bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Model to Assess the Effects of Osteoporosis Medications on Bone Quality
Authors: Sumner D. Rick , Ross Ryan 
Published: June 2021

In order to examine the effects of osteoporosis treatments on bone tissue that forms during drug administration, we have adapted a decades old model in the rat(1, 2). The premise of our work is that bone matrix mineralization within cortical bone is an important but oft‐neglected component of bone remodeling. Aberrant mineralization can reduce bone strength and increase fracture risk independent of changes in bone mass. Sodium fluoride represents an example of an osteoporosis treatment that alters the mineralization process, leading to increased fracture risk in spite of increased bone mass, thereby causing the very thing it was meant to cure. Unfortunately, small animal models to study matrix mineralization during remodeling of cortical bone in the adult skeleton did not exist when this drug was under development; so these unexpected effects were only discovered in patients.We have performed a series of studies to develop and validate a rodent model to study matrix mineralization during remodeling in adult cortical bone. Briefly, remodeling is induced by severely restricting dietary calcium in lactating animals (0.01% as opposed to the normal 0.6%). When the pups are weaned, the dams are immediately returned to the normal Ca diet. We study the bone that forms during the post‐weaning period in the dams. We have performed experiments to assess the most appropriate anatomical site for examining intra‐cortical remodeling and the effects of manipulating dietary Ca on mineral metabolism and mineralization kinetics. We found that the border between the distal femoral diaphysis and metaphysis is the best site for sampling intra‐cortical remodeling because this site had the most induced pores of a size consistent with rat secondary osteons(3). The increase in porosity was resolved 30 days after weaning, suggesting that the induced intra‐cortical resorption spaces had totally infilled. Endocortical remodeling can also be examined at this site. Studies using in vivo fluorochrome labeling, Fourier‐transform infrared microspectroscopy, back‐scatter scanning electron microscopy, microcomputed tomography, histology and serum assays indicate that matrix mineralization occurs normally and largely within a normal endocrine environment despite the manipulation of Ca in the diet. A major advantage of this model is that it provides multiple sites of synchronized matrix mineralization. We are currently using the model to study how common and emerging osteoporosis drugs affect matrix mineralization and mechanical behavior.Support or Funding InformationNIH Grant R21AR065604This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Pathophysiology of Anti‐resorptive Medication‐related Osteonecrosis
Authors: Aghaloo Tara 
Published: June 2021

Osteonecrosis of the jaws (ONJ) is a devastating complication of potent antiresorptive medications utilized for benign and malignant disorders of bone metabolism. Bisphosphonate related ONJ (BRONJ) was first identified in 2003 and 2004, and its prevalence is reported between 0.8–12%. Although significant progress has been made in our understanding of the disease, much more work needs to be done to completely explain its pathophysiology. Many hypotheses have been proposed, which have sparked empirically‐based treatment modalities. It is most likely that the pathophysiology of ONJ is multifactorial, where inflammation/infection and inhibition of bone remodeling are necessary for development of the disease. This presentation will present current evidence for ONJ pathophysiology, and prevention and treatment approaches that can be implemented in the dental office.Support or Funding InformationNIH/NIDCRAmgenThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
When PNS Assembly Goes Awry: Familial Dysautonomia
Authors: Lefcort Frances , Chaverra Marta , George Lynn 
Published: June 2021

Over a century of elegant work has contributed to our understanding of how neural crest cells migrate throughout the embryo to give rise to the majority of cell types in the peripheral nervous system (PNS). This rich foundation is the basis for our lab's investigation of the cellular and molecular mechanisms that go awry to result in the developmental disorder of the PNS, Familial dysautonomia (FD). Three of the key clinical hallmarks of FD include a reduction in pain and temperature sensation, misregulation of the sympathetic nervous system, and impaired gastrointestinal tract function. The neurons in all of these systems derive from the neural crest. Consequently, a prevailing hypothesis in the field was that FD resulted from faulty neural crest migration. To test this hypothesis, we generated mice in which the gene that is mutated to cause FD, IKBKAP/ELP1, was deleted selectively from the neural crest. Interestingly, by the end of embryogenesis, we found that in fact the number of pain and temperature receptors in the dorsal root ganglia were significantly reduced as were sympathetic neurons in the superior cervical ganglia, recapitulating the human disease phenotype (George et al., 2013, PNAS). However, these studies also demonstrated that this selective reduction in neuronal number was not due to faulty neural crest cell migration. Rather, the reductions were due to (1) the death and premature differentiation of the Pax3+ pain and temperature progenitor cells and (2) exacerbated apoptosis of TrkA+ pain and temperature receptors. Interestingly, the TrkC+ proprioceptors developed normally, although they later die progressively in adulthood (Elisabetta Morini and Susan Slaughenhaupt, personal communication). Upon the completion of neurogenesis in the dorsal root and sympathetic ganglia, PNS axons must innervate their targets to fully differentiate. Our work and others (Jackson et al., 2014, Development; Abashidze et al., 2015, PLoS One) demonstrate that IkbkapElp1 is required for normal axon outgrowth and target innervation. These and other findings for how and why PNS development is disrupted in FD will be discussed.Support or Funding InformationNIH R01 NS086796; Dysautonomia FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Authentic Anatomy Education: Leave your Ego at the Door to Create Memorable Learning Experiences
Authors: O'Loughlin Valerie Dean 
Published: June 2021

As teachers, we strive to inspire interest and wonder in the field of anatomy for our students. We seek to clarify the complex, we try to scaffold learning, and in so doing we facilitate the development of well‐grounded anatomical knowledge in our students. We also serve as mentors to our graduate students who are progressing along the path of future anatomy educators. Yet as we acquire our knowledge and experience, paradoxically we may become less relatable to our students, as they have not seen our hard fought path, mired with mistakes, to our current destination. In order to create authentic anatomy learning experiences and inspire a growth mindset in our students about learning, instructors should mention their past mistakes and failures, so as to let students know we have shared their struggles and have persisted. Likewise, as we train future anatomy educators, we must make visible our path from novice instructor to experienced educator, so as to instill a growth mindset in our future colleagues. Making these paths visible sometimes requires ‘leaving your ego by the door’ in order to create memorable learning moments. Here, I share some of my own examples of creating authentic anatomy learning experiences for my students and future anatomy educators.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Single protein‐catalyzed ubiquitination: Chemistry and implications in cell signaling
Authors: Luo Zhao‐Qing 
Published: June 2021

Posttranslational modification by the 76‐residue ubiquitin molecule participates in virtually every cellular process in eukaryotic cells, whereby it regulates the activity of substrate proteins by altering their turnover time, cellular localization or biochemical function. Classical ubiquitination is catalyzed by the action of E1, E2 and E3 enzymes that function coordinately to activate, conjugate and ligate the modifier to a protein substrate. We recently found that members of the SidE effector family such as SdeA catalyze ubiquitination a mechanism that completely differs from the canonical three‐enzyme cascade. In this scenario, ubiquitin is activated by ADP‐ribosylation at Arg42 (ADPR‐Ub) via a mono‐ADP‐ribosyltransferase (mART) motif. Subsequent works by others showed that the reaction intermediate is then utilized by a phosphodiesterase (PDE) activity also embedded in SdeA, which cleaves ADPR‐Ub to transfer the phosphoribosylated ubiquitin moiety to serine residues of the substrate. In this talk, I will discuss our recent findings on the functional significance of SidEs‐induced ubiquitination on host proteins. I will also discuss a new mechanism of ubiquitination catalyzed by another L. pneumophila effector and its implications in cell signaling.Support or Funding InformationNIH‐NIAID R01127465This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Conformational Regulation of Phospholipase C Enzymes
Authors: Lyon Angeline , Garland‐Kuntz Elisabeth E. , Vago Frank S. , Van Camp Michelle , Sieng Monita , Corpstein Clairissa , Blaine Arryn T. , Jiang Wen 
Published: June 2021

Phospholipase C (PLC) enzymes, in particular the PLCβ and PLCɛ subfamilies, are essential for normal cellular function in the cardiovascular system where they generate second messengers in response to extracellular signaling that increase calcium levels and activate protein kinase C. Crystal structures of PLCβ have provided some insights into its architecture and regulation, but there is no published structural data for PLCɛ or any catalytically active fragment of the enzyme. We have used small angle X‐ray scattering, electron microscopy, and biochemical assays to begin characterizing the solution structures and regulation of PLCɛ and PLCβ. We find that PLCɛ is conformationally dynamic in solution and that its PH domain is essential for maximum basal activity. We also find PLCβ adopts multiple conformations in solution, wherein its PH domain and EF hands are extended away from the catalytic core. Using site‐directed mutagenesis and functional assays, we find that stabilization of the PH domain in its extended or closed conformation impacts its activity. Taken together, our data support a more complex and global model for PLC regulation, wherein the conformation of the PH domain and EF hands relative to the catalytic core modulates its lipase activity at the membrane.Support or Funding InformationThis work is supported by an American Cancer Society Institutional Research Grant (IRG‐14‐190‐56) to the Purdue University Center for Cancer Research and an American Heart Association Scientist Development Grant 16SDG29930017 to A.M.L.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
MECHANISMS OF THE IDH1/2 MUTATIONS AND ITS ASSOCIATION WITH CONTRADICTORY SURVIVAL OF GLIOBLASTOMA PATIENTS VERSUS AML PATIENTS
Authors: van Noorden Cornelis J.F. , Khurshed Mohammed , Hira Vashendriya V.V. , Molenaar Remco J. 
Published: June 2021

Isocitrate dehydrogenase 1 and 2 (IDH1/2) is mutated (IDH1/2mt) in various types of human cancer such as glioma and acute myeloid leukemia (AML), a structural alteration that leads to catalysis of α‐ketoglutarate to the oncometabolite D‐2‐hydroxyglutarate (D2HG). Heterozygous IDH1/2mt cancer cells produce less IDH1/2‐mediated NADPH, such that after exposure to ionizing radiation (IR) there were higher levels of reactive oxygen species, DNA double‐strand breaks and cell death compared to IDH1 wild‐type (IDH1wt) cells. These effects were reversed by the IDH1mt inhibitor AGI‐5198. Exposure of IDH1wt cells to D2HG was sufficient to reduce IDH‐mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well‐described DNA hypermethylation phenotype in IDH1mt cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1mt glioma. Further, they offer an explanation for the relatively longer survival of patients with IDH1mt glioma, and they imply that administration of IDH1mt inhibitors in these patients may limit irradiation efficacy in this setting.Whether this also holds true for IDH1/2mt AML was investigated using primary human IDH1mt, IDH2mt and IDH1/2wt AML cells. It was investigated whether IDH1/2 mutations cause increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib. IDH1/2mt inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on killing of IDH1/2mt AML cells. We provide evidence that the therapy sensitivity of IDH1/2mt cells was caused by D2HG‐mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2mt AML cells. Thus, IDH1/2mt AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA‐damaging agent such as daunorubicin, whereas concomitant administration of IDH1/2‐mutant inhibitors during cytotoxic therapy decreases the efficacy of both agents in IDH1/2mt AML cells.Support or Funding InformationThis study was financially supported by the Dutch Cancer Society (KWF; UVA 2014‐6839; CJFVN, MK, VVVH, RJM)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 influence of high fiber diet and probiotic supplementation in a murine model of colitis
Authors: Owens Josh , Saeedi Bejan , Darby Trevor , Jones Rheinallt 
Published: June 2021

Probiotics are therapeutic agents administered to patients with IBD. In addition, it has recently been hypothesized that a high fiber diet may synergize with probiotics to exert an elevated cytoprotective effect on host tissue during colitis. Thus, we investigated the extent to which both orally administered probiotics and a high fiber diet protected intestinal tissue in a murine model of colitis. We administered the well‐studied probiotic, Lactobacillus rhamnosus GG (LGG) to 8 week‐old mice for two weeks before a 7‐day challenge with 3% Dextran Sodium Sulfate (DSS). Protection was assessed in terms of disease activity index and histology. Mice given LGG or a high fiber diet conferred modest protection from DSS‐induced colitis compared to controls. However, the cytoprotective effect was significantly strengthened in mice fed a high fiber diet in conjunction with LGG. Flow Cytometry analysis of immune cells in the colonic lamina propria revealed an immune‐modulatory effect of LGG, which was elevated under a high fiber diet. Together, these data suggest that a high fiber diet plus a probiotic can lead to enhanced cytoprotection against DSS‐induced colitis compared to either LGG feeding, or a high fiber diet alone.Support or Funding InformationResearch supported by NIH grant R01DK98391This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
PRAP1: A Novel Epithelial Secreted Protein
Authors: Wolfarth Alexandra , Neish Andrew 
Published: June 2021

Proline rich acidic protein‐1 (PRAP1) is a 17 kDa secreted intrinsically disordered protein encoded in higher chordates with no known function or recognizable sequence homology. In the course of evaluating transcriptional activation in murine gut by members of the Lactobacilli taxon, we found PRAP1 induced in the colon within 4 hours of oral gavage with 108 Lactobacilli. To define the physiological role of PRAP1, we have made polyclonal antibodies, PRAP1 recombinant protein and Prap1 null mice. Measurement of PRAP1 expression by qPCR and western blot reveal PRAP1 expression is highest in the proximal small intestine, and interestingly, in a hormonally dependent manner in uterine endometrial cells of female mice. This expression pattern is consistent with immunofluorescence staining demonstrating high expression of PRAP1 in the enterocytes of the duodenum, goblet cells of the ileum and uterine endometria, as well as in the extracellular space of the corresponding mucosal tissue. Preliminary in vivo data shows Prap1 null mice have increased inflammation in the gastrointestinal tract and uterus, along with increased systemic inflammation. Given the localization of PRAP1, its secretion into the lumen of the small intestine and uterus, and its effect on local and systemic inflammation, we hypothesize that PRAP1 is a novel intrinsically disordered protein that contributes to the intrinsic defenses of mucosal epithelial surfaces.Support or Funding InformationNIH RO1 AI 64462This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Anti‐cancer activity of non‐pungent capsaicin analogs: A Structure‐Activity Study
Authors: Friedman Jamie Rae , Gadapalli Rama S. , Akers Austin T. , Nolan Nicholas A. , Brown Kathleen C. , Colclough Kate W. , Miles Sarah L. , Rimoldi John M. , Dasgupta Piyali 
Published: June 2021

The nutritional compound capsaicin is the major spicy ingredient of chili peppers. Although traditionally associated with analgesic activity, recent studies have shown that capsaicin has profound anti‐neoplastic effects in several types of human cancers. However, the applications of capsaicin as a clinically viable drug are limited by its unpleasant side effects, such as gastric irritation, stomach cramps and burning sensation. This has led to extensive research focused on the identification and rational design of second‐generation capsaicin analogs. Previous studies have shown that addition of long‐chain unsaturated groups after the amide group of capsaicin were non‐pungent and retained the bioactivity of capsaicin. The chemical nature of these compounds are unsaturated N‐acylvanillamides (uN‐AVAMs). However, a majority of these uN‐AVAMs have been studied for their pain‐relieving activity. We synthesized a panel of uN‐AVAMs with 0–4 double bonds in the side chain of capsaicin. We investigated the growth‐inhibitory activity of these compounds with an MTT‐based screening assay. We selected our “hit compound” Arvanil for further studies. Next, we compared the apoptotic activity of arvanil and capsaicin in a panel of human small cell lung cancer (SCLC) cells. We observed that the non‐pungent capsaicin‐analog arvanil displayed greater magnitude of apoptosis than capsaicin. The pro‐apoptotic activity of arvanil and capsaicin was mediated by the intracellular calcium pathway. We measured the uN‐AVAM‐induced levels of intracellular calcium in SCLC cells. The pattern of uN‐AVAM‐induced intracellular calcium was analogous to the results obtained in the MTT assay. Therefore, the measurement of intracellular calcium may be used as a screening tool for capsaicin‐mimetics with anti‐cancer activity.Support or Funding InformationFunding for our study was supported by a NIH R15‐AREA Grant (2R15CA161491‐02). Furthermore, this study was supported in part by an Institutional Development Award (IDeA) Grant number P20GM104932 from the National Institute of General Medical Sciences (NIGMS) and the Research Core B of COBRE, a component of the National Institutes of Health (NIH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
BZW1 is an independent prognosis marker for non‐small‐cell lung cancer
Authors: Chiou Jean , Hsiao Michael 
Published: June 2021

Basic leucine zipper and W2 domain‐containing protein 1 (BZW1) plays a critical role in cell cycle for transcriptional control of histone H4 gene at the G1/S transition. Regarding that proliferation are dysregulated in cancer, we aim to unravel the role of BZW1 in lung cancer. Recent studies show that BZW1 promotes growth of salivary muocepodermoid carcinoma. The aim of the study is to determine the respective prognostic value of BZW1.First, we search public database and analyzed BZW1 protein expression by immunohistochemical staining on tissue microarray samples. Further, we examined BZW1 expression in NSCLC cell lines and verify the functional role of BZW1 in NSCLC cell lines.By searching public database, we found that BZW1 high expression was significantly correlated with poor prognosis in NSCLC, especially in lung adenocarcinoma. Similar trends were also shown in NSCLC patients tissue array. Knockdown of BZW1 inhibited cell migration and invasion but did not affect cell proliferation in NSCLC cell lines.In conclusion, BZW1 expression is an independent prognostic factor in NSCLC, especially in lung adenocarcinoma.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.