bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of Concanavalin A‐induced mediators of hepatocyte damage in hepatic stellate cells: A dual role of interferon regulatory factor‐1
Authors: Rani Richa , Kumar Sudhir , Gandhi Chandrashekhar R. 
Published: June 2021

Concanavalin A (ConA)‐induced liver injury in mice has been used extensively as a model to understand the role of immune cells. However, perisinusoidal hepatic stellate cells (HSCs), the primary cell type of liver fibrosis, were recently found to orchestrate ConA‐induced liver damage directly and by influencing recruitment and characteristics of immune cells. HSC‐released interferon‐β (IFNβ) and increased hepatic expression of a transcription factor, interferon regulatory factor 1 (IRF1), were determined to be major components of ConA‐induced liver injury. The aim of this study was to delineate the mechanisms of the actions of ConA on HSCs with specific focus on IRF1/IFNβ axis. HSCs and hepatocytes isolated from WT and IRF1−/− mice were used. HSCs were found to rapidly internalize FITC‐labeled ConA; internalized ConA was greatly concentrated in the perinuclear region. ConA increased the expression and nuclear translocation of IRF1 and NF‐κB in wild type (WT) HSCs and the expression of TNFα, IFNβ and CXCL1. These effects of ConA were abrogated in HSCs isolated from IRF1−/− mice. ConA induced JAK/STAT signaling in HSCs, and inhibitors of this signaling pathway ameliorated ConA‐induced IRF1 expression/nuclear translocation as well as cytokine/chemokine production. Finally, ConA‐stimulated WT but not IRF1−/− HSCs induced apoptosis of WT hepatocytes. Conversely, ConA‐stimulated WT HSCs were unable to induce apoptosis of IRF1−/− hepatocytes. Our findings suggest that IRF1 plays a dual role in ConA‐induced liver injury. On the one hand, ConA stimulates the synthesis of the mediators of hepatocyte injury through JAK/STAT signaling involving IRF1. On the other hand, IRF1 nuclear translocation in hepatocytes induced by ConA‐stimulated HSCs instigates apoptosis. While this mechanistic evaluation is performed using ConA, the findings could be relevant to liver injury due to lectins in the food products. In conclusion, HSC can be a potential therapeutic target for acute liver damage of various etiologies including lectins.Support or Funding InformationThis work was supported by a VA Merit Review Award 1IO1BX001174 to CRG.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Regulation of pancreatic islet cell fates
Authors: Sussel Lori 
Published: June 2021

The regulation of lineage specification is a challenging problem in organogenesis. Our studies are focused on identifying the gene regulatory networks underlying cell fate decisions in the pancreas, with an emphasis on the endocrine islet cell lineages. To this end, we have identified a number of coding and non‐coding genes that are essential for the specification of islet cell fates. In particular, Nkx2.2 is an essential transcriptional regulatory protein that is important for the formation and function of several islet cell lineages. Furthermore, Nkx2.2 continues to be essential for the active maintenance of both beta cell identity and function in the adult. Deletion of Nkx2.2 in mature beta cells caused these cells to acquire non‐beta cell endocrine features resulting in populations of reprogrammed cells. These studies demonstrate that Nkx2.2 is a conserved master regulatory protein that controls the acquisition and maintenance of beta cell identity by directly activating critical beta cell genes and actively repressing genes that specify the alternative islet endocrine cell lineages. These studies have been instrumental in understanding normal pancreatic cell differentiation processes during embryonic development and underscored the need to continually maintain these cell specific gene regulatory programs in the adult organ. Our findings have also demonstrated the existence of remarkable plasticity in adult pancreatic lineages.Support or Funding InformationNIH R01 DK082590This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Regulation of Functional Proteome by the Heat Shock Response and Proteostasis Network
Authors: Morimoto Richard I. 
Published: June 2021

Cellular health and proteome function is maintained by the proteostasis network (PN) comprised of molecular chaperones, transport pathways, the ubiquitin‐dependent proteasome, and autophagy clearance mechanisms. The dynamic properties of the PN are regulated by cell stress responses including the heat shock response (HSR) and the unfolded protein responses of the endoplasmic reticulum (UPRER) and mitochondria (UPRMITO). To understand the biology of organismal proteostasis, we have examined the properties of the PN in different tissues throughout the lifespan of C. elegans. The transition from development through reproduction into adulthood and aging places a tremendous demand on quality control processes and protein biogenesis. In early development, heat shock transcription factor HSF‐1 is essential, and target gene expression is co‐regulated with the cell cycle factor, E2F, to control a small subset of chaperone and PN genes involved in rapid anabolic growth. HSF‐1 is also involved in suppression of protein degradation pathways in early development. At reproductive maturity, the HSR is inhibited in somatic tissues by signals from the germ line stem cells that place repressive H3K27me3 chromatin marks at HS gene loci, repressing HSF‐1 DNA binding and transcription of chaperone genes, leading to the collapse of proteostasis in aging. These inhibitory signals on organismal proteostasis can be reversed genetically by overexpression of the jumonji demethylase, inhibition of germ line signaling, or induction of mitochondrial stress, either by mild downregulation of components of the electron transport chain, xenobiotics, and certain pathogenic bacteria to prevent the proteostasis collapse that occurs in early adult aging. These observations reveal that the regulation of molecular chaperones and other components of the PN by cell stress response pathways in aging is the basis for increased risk for misfolding and aggregation as occurs in neurodegenerative diseases and other protein conformational diseases.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endothelial Cell IQGAP1 is Required to Support Efficient Leukocyte Transmigration both In Vitro and In Vivo
Authors: Sullivan David P. , Dalal Prarthana J. , Muller William A. 
Published: June 2021

Inflammation is the body's fundamental response to tissue insult and damage. When operating correctly, it allows the organism to fight infection, repair injuries, and return the body to homeostasis. When the response is incorrectly directed, whether insufficient, excessive, or against an improper target, it contributes to and even directly causes numerous human pathologies. One of the critical components of inflammation is the recruitment of leukocytes to the target site. This process is a carefully choreographed series of sequential steps that leads to the net efflux of leukocytes out of the blood stream and into tissue. In the culminating and putative committed stage, the leukocyte squeezes between adjacent endothelial cells in a process commonly referred to as transendothelial migration (TEM). TEM is a critical step that requires several intercellular interactions and thus represents an attractive therapeutic target for regulating aberrant inflammation. During TEM, endothelial cells direct the lateral border recycling compartment (LBRC), a sub‐junctional membrane network, to the site of leukocyte migration to facilitate its passage. All manipulations that affect the function and delivery of the LBRC substantially reduce leukocyte efflux.To better understand the molecular components and function of the LBRC, we recently conducted a screen for LBRC‐interacting proteins and identified IQGAP1. IQGAP1 is a large multi‐domain cytoplasmic protein that is reported to bind several signaling proteins in other systems. Knockdown of endothelial cell IQGAP1 disrupted the directed movement of the LBRC and substantially reduced leukocyte TEM. To determine which domains of IQGAP1 are required for its function in TEM, we expressed a series of truncated constructs and examined their ability to rescue the knockdown of endogenous IQGAP1. We found that the actin‐binding domain of IQGAP1 is required for its localization to endothelial borders. Furthermore, both the actin‐binding domain and the IQ‐motifs are required for its function in TEM. We extended these studies in vivo by generating bone marrow chimeras, in which IQGAP1 knockout animals were reconstituted with wild‐type leukocytes. These studies show that IQGAP1 in endothelium is required for efficient TEM in vivo in two different inflammatory models. Together these findings detail a novel function for IQGAP1 in TEM that involves both its actin‐binding domain and IQ motifs which together coordinate the directed movement of the LBRC to the site of TEM.Support or Funding InformationFunding Support: R01HL046849, R01HL064774This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reduced RON Expression, DM1 resistance and MRP1 Upregulation Contributes to Resistance in Colon Cancer Cells against anti‐RON Antibody‐Drug Conjugate Zt/g4‐DM1
Authors: suthe sreedhar reddy , Yao Hang‐Ping , wang ming‐hai 
Published: June 2021

Zt/g4‐DM1 is an antibody‐drug conjugate that specifically delivers the potent cytotoxic payload maytansinoid (DM1) to RON receptor‐positive cells. Despite its impressive preclinical efficacy in the initial stages of treatment in xenograft models, tumors‐mediated by colon and PDAC cells were only partially inhibited by Zt/g4‐DM1. In light of these findings, we wanted to investigate mechanisms involved in Zt/g4‐DM1 resistance. As part of this work, we developed anti‐RON Zt/g4‐SMCC‐DM1 resistant colon cancer HT29, HCT116, SW620 cells derived from tumors by continuous treatment at lower doses followed by incremental dose increases. Approximately 100–200 fold resistance to Zt/g4‐DM1 developed in these cells and cross‐resistance was observed other ADCs containing drugs with similar mechanism of action. Reduced RON expression, DM1 resistance and increased expression of the ABCC1 (MRP1) drug exporter compared to parental cells were primary mediators of resistance. Interestingly we found a small percentage of RON positive population in resistant cells, when isolated these RON+ clones from three cell lines exhibited stable drug refractoriness and altered intracellular trafficking as a unique underlying mechanism of resistance to Zt/g4‐DM1. HT29R, HCT116R, SW620R cell lines showed resistance to unconjugated DM1 but not to other chemotherapeutic agents. Tumors derived from HT29R, HCT116R, SW620R grew in mice and were refractory to Zt/g4‐DM1 compared with parental cells. Hence, acquired resistance to Zt/g4‐DM1 was generated from cells derived from tumors by continuous drug exposure, and either increased ABCC1 protein or reduced RON expression and defective intracellular trafficking in case of RON+ resistant cells were primary mediators of resistance. These resistant cell models retained sensitivity to chemotherapeutics, suggesting that alternative therapies may help in overcoming acquired resistance.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
TIMP‐2 Inhibits Tumor Growth in Murine Model of Lung Cancer through EGFR signaling
Authors: Kumar Sarvesh , Jensen Sandra M. , Chowdhury Ananda , Peeney David , Wei Beiyang , Shih Joanna , Caterina John J. , Stetler‐Stevenson William G. 
Published: June 2021

The tissue inhibitor of metalloproteinase family of proteins (TIMPs 1–4) function as natural MMP inhibitors, and have been shown to play a role in maintenance and remodeling of the ECM as well as other cellular processes including proliferation, apoptosis and angiogenesis. TIMP‐2 is widely expressed in the stromal compartment of normal tissues, and has been shown to possess many MMP‐independent functions within the tumor microenvironment including inhibition of tumor growth and angiogenesis, reduced vascular permeability, and decreased tumor cell migration and invasion. In the current study, we used congenic mutant TIMP‐2 mice (mT2) with a loss of function mutation in the Timp‐2 gene to study TIMP‐2 associated effects in mice following intratracheal installation of Lewis Lung carcinoma cells labeled with luciferase (LL2‐Luc). The bioluminescence (BLI) data on 28 days post installation revealed a higher tumor burden in mT2 mice compared to wild type (wt) littermates, suggesting that loss of function mutation in Timp‐2 gene increases tumor growth (p<0.05), as well as an increase in the lung/body weight ratio (p<0.01). In agreement with these findings, Kaplan‐Meier analysis exhibited significantly higher mortality in mT2 mice compared to wt controls (p<0.01). Histologic analysis of H&E stained lung sections revealed a significant increase in the number of tumor nodules in mT2 mice compared to wt controls (p<0.01). In addition, we found that daily treatment (intraperitoneal injection) with exogenous recombinant TIMP2 (rTIMP2) protein (200ug/kg/day) significantly inhibited tumor growth (p<0.05) and lung/body weight ratio (p<0.01) in both mT2 and wt mice. Furthermore, both normal and tumor tissues from mice harboring the TIMP‐2 loss of function mutation demonstrated increased levels of EGFR phosphorylation (Tyr‐1068) by western blot analysis. In support of these findings, treatment of Lewis lung carcinoma cells by rTIMP‐2 inhibited EGF‐induced phosphorylation of EGFR (Tyr‐1068) in a dose dependent manner. In conclusion, these data indicate that the loss of function Timp‐2 mutation accelerates lung tumorigenesis, and that exogenous rTIMP‐2 treatment inhibits LL2 tumor growth via inhibition of EGFR signaling.Support or Funding InformationThis work is supported by center for cancer research, intramural research program, NCI/NIH research grants ZIA BC011204 & ZIA SC 009179 to WGSS.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Desmosomal Cadherins Desmoglein‐2 or Desmocollin‐2 Regulate Intestinal Epithelial Barrier Function and Mucosal Repair
Authors: Kusters Dennis , Flemming Sven , Luissint Anny‐Claude , Hilgarth Roland , Parkos Charles , Nusrat Asma 
Published: June 2021

The intestinal epithelial barrier plays a pivotal role in controlling mucosal homeostasis. In a number of pathological states such as inflammatory bowel disease, epithelial damage with disruption of the mucosal barrier results in a compromised intestinal mucosal homeostasis. To avoid chronic mucosal damage, efficient wound repair is critical in re‐establishing epithelial barrier properties and homeostasis. Epithelial barrier properties are achieved by intercellular junction proteins in the apical junctional complex and desmosomes. Intestinal epithelial cells express desmosomal cadherins, desmoglein 2 (Dsg2) and desmocollin 2 (Dsc2). To analyze contribution of these cadherins in controlling epithelial adhesion and homeostasis we generated mice with inducible intestinal epithelial specific (VillinCre‐ERT2) deletion of Dsg2 or Dsc2. Inducible downregulation of Dsg2 or Dsc2 resulted in compromised epithelial barrier function as assessed by paracellular FITC dextran flux using an intestinal loop model. Additionally, perturbation of these cadherins increased susceptibility to dextran sodium sulfate induced acute colitis.In addition to controlling epithelial barrier function, intercellular junction proteins have been reported to regulate signaling events involved in mediating repair. We therefore determined if desmosomal cadherins control intestinal mucosal repair. Knock‐down of either Dsg2 or Dsc2 delayed colonic mucosal wound repair in a murine biopsy induced colonic injury model. Since epithelial wound closure is mediated by collective migration of cells which coordinates forward movement of the epithelial sheet to cover denuded surfaces, we analyzed adhesive and migratory properties of in vitro model intestinal epithelial cells lacking Dsg2 or Dsc2. These studies revealed that down regulation of Dsg2 or Dsc2 decreased cohesiveness of cells and affected adhesion to the matrix, thereby suggesting an important role of Dsg2 and Dsc2 in controlling adhesion and homeostatic properties of intestinal epithelial cells.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Genetic Influences on Craniofacial Morphology
Authors: Sherwood Richard J. , Duren Dana L. , Subedi Janardan , Williams‐Blangero Sarah , Mahaney Michael C. 
Published: June 2021

Disorders of the craniofacial complex are among the most common congenital defects. Studies of these disorders have been confounded by a high level of genetic heterogeneity with single gene defects producing a variety of dysmorphisms or, conversely, by a variety of gene defects independently producing a similar phenotype. The identification of the underlying normal phenotypic variation, and its genetic basis, is critical to understanding the epidemiology of craniofacial anomalies. We have investigated the genetic architecture of traits from the craniofacial complex in three unique populations, including two human groups (the Fels Longitudinal Study, and the Jiri Dental Study) as well as an animal model (Papio hamadryas). Our ultimate objective is to elucidate fundamental aspects of the genetic architecture of the human craniofacial and dentognathic complexes.We captured a wide variety of quantitative phenotypes describing craniofacial and dentognathic morphology from lateral cephalographs and dental casts. A maximum‐likelihood variance components‐based method (as implemented in SOLAR) was used to estimate heritability, and conduct multipoint linkage analysis, and genomewide association analysis (GWA). All traits were significantly heritable and were generally of moderate magnitude for skeletal traits (~35–60%) and somewhat higher for dental traits (~70–90%). Linkage analyses identified a number of significant QTL for quantitative traits from cephalographs for both human and baboon crania.GWA analyses for the Jiri Dental Study have recently identified 46 SNPs for which there was at least suggestive evidence (P ≤ 1.60E‐6) for association with 31 different orofacial and dental traits; 9 of the 46 associations exhibited genome‐wide significance (P ≤ 2.74E‐7). Several of the implicated genes are associated with normal and abnormal growth and development of head and neck: ACAN, ERAP2, GPX3, NR2C2, & RORA. Pathway analysis revealed the gene harboring the strongest association, micro‐RNA locus MIRLET7D, regulates six genes that are in a tooth development pathway.The combination of human and non‐human primate genetic studies of the craniofacial complex are providing insight on novel pathways for both normal morphology and congenital disorders of this important region.Support or Funding InformationSupported by the National Institute of Dental and Craniofacial Research/NIH R01DE018497, R01DE016692, R21 DE016408, and National Institute of Allergy and Infectious Diseases/NIH R01AI037091, R01AI044406.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Constraints and Catalysts in Cerebellar Evolution
Authors: Wingate Richard 
Published: June 2021

The cerebellum comprises a remarkably stereotyped neural circuit, elements of which, such as the granule cell‐Purkinje cell synapse, are highly conserved across vertebrates. It functions as an adaptive filter that can be employed in regulating feed forward control of movement, but has a wider range of functions including in mammals, a demonstrable role in cognitive development. The range of neural functions modulated by cerebellar activity is a product of its output connections. In many species these are mediated by cerebellar nuclei whose number and projections vary systematically across major classes of vertebrates. Notably, the connection of cerebellar nuclei to the thalamus and hence the ability of the cerebellum to participate in forebrain activity is a mammalian innovation. Cerebellum size is also a key adaptive variable amongst different species with some species of both fish and mammals displaying relatively large, elaborately foliated cerebellum. Different strategies for generating large numbers of cells are adopted by different classes of vertebrates. In particular, the appearance of a transient, external granule cell layer (EGL) in cerebellar development is a tetrapod innovation. In some reptiles, birds and mammals, the EGL becomes a proliferative layer, which leads to a rapid clonal expansion of granule cells and the potential for foliation. Both the diversification of connectivity (cerebellar nuclei) and transit amplification (in the EGL) are adaptive properties within derivatives of a single defined pool of progenitors at the embryonic “rhombic lip”. Different derivatives are generated within distinct cohorts. Within these cohorts the heterochronic shift in the expression of a small number of genes appears to be responsible for generating the key changes in cerebellar development in vertebrates.Support or Funding InformationMedical Research Council, UKBBSRCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A mixed model for the relationship between latitude and human post‐cranial form
Authors: Savell Kristen R. R. , Katz David C. , Auerbach Benjamin M. , Weaver Timothy D. 
Published: June 2021

The general adherence of modern human body proportions to ecogeographic rules is frequently argued to be the result of thermoregulatory adaptation to climate. However, much of the history of human migrations follows the same clines that are associated with trends in body form. It is therefore important to test hypotheses about human adaptation to climate with approaches that account for population history and structure.In this project, we investigate the relationship between latitude and post‐cranial form in modern humans, with the goal of accounting for population history/structure and providing estimates of effects sizes and error. Using a multivariate quantitative genetics mixed model, we estimate morphological effects associated with latitude for long bone lengths and body size using osteometric data from 121 globally‐distributed populations and geographically matched genetic data representing 28 populations. The model includes a random effect for population structure (genetic relatedness) and a fixed effect for latitude. We found that among‐group variation was tightly correlated between limb lengths and body size measures respectively, but that these trait groups were fairly independent of each other. In addition, only bi‐iliac breadth demonstrates a clear directional effect once population history is taken into consideration, though directional trends skew positive for humeral length and negative for distal limb lengths, supporting previous research.By disentangling latitudinal effects from population structure using a mixed model approach, we add to the growing body of research exploring these strong underlying associations, and allow for a better understanding of the relationship between environmental and post‐cranial morphological diversity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.