bluuebunny/crossref_metadata_2025_split huggingface dataset:
PAF Expression in Skin Tumors of Smokers and Never Smokers: a Potential Role in Skin Cancer Development
Authors: McHowat Jane , Lozano Juan Carlos , Missall Patricia 
Published: June 2021

Significant progress has been made in the management and understanding of cancer, but there remains a large disparity in cancer health within our population. One of the most well‐known cancer risk factors, cigarette smoking, maintains a disproportionate prevalence in populations distinguished by socioeconomic status, race, and gender. Previous studies have demonstrated that cigarette smoking is associated with changes in phospholipase A2 (PLA2)‐mediated pathways that are implicated in cancer development and progression. More specifically, PLA2 activation leads to increased platelet‐activating factor (PAF) synthesis, a metabolite that is increased in cancer cells. PAF accumulation is further enhanced with cigarette smoke via inhibition of PAF‐acetylhydrolase, the enzyme responsible for PAF hydrolysis and inactivation. Much remains unknown about the biochemical effects of smoking on the development of skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). However, a recent meta‐analysis study demonstrated that cigarette smoking is associated with a 52% increase in the risk for SCC, but does not appear to modify the risk for BCC. In order to assess the effects of cigarette smoking in these two skin cancers, we analyzed PAF expression in skin biopsies from six smokers and non‐smokers with SCC, and six smokers and non‐smokers with BCC. The biopsy samples were immunohistochemically stained with antibodies specific to PAF and PAF‐receptor. Immunohistochemistry revealed positive PAF and PAF‐R expression with nuclear localization in all patient samples, including SCC and adjacent normal sun exposed skin. There was no significant difference between the PAF or PAF‐R expression in samples of smokers when compared to nonsmokers. However, immunohistochemical analysis demonstrated a significant difference in PAF expression between SCC and BCC cells. SCC cells expressed nuclear PAF, but PAF was not detectable in BCC samples. PAF signal was also not detectable in the basal cell epidermal layer in all patient samples. These findings support a biochemical difference in SCC and BCC cells in association with PAF, which is traditionally upregulated with cigarette smoking.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chlorinated lipids mediate small airway epithelial dysfunction
Authors: McHowat Jane , Albert Carolyn , Hartman Celine , Pike Daniel , Ford David 
Published: June 2021

Neutrophil myeloperoxidase is a major mediator of microbicidal activity, catalyzing the conversion of hydrogen peroxide to hypochlorous acid (HOCl), a potent oxidant that reacts with both microbial and host molecular targets. HOCl targets the vinyl ether bond of plasmalogen lipids, resulting in the production of 2‐chlorofatty aldehyde, which is in turn metabolized to 2‐chlorofatty acid (2‐ClFA). Recently, we have shown that free 2‐ClFA levels are significantly associated with acute respiratory distress syndrome (ARDS) in sepsis patients. Lung endothelial cells treated with 2‐ClFA showed increased permeability, surface expression of adhesion molecules, and neutrophil and platelet adherence. These data indicate that plasma 2‐ClFA is a predictor for ARDS, likely through effects on the lung microvasculature. In this study, we determined the effect of 2‐ClFA on human small airways epithelial cell (SAEC) function. Incubation of SAEC with 2‐ClFA (100 nM‐10 μM, up to 24 hours) resulted in a concentration‐ and time‐dependent decrease in electrical resistance, with no change in resistance noted when SAEC were incubated with non‐chlorinated fatty acid (FA). Our recently published studies published recently by us show that 2‐ClFA (1 μM) treatment of lung microvascular endothelial cells resulted in a 2‐fold increase in cell surface expression of intercellular adhesion molecule 1 (ICAM‐1) and a 1.7‐fold increase in vascular cell adhesion molecule 1 (VCAM‐1) after a 4‐hour incubation. We now show that incubation with 2‐ClFA for 4 hours resulted in a 3.3‐fold increase in cell surface expression of ICAM‐1 and a 4.4‐fold increase of VCAM‐1 in SAEC. No increase in adhesion molecules was observed with FA incubation. 2‐ClFA treatment resulted in neutrophil adherence to SAEC and enhanced transmigration across the SAEC monolayer after 2‐ClFA treatment. Neutrophil transmigration across SAEC was 3‐fold greater in a basolateral‐to‐apical direction when compared to apical‐to‐basolateral. Taken together, these data suggest that 2‐ClFA mediates small airways epithelial dysfunction and neutrophil transmigration that may contribute to fluid accumulation and inflammation observed in ARDS patients.Support or Funding InformationNIH R01 GM115553 (to D.A.F. and J.M.)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Pak2 promotes ER‐dependent cardioprotection
Authors: Binder Pablo , Wang Shunyao , Zi Min , Collins Lucy , Liu Wei , Wang Xin 
Published: June 2021

Heart failure is a devastating condition affecting millions of people globally with a rising prevalence due to an expansion of the ageing population and epidemics of obesity, diabetes and hypertension. Despite numerous causative factors, the majority of heart failure cases are the consequence of massive cardiomyocyte loss. As cardiomyocytes hold very little potential in replication, exquisite regulation of cellular homeostasis and integrity reliant on protein quality control is crucial for cardiomyocyte survival and function, particularly under stress. A major site of protein quality control is the endoplasmic reticulum (ER). The endoplasmic reticulum is the site for synthesis and folding of secreted and membrane‐bound proteins, which account for 1/3 of total proteins. Loss of ER homeostasis and function culminates in a greater risk of cardiomyocyte death and it has been shown that detrimental ER stress underlies the pathogenesis of many forms of heart disease.With the aim to uncover novel ER stress regulation mechanisms, we examined the expression pattern of p21activated kinase 2 (Pak2) in cardiomyocytes and myocardium across species. We investigated its role in cardioprotection using Pak2 cardiac deleted mice (Pak2‐CKO) under ER stress conditions. Molecular elucidation unveiled a new mechanism by which Pak2 promoted the protective ER stress response. The translational relevance of this protective mechanism was evaluated in human induced pluripotent stem cells‐derived cardiomyocytes (iPSC‐CMs), and the therapeutic potential was explored by inducing Pak2 activation using a genetic approach or AAV9‐based gene delivery.We found that Pak2 was an ER‐resident stress‐responsive kinase in cardiomyocytes, and showed that Pak2‐CKO mice under stress manifested defective ER response, cardiac dysfunction and profound cell death. Pak2 loss‐induced cardiac damage was an ER‐dependent event. Mechanistic studies in rat cardiomyocytes and human iPSC‐CMs, revealed that Pak2 regulation of protective ER function was via the IRE1/XBP1s‐dependent pathway. Therapeutically, Pak2 activation was capable of strengthening ER function, improving cardiac performance and diminishing apoptosis, thus protecting the heart from failure. Our findings reveal a novel ER‐centered cardioprotective mechanism, which promotes the protective ER stress response via modulation of Pak2; this novel therapeutic strategy may be used to treat cardiac disease and heart failure.Support or Funding InformationThis research project was supported by the British Heart FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Policing Cell‐Cell Connections: A Novel Role for the COP9 Signalosome in Mechanisms Underlying Arrhythmogenic Heart Disease and Sudden Death
Authors: Sheikh Farah , Liang Yan , Lyon Robert , Pellman Jason , Mezzano Valeria , Gu Yusu , Dalton Nancy , Lee Mong‐Hong , Iwakuma Tomoo , Nigam Vishal , Peterson Kirk 
Published: June 2021

Arrhythmogenic right ventricular cardiomyopathy is a genetic based cardiomyopathy, characterized by ventricular dysfunction, fibrofatty replacement of the ventricle and ventricular arrhythmias leading to sudden cardiac death in young people. ARVC is termed a “disease of the desmosome”; however, limited information exists on how desmosomal protein dysregulation/loss triggers ARVC. To identify novel protein targets that impact desmosomal biology and the desmosomal disease, ARVC, we performed a yeast two hybrid screen using the desmosomal gene, desmoplakin (DSP) as bait to screen an adult human heart cDNA library. We identified CSN6, subunit 6 of the COP9 signalosome, as a novel cardiac desmosomal interacting protein (via desmoplakin, DSP). Traditional functions of the CSN complex (composed of subunits 1–8) are to inhibit protein degradation by “turning off” ubiquitinatin‐mediated protein degradation via deneddlylation; however, the role of CSN6 in the heart is undefined. We show that CSN6 uniquely protects the cardiac desmosome and its loss accelerates desmosome destruction as (i) CSN6 co‐localizes to desmosomal junctions, (ii) CSN6 co‐immunoprecipitates with desmosomal proteins and (iii) hearts from novel cardiac‐specific CSN6 knockout (CSN6‐cKO) mice display selective loss of desmosomal protein levels (and its primary target, connexin43). CSN6 loss is a trigger for ARVC as CSN6‐cKO mice exhibit sudden death and cardiac disease features associated with a biventricular form of ARVC, similar to our cardiac‐specific DSP knockout mice (DSP‐cKO) that is a classic biventricular model of ARVC. CSN6 and DSP‐cKO hearts both selectively display underlying hyper‐accumulation of protein degradation machinery at the cell junction, specifically linking CSN6 pathways to the desmosome. CSN6 pathways are relevant to human ARVC as (i) CSN6 levels are down‐regulated in ARVC hiPSC‐derived cardiac cells that exhibit striking desmosomal defects and arrhythmogenic behavior and (ii) CSN6 localization is lost from cell junctions in a cardiac biopsy from an ARVC patient harboring desmosomal (DSP (R315C) and plakophilin‐2 (PKP2 IVS10‐1 G>C) mutations. Yeast and in silico modeling assays reveal that this DSP R315C mutation is sufficient to abrogate DSP binding to CSN6. We highlight the importance of CSN6 at the cardiac desmosome in maintaining desmosomal protein turnover (“desmophagy”), and suggest that loss of CSN6 and desmosomal protein turnover as new underlying mechanisms driving ARVC and sudden death.Support or Funding InformationF.S. is supported by grants from National Institutes of Health (NHLBI), American Heart Association and Tobacco Related Disease Research Program.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 Role of Neuropeptides in Peripheral Taste Signaling
Authors: Huang Anthony Y. , Wu Sandy Y. 
Published: June 2021

Chemesthesis, the general chemical sensitivity of the skin and mucus membranes in the oronasal cavities and being perceived as pungency, irritation or heat, impacts taste responsiveness. The modulation of taste nerve responses is thought to be produced indirectly, via stimulation of peripheral sensory nerve terminals that have ability to release stored transmitters, e.g., calcitonin gene‐related peptide (CGRP) and substance P (SP), onto taste cells implying playing a role in gustatory signaling, by the functions of somatosensory neurons. The underlying assumption has been that neuropeptides exert their effects on taste transmitter secretion in taste buds of mice, a well‐accepted model for studying taste bud functions, as theoretically may relate to the processing of the gustatory information. Indeed, CGRP shapes peripheral taste signals via serotonergic signaling. In this study, using a combination of Ca2+ imaging with cellular biosensors – genetically‐engineered Chinese Hamster Ovary (CHO) cells, transgenic mice expressing green fluorescent protein (GFP) in the specific taste cell type and immunostaining, we showed that the net effect of SP reduced taste‐evoked ATP secretion from mouse taste buds. Specifically, SP elicited phospholipase C (PLC) activation‐dependent intracellular Ca2+ transients in taste cells via neurokinin 1 (NK1) receptors, most likely on glutamate‐aspartate transporter (GLAST)‐expressing Type I cells. Recently, γ‐aminobutyric acid (GABA) as well as the associated synthetic enzyme have been identified in Type I cells. Consequently, Type I cells secrete GABA in respond to SP. Combined with the recent findings that GABA provides negative paracrine feedback onto Receptor (Type II) cells by activating GABAA and/or GABAB receptors and reducing taste‐evoked ATP secretion, our results showed that taste‐evoked ATP secretion from intact taste buds, which remain cell‐cell communication intact, was reduced when SP was co‐applied with taste stimuli in the bath medium. We conclude that SP plays a role as an inhibitory transmitter that shapes peripheral taste signals via GABAergic signaling during processing gustatory information in taste buds. This seemingly tangled complex represents a new concept of taste signaling and that neuropeptides released from afferent sensory terminals play a regulatory role in processing taste signals.Support or Funding InformationAAA Fellows Grant Award Program Research Seed Grant to AYH (AAA‐3419).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hair Follicle‐derived Neural Crest Stem Cells (HF‐NCSCs) as a Cell Source of Enteric Neurons
Authors: Wang Zitian , ZHAO Hui , LEE Tin Lap , RUDD John , CHAN Wood Yee 
Published: June 2021

The enteric nervous system (ENS), which regulates most of the gastrointestinal functions, is derived from neural crest cells during early embryonic development. Abnormal migration and differentiation of neural crest cells may cause defective formation of the ENS, thus leading to enteric aganglionosis (absence of ganglia consisting of neurons and glial cells) in the distal colon. In the present study, we aimed to regenerate enteric neurons by transplanting hair follicle‐derived neural crest stem cells (HF‐NCSCs) to the aganglionic distal colon. We first isolated hair follicle bulges from the vibrissa whisker pad of mice, and cultured the bulges for 3 to 4 days. After HF‐NCSCs migrated onto the culture surface, the bulges were removed, and HF‐NCSCs were cultured in an expansion medium for another week. HF‐NCSCs were found to be able to differentiate into myocytes, neurons and glial cells in different differentiation media. Ten days after they were transplanted to the hindgut explants isolated from E13.5 mouse embryos, the transplanted HF‐NCSCs spread along the gut explant cultured ex vivo and differentiated into neurons. Immunostaining of the serial cross sections indicated most of the transplanted cells were located in the myenteric plexus between two muscle layers. HF‐NCSCs were also transplanted to the descending colon of an adult mouse in vivo after laparotomy. One week later, the cells spread along the colon and differentiate into Tuj1 and PGP9.5 immunoreactive cells. Ten days after transplantation in vivo, subtype inhibitory neurons immunoreactive to nNOS were found among the transplanted cells, and a small number of transplanted cells differentiated into excitatory neurons immunoreactive to ChAT. Additionally, almost all the transplanted cells were found in the myenteric plexus which is also the normal location of endogenous enteric neurons between the longitudinal muscle and circular muscle layers 6 days after transplantation. These results showed that (1) enough HF‐NCSCs were obtained for cell transplantation from a small number of skin hair follicles, and (2) HF‐NCSCs from hair follicles could serve as a cell source for stem cell‐based therapy. This work also gives insights into the feasibility of using autologous cell transplantation with a less invasive hair follicle isolation method on patients with ENS defects in the colon.Support or Funding InformationThe work was supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No.: 14175017).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Initiation, targeting and sculpting of the phagophore
Authors: Hurley James H. 
Published: June 2021

Autophagy is a conserved mechanism that is essential for cell survival in starvation and for cellular homeostasis. The autophagosome and the proteasome comprise the two main pathways for the degradation of proteins. Autophagy proceeds by the engulfment of bulk cytosol and organelles by a cup‐shaped double membrane sheet known as the phagophore, which matures into the autophagosome. Two protein complexes control the initiation of the phagophore: the Atg1/ULK1 kinase complex and the class III phosphatidylinositol 3‐kinase complex I (PI3KC3‐C1). Our laboratory has been applying crystallography, electron microscopy, mass spectrometry, and allied biophysical techniques, in conjunction with cell biology approaches, to understand how these complexes are organized in three dimensional space and time, and how their architectures underpin their regulation and activity.Support or Funding InformationNIGMS R01 111730 and P01 051487This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Discovery and Engineering of Plant Chemistry for Plant and Human Health
Authors: Sattely Elizabeth 
Published: June 2021

Plants are some of the best chemists on the planet and produce an impressive array of small molecules. We are inspired by the fact that humans have become extraordinarily reliant on plant‐derived molecules for food, medicine, and energy. However, remarkably little is known about how plants make these molecules, limiting our ability to engineer and optimize plant metabolic pathways. New plant genome sequences and synthetic biology tools have opened the door to three transformative research areas under investigation in my lab: 1) Identifying the minimum set of enzymes required to make known plant‐derived molecules and non‐natural derivatives through metabolic engineering, and 2) discovering new molecules from plants, and 3) developing new strategies to enhance plant fitness. In this talk, I will describe some of our recent efforts to accelerate the discovery of complete plant pathways for known and novel molecules, not only in the model plant Arabidopsis but also in non‐model plants.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Structure and Signaling Mechanisms of G Protein‐Coupled and b‐Arrestin‐Biased Chemokine Receptors
Authors: Handel Tracy , Gustavsson Martin , Zheng Yi , Stephens Bryan , Baker Genevieve , Ngo Tony , Holden Lauren , Stevens Ray , Cherezov Vadim , Abagyan Ruben , Kufareva Irina 
Published: June 2021

Most chemokine receptors are G Protein‐Coupled Receptors (GPCRs), and are best known for their role in controlling cell migration in the context of immune system function. They are also implicated in many diseases particularly inflammatory diseases as well as cancer and HIV, making them important therapeutic targets. Recent structurally and biophysical studies have revealed that the recognition interface between chemokines and receptors is very large and characterized by more complex epitopes than previously believed. In this presentation, our current understanding of how chemokines bind and activate their receptors will be described, as well mechanisms for inhibiting chemokine receptor signaling with orthosteric and allosteric ligands. Common and unique features of G protein‐coupled versus b‐arrestin‐biased receptors will also be described, focusing on CXCR4 (a GPCR) and the b‐arrestin‐biased, atypical chemokine receptor 3 (ACKR3) both of which respond to the chemokine CXCL12.Support or Funding InformationFunded by NIH grants R01 GM117424 and R01 AI118985This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The PAX‐5 transcript is submitted to 3'UTR editing which regulates its oncogenic expression in cancer cells
Authors: Robichaud Gilles A. , Beauregard Annie‐Pier , Guerrette Roxann , Crapoulet Nicolas , Finn Nicolas , St‐Hilaire Ève 
Published: June 2021

The Pax‐5 oncogene is a major factor in various cancer lesions such as hematopoietic cancers. Recently, we have also shown that Pax‐5 regulates breast cancer phenotypic transitioning processes (EMT‐MET) leading to the regulation of cancer cell malignancy. To date, the aberrant expression of Pax‐5 in cancer cells is still unknown. Our team has thus turned its attention to the post‐transcriptional regulation of Pax‐5 expression by important regulatory elements such as miRNAs and alternative polyadenylation (APA). Upon our analysis of the Pax‐5 transcript in Pax‐5 bearing cells (breast epithelia and B lymphocytes), we found that not only is the 3'UTR submitted to APA; but also, alternative splicing of the Pax‐5 mRNA 3'UTR. Interestingly, upon rapid amplification of cDNA ends (3'RACE) from polysomal fractions, we found that Pax‐5 3'UTR shortening correlates with increased translation frequency. These observations were also validated using reporter gene assays where various truncated 3'UTRs cloned downstream of a luciferase gene resulted in differentially translational expression. More importantly, we also found that Pax‐5 transcripts characterized with shorter 3'UTRs were also associated with advanced staging of hematopoietic cancer lesions. Our findings identify novel molecular mechanisms, which account for Pax‐5 aberrant expression and function in cancer cells. These findings will further elucidate Pax‐5‐mediated cancer processes and may provide new avenues for therapeutic intervention.Support or Funding InformationThis work was supported by grants from the New Brunswick (NB) Innovation Foundation, the Canadian Breast Cancer Foundation, the Canadian Breast Cancer Society/QEII Foundation, the NB Health Research Foundation and by the Beatrice Hunter Cancer Research InstituteThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.