bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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
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
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.
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.
Alcohol‐induced tight junction dysfunction primes airways for RSV infection (538.1)
Authors: Simet Samantha , Wyatt Todd , Pavlik Jacqueline , Sisson Joseph 
Published: June 2021

Tight junctions form a belt‐like structure between adjacent cells whose degree of permeability changes according to external stimuli, physiological and pathological conditions. We have previously shown that alcohol increases tight junction permeability and disrupts tight junction proteins (ZO‐1 and claudin) in cultured airway epithelial cells through PKCα. It is well established that individuals who consume heavy and prolonged amounts of alcohol are more likely to suffer from pulmonary diseases and infections. Alcohol triggers tight junctions in airway epithelial cells to “leak”, which likely primes the airways for pulmonary infections. Thus, a second injury, such as viral or bacterial infection, is likely intensified by alcohol consumption. To date, very few studies have focused on the combination of alcohol and RSV infection. While both alcohol and RSV have been separately shown to disrupt tight junctions, little research has examined the combination of alcohol and RSV infection on tight junction function.We hypothesize that alcohol primes the airways for RSV infection and exacerbates RSV infection significantly increasing tight junction permeability and airway epithelial injury. Preliminary cell culture data demonstrates that Gö6976, a PKCαinhibitor, and Y27632, a Rho‐associated protein kinase (ROCK) inhibitor, prevent alcohol‐induced tight junction “leak”. In addition, the combination of alcohol exposure and RSV infection increase tight junction permeability considerably more than RSV or alcohol alone. Together our preliminary data suggest that alcohol‐induced tight junction disruption primes the airways for RSV infection.Grant Funding Source: Supported by I01BX000728 (TAW) and R01AA008769 (JHS)
Satellite cell activation and populations on single muscle‐fiber cultures from adult zebrafish (Danio rerio) (539.8)
Authors: Zhang Helia , Anderson Judy 
Published: June 2021

Satellite cell activation and populations on single muscle‐fiber cultures from adult zebrafish (Danio rerio) Helia Zhang and Judy E Anderson, Department of Biological Sciences, University of Manitoba, Canada Satellite‐stem cells in adult mouse skeletal muscle are activated for growth or regeneration by signaling via nitric oxide, hepatocyte growth factor (HGF) and the c‐met receptor. Here, the regulation of satellite cell activation in adult zebrafish was assessed using the model system of isolated fibers cultured at 27°C and 21°C. Satellite cells were identified c‐met+ staining; activation was determined by uptake of bromodeoxyuridine. Satellite cells were maximally activated by the NO‐donor isosorbide dinitrate (ISDN, 1mM) or HGF (10 ng/mL); levels lower and higher respectively, than in mouse fibers. HGF‐induced activation was blocked by anti‐c‐met antibody, and reduced at 21°C. Cyclical stretch (3 hr at 4 cycles per min) increased activation; NOS inhibition and culture at 21°C reduced stretch activation. Stretching rapidly increased the number of c‐met+ cells/fiber (by 3 hr). Satellite cell activation signaling on zebrafish fibers, in particular temperature‐dependent responses to HGF and stretch, give new insights into the influences of ectothermy in regulating muscle growth and suggest the single‐fiber model system can be used to explore the basis of fiber hyperplasia in teleosts.Grant Funding Source: Supported by Natural Sciences and Engineering Research Council
Perineural invasion as an indicator of clinical outcome in vulvar carcinoma (54.2)
Authors: Holthoff Emily , Jeffus Susanne , Stone Rebecca , Gehlot Ashita , Quick Charles , Post Steven 
Published: June 2021

Vulvar squamous cell carcinoma (vSCC) is a disfiguring malignancy that represents 4% of all gynecological cancers. A pathological feature that is commonly used in determining clinical prognosis and treatment is depth of tumor invasion. Perineural invasion (PNI) is another feature that is sometimes noted in pathology reports; however, the relevance of PNI to clinical outcomes in vSCC patients is not well defined. The purpose of this study was to determine the correlation between PNI and relevant clinical parameters including cancer stage and recurrence. 146 cases of vSCC were evaluated for PNI using pathology report review, H&amp;E morphology, and IHC dual‐chromagen staining for S‐100 &amp; AE1/3. Medical records were reviewed for clinical and follow‐up data. Statistical evaluation was performed using chi‐squared and t‐test calculations to correlate PNI with various parameters.Patients with PNI had a 2.7‐fold higher risk of cancer recurrence (p=0.0298). Furthermore, 50% of patients with stage IV carcinoma had tumor‐associated PNI, whereas PNI was associated with <30% of stages I‐III tumors. PNI was also more closely associated with fibromyxoid stromal response (40%) than inflammatory stromal response (18%); however, this correlation was not statistically significant. Neither lymph node involvement nor lymphovascular infiltration was associated with presence of PNI. Interestingly, our data showed no significant correlation between the presence of PNI and depth of tumor invasion suggesting that PNI is an independent prognostic indicator of cancer recurrence. The significant association of PNI with recurrence, independent of tumor depth of invasion, should cause practicing pathologists to thoroughly search for and report its presence in vSCC.
Using zebrafish to identify and characterize gene‐ethanol interactions (540.10)
Authors: Lovely C. , McCarthy Neil , Sidik Alfire , Swartz Mary , Eberhart Johann 
Published: June 2021

Fetal Alcohol Spectrum Disorders (FASD) is a complex set of ethanol‐induced defects with diverse phenotypes, particularly to the face. Though little is known of the genetic predisposition to FASD, this predisposition may help explain variation within FASD. The zebrafish is well suited for identifying and characterizing gene‐ethanol interactions because of its external fertilization, transparency, rapid development and genetic amenability. Across a set of small genetic screens, we have identified gene‐ethanol interactions in the Pdgf, Fgf, Bmp, and Wnt signaling pathways. Synergy is an underlying commonality among these interactions. Ethanol‐induced phenotypes are not predicted on the basis of the untreated mutant phenotype, and ethanol‐induced haploinsufficiency is observed that is not present in the untreated heterozygotes. For instance, a cell migratory defect causes facial defects in untreated pdgfra mutants with no elevation in cell death. Ethanol exposure results in a dramatic increase in cell death leading to facial defects in the majority of heterozygotes. The phenotypic spectrum for each gene‐ethanol interaction is unique, supporting the model that susceptibility loci govern some variation in FASD. Because of the success of our initial screens, we initiated a forward genetic screen to identify novel ethanol‐sensitive mutations. We have recovered and are currently characterizing 8 ethanol‐sensitive mutants. Most of these mutants display no overt phenotype in the absence of ethanol and genetic mapping of one of these places it in a region of the genome not containing a previously characterized mutant. These data demonstrate that zebrafish will be a useful model to identify and characterize gene‐ethanol interactions that may lead to variability in FASD.Grant Funding Source: Supported by ABMRF and NIH