bluuebunny/crossref_metadata_2025_split huggingface dataset:
N‐Cadherin Juxtacrine Signaling Maintains Blood Brain Barrier and Cognitive Function
Authors: Lee Quinn S. , Kruse Kevin N. , Marottoli Felecia M. , Thomas Riya , Sun Ying , Tai Leon M. , Komarova Yulia A. 
Published: June 2021

The blood brain barrier (BBB) consists of a specialized microvasculature with highly restricted permeability to both low and high molecular weight proteins. The BBB plays a critical role in maintaining tissue‐fluid homeostasis and preventing blood‐to‐brain paracellular diffusion of plasma components that can cause neuronal dysfunction. The BBB is composed of brain endothelial cells (BEC), which physically interact with pericytes at the basement membrane. BECs and pericytes express N‐cadherin, which forms homophilic adhesions to establish cross‐communications between these cell types. The role of N‐cadherin in the BBB is not well understood. We have demonstrated that an endothelial specific deletion of N‐cadherin gene (Cdh2) in mice resulted in increased permeability of the BBB in a size dependent manner, suggesting that N‐cadherin juxtacrine signaling in endothelial cells restricts BBB permeability. These changes in the BBB permeability were not associated with pericyte loss since we observed an increase in capillary coverage by pericytes in the cerebral cortex in these mice. To gain a holistic picture of N‐cadherin juxtacrine signaling in maintenance of the BBB, we utilized N‐cadherin biomimetic surfaces to induce signaling in a cell culture model. We found that Trio, a Rho guanine nucleotide exchange factor consisting of two GEFs, is recruited to N‐cadherin adhesions to induce Rac1 signaling through activation of GEF1. Genetic studies in humans provide a causal link between a deficiency of Trio GEF1 activity and neurodevelopmental diseases such as intellectual disability, suggesting that increased vascular leakage and associated neurotoxicity impairs cognitive function. Therefore, we tested whether N‐cadherin deficient mice exhibited cognitive deficit. Using the Morris water navigation task, we demonstrated that loss of N‐cadherin in endothelial cells results in a deficit in spatial learning and memory. This difference to control mice became indistinguishable with age, suggesting that deficiency of N‐cadherin juxtacrine signaling may be an underlying cause for cognitive dysfunction in the elderly population. Hence, mice lacking Cdh2 gene in endothelial cells may serve as an animal model to study vascular leakage and cognitive function in aging.Support or Funding InformationNIH T32 HL027829, NIH R01 HL103922This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mutations in the PH Domain of SH2B1 Result in Energy Imbalance and/or Impaired Glucose Metabolism
Authors: Flores Anabel , DeSantis Lauren C. , Malaga Alvaro , Clutter Erik S. , Argetsinger Lawrence S. , Myers Martin G. , Carter‐Su Christin 
Published: June 2021

Mutations in the scaffold protein SH2B1 have been identified in individuals with severe early‐onset childhood obesity, insulin resistance, and hyperphagia. This phenotype is mirrored in mice lacking SH2B1 (SH2B1‐KO mice). Three of these mutations, including the P322S mutation, are located in the pleckstrin homology (PH) domain of SH2B1, suggesting that the PH domain is important for the overall function of SH2B1. To gain insight into how SH2B1 regulates energy balance and the function of the PH domain in SH2B1, we used CRISPR‐Cas9 to make a mouse model containing the human P322S obesity‐associated mutation. We also obtained a mouse with an indel that produced a two‐amino acid deletion (ΔP317, R318) in the PH domain. Body weight, food intake, glucose tolerance and insulin tolerance do not appear to be substantially altered by the P322S mutation when mice are fed normal chow (9% fat). However, when the mice were challenged by a high fat (60%) diet, the P322S mutation decreased glucose tolerance. No effect on insulin tolerance was noted. The results with the P322S mouse suggest that the P322S mutation does not have as profound an effect on energy balance as the P322S mutation in humans. However, the decreased glucose tolerance in the absence of insulin sensitivity seen in the P322S mice versus WT control littermates challenged with a high fat diet raises the possibility that the P322S mutation impairs the function of SH2B1 in beta cells and/or liver. While the P322S mutation does not have a profound effect on energy balance, the P322S mutation negatively impacts the survival of SH2B1 P322S homozygote mice. Homozygotes are born at half the expected Mendelian ratio, suggesting that SH2B1 may play a role in the implantation of the fetus and/or development of the pups in the womb. Similar to the SH2B1‐KO mice, the ΔP317, R318 mice show increased body weight, decreased glucose tolerance, decreased insulin sensitivity, and increased adiposity. Surprisingly, the ΔP317, R318 mice do not show increased food intake, suggesting that their increased body weight is due to decreased energy expenditure. These two mouse models emphasize the importance of SH2B1, and in particular, the PH domain of SH2B1, in regulating energy balance and glucose homeostasis.Support or Funding InformationHoward Hughes Medical Institute Gilliam Fellowship, NIH T32‐GM008322, NIH RO1‐DK54222, NIH RO1‐DK107730, Univ of Michigan Rackham Merit FellowshipThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A comparison of liquid vinegar and commercial vinegar pills for managing insulin resistance and postprandial glucose concentrations
Authors: Johnston Carol S. , Feise Natasha 
Published: June 2021

A recent meta‐analysis concluded that vinegar consumption could be considered effective adjunct therapy for improving glycemic control. However, liquid vinegar consumption is often poorly tolerated and ingestion can invoke nausea. These investigations examined the effect of liquid vinegar versus commercial vinegar pills on insulin resistance and postprandial glycemia in healthy adults. These trials were approved by the university IRB, and all participants provided written consent. All participants were healthy (fasting glucose concentrations averaging 91–94 mg/dl). An 8‐week, parallel arm, randomized controlled trial examined the efficacy of liquid vinegar ingestion (2 Tbsp. red wine vinegar twice daily with meals [3.6 g acetic acid]) versus vinegar pill ingestion (2 vinegar tablets daily with meals [0.045 g acetic acid]) on HOMA‐IR. Eleven participants (28.6±7.0 y; 29.3±4.4 kg/m2) and twelve participants (28.0±7.7 y; 28.2±5.9 kg/m2) completed the trial in the liquid and pill groups respectively. After 8 weeks, insulin resistance was reduced 12% in the liquid vinegar group as compared to a 7% rise the pill group (change in HOMA‐IR scores: −0.66±1.3 vs. +0.31±1.1; p=0.079). A crossover trial (n=12) examined the efficacy of liquid vinegar ingestion (25 g apple cider vinegar [1.25 g acetic acid]) versus vinegar pill ingestion (4 vinegar tablets [0.70 g acetic acid] either consumed whole or crushed and dissolved in water) on postprandial glycemia. At 30 minutes following meal ingestion (buttered bagel + juice; 106 g carbohydrate), blood glucose concentrations at 30 minutes post‐meal were reduced 12% in comparison to the pill group or to a no vinegar control (135.6±15.8, 154.3±22.2, 152.7±30.6, and 157.7±22.8 mg/dl for the liquid vinegar, whole pill, crushed pill, and control groups respectively; p=0.023). These data suggest that in healthy adults, commercial vinegar pills with acetic acid content ranging from 45–700 mg acetic acid per serving are not effective for improving glycemic control.Support or Funding InformationThis work was supported by the Barrett Honors College, Arizona State University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exogenous ketones lower blood glucose level
Authors: Ari Csilla , Kovacs Zsolt , Murdun Cem , Koutnik Andrew P. , Goldhagen Craig R. , Rogers Christopher , Park Collin , Bharwani Sahil , Diamond David M. , D'Agostino Dominic P. 
Published: June 2021

Certain disease conditions, involving inflammation and oxidative stress, are accelerated by high blood glucose levels. The safe reduction of blood glucose levels is difficult due to their regulation by powerful homeostatic mechanisms. The ketogenic diet (KD) induces a metabolic shift towards fatty acid oxidation and hepatic ketogenesis, elevating the ketone bodies acetoacetate (AcAc), β‐hydroxybutyrate (βHB), and acetone in the blood, which serve as alternative metabolic substrates to glucose. However, patient compliance to KD can be low; therefore, exogenous ketones provide an alternative method to establish and maintain elevated blood ketone levels. In this study, we tested the changes in blood glucose and ketone (βHB) levels in response to acute, sub‐chronic and chronic administration of one or more ketogenic compounds in either a post‐exercise or rested state. Rodent models with (WAG/Rij rats, WR and GLUT1Deficiency Syndrome mice, GLUT1D) and without (Sprague Dawley rats, SPD) pathology were tested. Experimental groups included either KD, standard diet with water (control, C) or in combination with the following ketogenic compounds: 1,3 butanediol (BD), beta hydroxybutyrate ketone mineral salt (KS), KS with medium chain triglyceride (KSMCT), BD acetoacetate diester (KE), KE with MCT (KEMCT), and KE with KS (KEKS).In SPD rats without exercise, KD, KS, KE and KSMCT significantly reduced blood glucose levels, compared to control. After exercise blood glucose was significantly lower in the KEMCT group, compared to control. In WR rats KE, KS, KSMCT, KEKS and KEMCT groups had lower blood glucose than control, in both a rested or post‐exercise state. In GLUT1D mice without exercise, KD and KS resulted in significantly lower glucose levels. These results indicate that ketogenic compounds were efficacious in reducing blood glucose levels in and outside the context of exercise.Support or Funding InformationUniversity of South Florida Foundation, GLUT1 Deficiency Syndrome Foundation, National Development Agency of HungaryThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Leucine improves markers energy metabolism in C2C12 myotubes treated with palmitate
Authors: Wu Hexirui , Dridi Sami , Baum Jamie I. 
Published: June 2021

More than one‐third of adults and 17% of children in the United States are classified as obese. One contributor to the development of obesity is an increase energy intake accompanied by a decrease energy expenditure. Muscle plays an important role in energy utilization and production in human body. Excessive fat mass accumulation in muscle blunts energy production such as fatty acid oxidation. The objectives of this study were to: 1) determine if the branched‐chain amino acid leucine lowers intracellular fatty acid uptake, and 2) determine if mitochondria are involved in the leucine‐mediated effect on fatty acid uptake. C2C12 myotubes were used as a cell model for muscle. Cells were treated with palmitate for 24 hours in order create an obesogenic muscle model. All cells were serum and leucine starved for 24 hours before receiving one of the following four treatments: control (CON), palmitate (PALM, palmitate treated for 24h), palmitate + 0.5mM leucine (PALM+0.5mM LEU,, palmitate and 0.5mM leucine co‐treated for 24h), palmitate + 1.5mM leucine (PALM+1.5mM LEU,, palmitate and 1.5mM leucine co‐treated for 24h). Intracellular lipid deposition was measured using oil red o staining kit and quantified using ImageJ software. Both doses of leucine showed significant effect (p<0.05) on lowering the intake of intracellular lipid uptake in PALM treated cells. Real‐time PCR results showed higher (p<0.05) expression of uncoupling proteins (UCP2 and UCP3), which are involved in ATP synthesis, in both leucine treatment groups compared with PALM. There was no significant difference in gene expression of NRF1, SIRT1, Tfam, PPARγ and ANT1, all involved in mitochondria DNA transcription. In conclusion, these data suggest leucine promotes energy metabolism through regulating uncoupling protein in mitochondria in C2C12 myotubes, indicating a possible target for improving obesity.Support or Funding InformationArkansas Biosciences InstituteThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Discovering drug resistance‐associated biomarkers from malignant pleural effusion of lung cancer by quantitative proteomic approaches
Authors: Yu Chia‐Jung , Chiou Ien‐Chiuam , Wang Chih‐Liang , Hsiao Ting‐Feng 
Published: June 2021

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) have been approved for the treatment of patients with advanced lung adenocarcinoma (ADC) harboring EGFR activating mutations. Although the EGFR‐TKIs or combined treatments of EGFR‐TKIs and chemotherapy would benefit patients, the following drug‐resistant issue eventually led to the poor survival of cancer patients. Therefore, it is important to search the drug resistance‐associated biomarkers for monitoring the treatment efficacy and/or prognosis in lung ADC. We herein applied high‐abundant protein removal system and iTRAQ‐based quantitative proteomics approach to generate the drug resistance‐associated malignant pleural effusion (MPE) proteome data sets from lung ADC patients who were sensitive, resistant to TKI, or resistant to TKI/chemotherapy. Among the 565 quantified MPE proteins, five potential biomarkers (CEACAM5, DMBT1, HGFAC, MMP3, CDHP) were isolated for preclinical validation using ELISA. The MPE levels of these five candidates were increased in patients with drug‐resistant as compared to patients with treatment naïve. Importantly, the levels of MMP3 and CDHP in serum samples were significantly associated with patients' survival and treatment efficacy. Our results collectively provide the potential biomarkers for prediction of drug resistance as well as prognosis in lung ADC.Support or Funding InformationThis work was financially supported by grants from the Ministry of Science and Technology, Taiwan (104‐2320‐B‐182‐027 and 105‐2320‐B‐182‐035‐MY3), and from Chang Gung Memorial Hospital, Taoyuan, Taiwan (BMRP894).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
p53 mediated regulation of Coactivator associated arginine methyltransferase 1 (CARM1) expression is critical for suppression of adipogenesis
Authors: Behera Amit Kumar , Bhattacharya Aditya , Vasudevan Madavan , Kundu Tapas Kumar 
Published: June 2021

Coactivator associated arginine methyltransferase 1 (CARM1/PRMT4) is a type I arginine methyltransferase that mediates transcriptional activation via methylation of histone H3 on R17, R26 and R42. CARM1 acts as a coactivator of transcription of various transcription factors such as NF‐kB, MEF2C, β‐catenin, p53, PPAR‐gamma etc. CARM1 has been functionally implicated in maintenance of pluripotency, cellular differentiation and tumorigenesis; where its expression status plays an important role. Although its expression has been shown to be regulated by a few miRNAs in different contexts at post‐transcriptional level, transcriptional regulation of CARM1 gene is still unexplored. In the present study we demonstrate that CARM1 is a p53 responsive gene, where p53 could suppress CARM1 promoter driven luciferase expression. CARM1 gene expression was found to be repressed by p53 in 3T3L1 preadipocytes when activated with Nutlin‐3a treatment. Ectopic overexpression of CARM1 could rescue inhibitory effect of p53 on adipogenesis, suggesting a role of p53‐CARM1 axis of regulation operational in the context of adipocyte differentiation. p53 and CARM1 showed antagonistic regulatory influence on PPAR‐gamma expression; which suggests that p53 mediated suppression of adipogenesis could be partly via repression of CARM1 expression. Taken together these observations provide convincing mechanistic explanation for p53 function in the context of adipocyte differentiation process.Support or Funding InformationTKK is recipient of JC Bose fellowship from Dept. of Science and technology, Govt. of India (SR/S2/JCB‐28/2010). AKB is a research associate of JNCASR. AB is a senior research fellow of UGC, India. This work was supported by funding from Dept. of Biotchnology, Govt. of India (BT/01/CEIB/10/III/01) and JNCASR, India.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The receptor tyrosine kinases Tyro3 and Axl are co‐regulated and activate discrete signaling pathways for cancer cell proliferation and invasion respectively
Authors: Hafizi Sassan , Al Kafri Nour , Vouri Mikaella 
Published: June 2021

The TAM (Tyro3, Axl, Mer) subfamily of receptor tyrosine kinases (RTKs) have been implicated in tumor growth and spread in several different cancers, with Axl in particular being shown to regulate cell invasion as well as resistance to other targeted therapies such as EGFR blockade. However, little is known about Tyro3, which although having a more restricted tissue pattern, is also found overexpressed in several solid cancers. The aim of this study is to elucidate the specific signaling pathways emanating from Tyro3 activation in cancer cells. In addition to signaling via homodimeric activation of RTKs, diversity in signaling may be achieved by cross‐talk amongst different RTKs via e.g. heterodimerization. Therefore, a further aim is to identify such novel, unconventional activation mechanisms for the TAMs in cancer cells.A range of human cancer cell lines that overexpress specific TAM RTKs were cultured for this study. Western blot was used to detect protein expression and phosphorylation. The TAM ligand Gas6 rapidly stimulated Axl phosphorylation within minutes but did not alter Tyro3 phosphorylation. Conversely, the related TAM ligand ProS1 rapidly stimulated Tyro3 phosphorylation but with no effect on Axl. Incubation of cells with the Axl‐selective small molecule inhibitor BGB324 led to a blockade of not only basal Axl activity, but also Tyro3 phosphorylation, suggesting that Tyro3 may be activated through a heterodimeric interaction with Axl. This interaction was confirmed by coimmunoprecipitation of Axl‐Tyro3 complexes from cell lysates, which was further strengthened by Gas6 stimulation. In addition, we found that Tyro3 protein stability was dependent on Axl co‐expression, as Axl siRNA knockdown reduced presence of cellular Tyro3 protein but not its mRNA. This suggests the Axl‐Tyro3 heterodimerization stabilizes Tyro3 presence at the cell surface. Furthermore, siRNA knockdown of Tyro3 in cells revealed that Tyro3 functions as a mediator of signaling for cell survival and cell cycle progression through regulation of cyclin D1 – a role distinct from the known proinvasion role of Axl.Based on these findings, we propose that Tyro3 may be a driver of tumor persistence and chemoresistance through association with Axl and potentially other RTKs. Our current work is further revealing the divergence of downstream signaling pathways to emanate from TAM RTKs activated in different ways, and how these regulate the major cellular behaviors during tumor progression and spread.Support or Funding InformationThis research is funded by the University of Portsmouth and by the Council for At‐Risk Academics (Cara).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reconstitution of RNA polymerase I Upstream Activating Factor and the roles of histones H3 and H4 in complex assembly
Authors: Knutson Bruce A , Smith Marissa L , Cui Weidong , Jackobel Ashleigh J , Walker‐Kopp Nancy A 
Published: June 2021

RNA polymerase I (Pol I) transcription in Saccharomyces cerevisiae requires four separate factors that recruit Pol I to the promoter to form a pre‐initiation complex (PIC). Upstream Activating Factor (UAF) is one of two multi‐subunit complexes that regulate PIC formation by binding to the ribosomal DNA promoter and by stimulating recruitment of downstream Pol I factors. UAF is composed of Rrn9, Rrn5, Rrn10, Uaf30, and histones H3 and H4. We developed a recombinant E. coli based system to coexpress and purify transcriptionally active UAF complex and to investigate the importance of each subunit in complex formation. We found that no single subunit is required for UAF assembly, including histones H3 and H4. We also demonstrate that histone H3 is able to interact with each UAF‐specific subunit, and show that there are at least two copies of histone H3 and one copy of H4 present in the complex. Together, our results provide a new model suggesting that UAF contains a hybrid H3‐ H4 tetramer‐like subcomplex.Support or Funding InformationThe work was supported by B.A.K. grants from the US National Institutes of Health (NIH) NCI (5K22CA184235), a Sinsheimer Scholar award from the Alexandrine and Alexander L. Sinsheimer Fund, Central New York Community Foundation, Joseph C. George Fund, and Virginia Simons & Dr. C. Adele Brown Fund. Native MS measurements were financed by the NIH NIGMS (P41 GM103422).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Who perceives they're smarter? Exploring the influence of student characteristics on student academic self‐concept in physiology
Authors: Brownell Sara , Cooper Katelyn , Krieg Anna 
Published: June 2021

Academic self‐concept is one's perception of his or her ability in an academic domain and is formed by comparing oneself to other students. As college biology classrooms transition from lecturing to active learning, students interact more with each other and are likely comparing themselves more to other students in the class. Student characteristics can impact students' academic self‐concept, however this has been unexplored in the context of undergraduate biology. In this study, we explored whether student characteristics can affect academic self‐concept in the context of an active‐learning college physiology course. Using a survey, students self‐reported how smart they perceived themselves in the context of physiology relative to the whole class and relative to their groupmate‐ the student they worked most closely with in class. Using linear regression, we found that males and native English speakers had significantly higher academic self‐concept relative to the whole class compared with females and non‐native English speakers. Using logistic regression, we found that males had significantly higher academic self‐concept relative to their groupmate compared with females. Using constant comparison methods, we identified nine factors that students reported influenced how they determined whether they are more or less smart than their groupmate. Finally, we found that students were more likely to report participating more than their groupmate if they had a higher academic self‐concept. These findings suggest that student characteristics can influence students' academic self‐concept, which in turn may influence their participation in small group discussion and their academic achievement in active learning classes.Support or Funding InformationNONEThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.