mRNA expression in the NAc was unaffected by diets. However, turnover rate of homovanillic acid, but not di‐hydroxypheneylactic acid, was significantly lower in HV dams (p<0.05). In conclusion, HV diet during pregnancy in Wistar rat dams induces DA dysregulation in the NAc later in life and is consistent with PW weight gain.

Grant Funding Source: Supported by Canadian Institutes of Health Research, Institue of Nutrition, Metabolism and Diabetes
Personalized medicine: personal omics profiling of healthy and disease states (475.1)
Authors: Snyder Michael
Published: June 2021

Personalized medicine is expected to benefit from the combination of genomic information with the global monitoring of molecular components and physiological states. To ascertain whether this can be achieved, we determined the whole genome sequence of an individual at high accuracy and performed an integrated Personal Omics Profiling (iPOP) analysis, combining genomic, transcriptomic, proteomic, metabolomic, and autoantibodyomic information, over a 38‐month period that included healthy and two virally infected states. Our iPOP analysis of blood components revealed extensive, dynamic and broad changes in diverse molecular components and biological pathways across healthy and disease conditions. Importantly, genomic information was also used to estimate medical risks, including Type 2 Diabetes, whose onset was observed during the course of our study. Our study demonstrates that longitudinal personal omics profiling can relate genomic information to global functional omics activity for physiological and medical interpretation of healthy and disease states.
Mapping dysregulated lipid metabolism in disease using chemoproteomic and metabolomic platforms (476.3)
Authors: Nomura Daniel
Published: June 2021

Cancer cells possess fundamentally altered metabolism that drives every aspect of cancer pathogenicity. While targeting dysregulated metabolism shows great promise for cancer therapy, most research has focused on well‐understood pathways in metabolism (i.e. Warburg), and has largely ignored the majority of metabolic pathways despite indications of their importance to cancer, leaving untapped the large therapeutic potential that remains in the unexplored metabolic genome. Here, we will discuss progress towards performing massively parallel metabolic mapping studies to identify nodal altered metabolic pathways underlying cancer pathogenesis.
Illuminating the mechanics of touch (479.5)
Authors: Goodman Miriam
Published: June 2021

The energy carried by every touch opens mechano‐electrical transduction (MeT) channels expressed in somatosensory neurons. Likewise, every bend of each limb activates MeT channels in proprioceptors embedded in muscles and tendons. The protein partners that form such channels have been identified in several classes of C. elegans mechanoreceptor neurons and key pore‐forming subunits include DEG/ENaC sodium channels and TRP cation channels. Such channels activate in response to both the application and removal of external loads, response dynamics that are also found in some mammalian somatosensory neurons. Exactly how external loads open MeT channels remains unknown. Using genetic dissection, new optical probes of molecular strain (TsMod), and AFM tether pulling, we will present evidence that membrane lipids and the cytoskeleton help to regulate touch receptor neuron mechanics and that both elements are needed for normal touch sensitivity.
Contribution of human deneddylase‐1/SENP8 to the mucosal inflammatory response (488.1)
Authors: Curtis Valerie , Ehrentraut Stefan , Campbell Eric , Glover Louise , Bowers Brittelle , Bayless Amanda , Kelly Caleb , Kominsky Douglas , Colgan Sean
Published: June 2021

Recent work has revealed a central role for neddylation (conjugation of a Nedd8 to proteins) to Cullin‐proteins in the induction of the NFκB (via Cullin‐1) and stabilization of hypoxia‐inducible factor (HIF, via Cullin‐2). Here, we elucidate the role of the human deneddylase‐1 (also called SENP8) in inflammatory responses in vitro / in vivo and define mechanisms for targeting SENP8 in models of inflammation. Human endothelial and epithelial cells exposure to inflammatory stimuli significantly induced the neddylation of Cullin‐1 and increased NFκB transactivation. These responses were nearly completely lost in cells lacking SENP8 via lentiviral knock‐down. Further analysis revealed that HIF‐1α protein was stabilized by LPS exposure in wild‐type cells but not in SENP8 knockdown cells. HIF promoter activity was increased following LPS compared to untreated controls. Pharmacological targeting of neddylation (MLN4924) abrogated NFκB responses, stabilized HIF‐1α protein and activated HIF promoter activity. Likewise, MLN4924 reduced secretion of TNF‐α‐elicited pro‐inflammatory cytokines from endothelial cells. In vivo, the neddylation inhibitor MLN4924 led to increased deneddylated Cullin‐1 in a TNBS colitis model and stabilized HIF while treatment with MLN4924 in a DSS colitis model abrogated disease severity. In conclusion, SENP8 is a proximal regulator of Cullin neddylation and fine‐tunes the inflammatory response in vitro and in vivo. Pharmacological inhibition of Cullin neddylation may provide a viable therapeutic opportunity.

Grant Funding Source: Supported by NIH grants DK50189, DK96491 and HL60569.
Assessment of an APS PhUn week activity in second grade school children of a rural area (531.22)
Authors: Edelman James , Gurovich Alvaro
Published: June 2021

In the last few years the United States has been on the decline in the fields of science and technology. The American Physiological Society (APS) has developed a program to engage young minds with scientists. Physiology Understanding Week (PhUn) is the APS initiative to use interactive experiments to engage school‐age children with science and physiology. Even though PhUn week has been going on since 2005, systematic assessment of the activities effects is rare. Here, we sought to assess if an APS PhUn week activity enhances physiology understanding and interest in science in second grade children form a rural area. The assessment design was a pre/post PhUn week activity survey. The PhUn week event included two parts: 1) on stage ‘magic’ show, performing live experiments about the neurological, cardiovascular, and renal systems, and 2) small‐group hands‐on activities featuring the respiratory, renal, cardiovascular, and neurological systems. One day before and within a week after the event the children answered a brief 19‐question survey including general questions about their interest in science and specific questions about the topics covered during the event. Ninety‐eight children attended the PhUn week event. Five out of 98 children did not answer the pre‐event survey. The average pre‐event survey score was 45.8% (±13.1%) and two thirds of the children liked science. After the event, the average survey score was 65.3% (±14.5%)(significantly higher when compared to pre‐event, p<0.001) and 83% of the children liked science. This APS PhUn week assessment showed an improvement in knowledge and appreciation for science in second grade children from a rural area.
Student perception of premedical coursework in the anatomical sciences (535.3)
Authors: Brown Kirsten , Harrison Steven , Jurjus Rosalyn
Published: June 2021

A common assumption among anatomy educators is that students take upper‐level undergraduate anatomy courses to excel in post‐graduate work in the health sciences; however, the motivations of these students has never been explicitly questioned. The goal of this study was to assess the motivations of students taking undergraduate anatomy courses, if their perceptions changed throughout the semester, and if a changed perception affected their career path. Undergraduate students were recruited to participate in this study from four undergraduate anatomy courses at George Washington University (GWU). Participants were asked to respond to two online surveys, one at the beginning (pre‐course) and one at the end (post‐course) of the course. Pre‐course questions assessed the students’ motivations and expectations of the class, while post‐course questions assessed if the students’ perception of the class had changed. Analyses from the pre‐course survey revealed that 79% of respondents enrolled in preparation for a career in the health sciences. Importantly after completing the course, 80% of the respondents felt that their course was an impetus to pursue a career in health sciences. Overall, these results indicate that GWU undergraduate students use anatomy courses as a standard for excelling in post‐graduate work. Moreover, they are also not deterred, but rather inspired to continue with educational pursuits.
Development of a placental specimen collection for use in an educational module correlating placental pathology and clinical outcomes (536.1)
Authors: McRae Karalyn , Davies Gregory , Easteal Ronald , Smith Graeme
Published: June 2021

Understanding the anatomy of the placenta is essential in order to identify potential clinical problems during pregnancy. However, it is an organ that is difficult to study without a three‐dimensional appreciation of its structure. The aim of this study was to develop a collection of normal and abnormal plastinated placenta models and accompanying clinical and educational materials to provide information on anatomical abnormalities and their associated pregnancy outcomes. The placentas were plastinated using standard S10 silicone plastination and educational modules were developed, which included clinical information, ultrasound images, photographs and background information on the pregnancy outcomes. The plastinates were evaluated by a questionnaire distributed to undergraduate students at Queen’s University (n=16) and attendees at the 8th Annual Human Placenta Workshop (n=18). Data collected from the questionnaire included 76.5% of respondents rating the usefulness of the specimens an 8 out of 10 or greater and 100% of respondents that wished to have the plastinated placentas available for future learning opportunities. There was a positive response towards the use of plastinates as a supplement to the current methods used in teaching anatomy of the placenta. Plastinates are a valuable addition to teaching resources and students would benefit from the addition of plastinates as learning tools.
Infrequently performed lifesaving procedures utilizing a cadaveric teaching model (536.15)
Authors: Heltzel Sara , Hartka Thomas , Sochor Mark
Published: June 2021

OBJECTIVE: Emergency Medical Technicians & paramedics(course participants) need to execute a number of life‐saving procedures that are infrequently performed. Fresh frozen cadavers(FFC) serve as realistic models on which to teach and practice medical procedures. METHODS: A workshop was developed to train course participants in medical procedures using trainer manikins & FFCs. Two 45‐minute lectures were presented followed by two two‐hour blocks in which participants performed procedures on trainer manikins & on cadavers. Both FFC (un‐embalmed) & soft embalmed (Thiel) cadavers were utilized. Medical procedures included: intubation & endotracheal tube (ETT) placement, tibial/ humeral IO line placement, thoracostomy & chest tube placement, cricothyrotomy, pericardiocentesis, needle decompression, central line placement, & thoracotomy with inspection of chest contents (heart, lungs, great vessels, etc). Participants were asked to complete a questionnaire on a 5‐point Likert scale (1‐poor, 5‐superior). RESULTS: 35 participants have attended this workshop. Overall course evaluation was 4.8. Trainer manikin section was 4.6. Participants gave a superior response to cadaveric workshop (Likert=5). FFCs favored over Thiel for majority of medical procedures performed. CONCLUSION: Cadaveric portion of workshop received highest possible evaluation scores. Participants commented on educational value of training with cadaveric tissue & opportunity to visualize internal anatomical structures. FFC preference over Thiel was likely a result of presence of blood & realistic skin/tissue textures. Thiels provided a more difficult airway for intubation training, allowing course participants to implement airway scoring systems & difficult airway identification techniques. High course evaluations suggest continuation & expansion of future instruction. Future considerations are FFC utilization for surgical technique training. Overall cost for course participant was $515.
Are there misconceptions about the coronary system’s role in heart attacks? A novel and reproducible approach to demonstrate the anatomy of a heart attack (536.8)
Authors: Hakman Eryk , Tanner Kimberly , Nusse Gloria
Published: June 2021

Data collected has shown that misconceptions of the Coronary System’s role in heart attacks exist amongst the undergraduate anatomy students surveyed. Namely demonstrated was a misunderstanding of how the heart receives its own blood for its metabolism. Understanding one of the leading causes of death in the United States, Myocardial Infarction or heart attacks, is a part of the undergraduate anatomy curriculum. While studying the anatomy and physiology of the heart, students may have focused more of their time learning about the larger vessels associated with the circulatory system, with less attention paid to the smaller coronary arteries. The purpose of this study was three‐fold: 1) To assess whether there were any misconceptions about heart attacks such as the misconception that heart attacks are caused by cessation in systemic circulation (Sudden Cardiac Arrest).

2) To design the Coronary Blood Flow Bio Model (CBBM), a reproducible demonstration of the Coronary System, that is easily implemented in any class setting and is inexpensive to produce.

3) To evaluate the efficacy of the CBBM in regards to students’ understanding of the coronary arteries and their role in heart attacks.

Post demonstration assessment suggests that the CBBM demonstration helped clear up misconceptions about heart attacks. The CBBM design allows for a Myocardial Infarction to be simulated by using a cut sponge for the myocardium, wrapped with vinyl tubing to represent the coronary arteries. Using a syringe filled with a red solution and a simple hemostat to simulate an occlusion, students were able to visualize the cessation of perfusion in a coronary artery, leading to cell death, and manifestation as a heart attack.