bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanoresponsive skeletal stem cells acquire primitive neural crest identity during distraction osteogenesis
Authors: Longaker Michael 
Published: June 2021

The cellular mode of regeneration in response to mandibular distraction is of great interest, as this represents a successful clinical strategy to elicit the endogenous regenerative potential of postnatal tissue. Much like regeneration of distal digit tip in mice, mandibular distraction enacts the integrated outgrowth of multiple tissues within 2–3 months, reaching a form that is similar to normal mandible in form and function. Our previous studies in the mouse digit tip have reported a lineage restriction of stem/progenitor cells as an evolutionarily conserved paradigm in which de‐differentiation of resident cells into multipotent progenitors does not occur in post‐natal repair and regeneration. Here we provide evidence, for the first time, that controlled mechanical advancement of the lower jaw activates FAK signaling events which unlock gene regulatory programs normally active in cranial neural crest cells during facial morphogenesis, leading to an enhanced regenerative potential of tissue‐resident SSCs in the adult mandible.Support or Funding InformationNIH R01 DE026730, Hagey Laboratory for Pediatric Regenerative Medicine, The Gunn/Olivier Fund, Stinehart/Reed awardThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Consider the Lung as a Sensory Organ
Authors: Sun Xin 
Published: June 2021

At resting, an average person inhales/exhales 5–8 litters of air. This air may vary in oxygen content, carry allergen, pollutants or pathogens. To address how the lung senses and responds to these signals, we focused on pulmonary neuroendocrine cells (PNECs). PNECs are rare airway epithelial cells that are preferentially localized to airway branch point junctions. They are innervated by nerves, and can produce potent neuropeptides, neurotransmitters and amines. Our data suggest that proper aggregation of PNECs into neuroepithelial bodies is essential for their normal function. Disruption of PNEC clustering led to increased PNEC products and heightened baseline immune signature. We are currently testing the hypothesis that these cells serve as key nodes that mediate lung, environment, immune and nervous system interactions.Support or Funding InformationNHLBI HL119946NHLBI HL122406NICHD P01HD068250NIHOD OT2OD023857This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Targeting protein‐protein interactions in chaperone complexes to normalize proteostasis
Authors: Gestwicki Jason E. 
Published: June 2021

The ~300 molecular chaperones in mammals are thought to work together to maintain protein homeostasis (proteostasis). Often, this process is carried out by groups of chaperones that physically interact with each other and with their client proteins. Thus, chaperones can be thought of as a network that is held together by either stable or transient protein‐protein interactions (PPIs). This chaperone network protects unfolded clients and shepards them through folding, function and turnover. Our goal is to understand the logic of chaperone‐mediated protein quality control decisions. Our approach is to: (a) study the PPIs between chaperones and clients and (b) create drug‐like small molecules that perturb these PPIs. In turn, we can use these molecules to probe the role of specific PPIs in quality control.Towards this goal, we have mapped the interactions of a model client, tau, with chaperone subnetworks and identified chaperones that bind directly to this client. Interestingly, we found that a subset of these chaperones had strong anti‐aggregation and anti‐prion activity. Leveraging this knowledge, we created high throughput screening (HTS) platforms to activate the specific anti‐aggregation sub‐network. Following a medicinal chemistry campaign, the lead molecules promoted turnover of tau in multiple disease models, consistent with the model. Together, these ongoing studies have illuminated the logic of protein quality control and provided a set of chemical tools for addressing chaperone function in other systems.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 Use of Voluntary 3‐D Technology and Upper‐Class Peer‐Mentoring to Enhance Anatomy Performance of Under‐Represented Minority Students in Physical Therapy
Authors: Ortiz Alexis , Bickley Christina , Kliefoth Maria 
Published: June 2021

Under‐represented minority students have the greater attrition rate in health‐related graduate programs. Several strategies such as 3D enhanced educational strategies and peer‐tutoring have proven to be effective in improving student learning outcomes.PURPOSEThe purpose of this study was to estimate the association between the voluntary use of 3D enhanced studying materials and peer‐tutoring in the grades of under‐represented minority students during practical and written anatomy exams and final overall grade in a first‐year anatomy course at a school of physical therapy.METHODS3D narrated dissection animation videos were available through an educational computerized platform. The times the video was accessed per student (hits) was measured. Hours attended to peer‐mentoring and tutoring was also measured. Each of three practical and written exams were averaged and the final grade for the course was also calculated. Descriptive statistics were calculated for all variables of interest. Multiple linear regressions were performed with hits and mentorship hours as predictors and grades as outcomes.RESULTSAverage practical, written, and final grade were 80.45 ± 8.80, 80.94 ± 9.14, and 80.69 ± 8.73, respectively. Average 3D materials were 16.82 ± 4.95/hits per student while average hours of peer‐tutoring were 16.82 ± 4.95. The regression models with greater association to grades were those with both, hits and peer‐tutoring combined. The association between hits of 3D enhanced material and peer‐tutoring to practice exam grades was not statistically significant (r = 0.29, p = 0.57). The association between predictors and written exam was r = 0.27, p = 0.62, while the association with final grade was r = 0.29, p = 0.57.CONCLUSIONAlthough the use of 3D enhanced anatomy studying materials and peer‐tutoring have proven effective in improving student learning outcomes and grades it appears these improvements are when such programs are mandatory. Our study demonstrated that when such services are voluntary students don't utilize them enough to have an impact on grading criteria for both, practical and written examination in anatomy in a physical therapy curriculum.Support or Funding InformationThis work was supported in whole or in part by a grant from the Texas Higher Education Coordinating Board (THECB). The opinions and conclusions expressed in this document are those of the author(s) and do not necessarily represent the opinions or policy of the THECB.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 Altered Metabolic States in Cancer and Other Human Diseases
Authors: DeBerardinis Ralph J. 
Published: June 2021

Altered metabolism is a rich source of phenotypic diversity throughout nature, and it contributes to a very large number of human disease phenotypes, including cancer and pediatric inborn errors of metabolism (IEMs). In cancer, mutations in oncogenes and tumor suppressors reprogram metabolic preferences in malignant cells so as to enhance their ability to grow and withstand stress within tumors. IEMs constitute the single largest category of human genetic diseases. They are caused by germline defects in genes encoding metabolic enzymes and nutrient transporters, and they result in chronic, sometimes fatal dysfunction of the brain, liver and other organs, usually manifesting first in children. Crucially, in both cancer and IEMs, understanding the underlying metabolic perturbation and its relationship to the phenotype can produce opportunities for therapeutic intervention. Thus, applying modern, comprehensive techniques in metabolic analysis to human subjects could translate into better clinical management of a number of diseases. I will discuss the use of metabolomics (profiling of steady‐state metabolite abundances) and metabolic flux analysis (the use of stable‐isotope tracers to measure flow through metabolic pathways in living tissue) in human subjects with cancer and IEMs to understand the metabolic basis of tissue dysfunction, to identify therapeutic opportunities, and to discover entirely new human disease phenotypes.Support or Funding InformationHoward Hughes Medical Institute (Faculty Scholars Program), National Cancer Institute, Robert L. Moody Faculty ScholarThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Virion display (VirD) approach to characterizing non‐odorant GPCRs in Humans
Authors: Zhu Heng , Desai Prashant , Syu Guan‐Da 
Published: June 2021

Approximately one‐third of the human proteome is comprised of membrane proteins that belong to protein families with a wide variety of biochemical activities, such as transporters, channels, receptors, recognition molecules, and adhesion molecules. Among them, the GPCR protein family is of particular importance because they exhibit a wide variety of signaling pathways depending on ligand binding specificity and various coupling proteins during activation. In deed, they are most preferred drug targets. However, GPCRs are notoriously difficult to study because they have to be embedded in a membrane to maintain a native conformation and many require proper posttranslational modifications (PTMs), such as glycosylation. To facilitate high‐throughput biochemical analyses of GPCRs, we have recently developed a VirD array technology by which a GPCR is displayed in the membrane envelop of herpes simplex (i.e., HSV‐1) virions to maintain their native conformation. To date, we have displayed 315 non‐odorant GPCRs on the virions and formed a GPCR VirD array by spotting down the purified viruses. To characterize the virion‐displayed GPCRs, we first tested the orientation and ligand binding activities of selected GPCRs. Of the 20 commercial mAbs targeting ectodomains of GPCRs, 11 could specifically recognize their intended targets on the VirD arrays. For the nine GPCRs that failed to be recognized by the commercial mAbs, we showed that they could readily recognize their canonical ligands using single molecule imaging. Moreover, using an SPR‐based technology, we could obtain real‐time binding kinetics and deduce binding affinity for selected ligand‐GPCR pairs, indicating that they were all folded correctly. To determine whether VirD technology could help de‐orphanize GPCRs, ~80 fluorescently labeled orphan GPCR virions were individually probed to HuProt array, each comprised of 20,240 human proteins. Many secreted and transmembrane proteins were identified as specific targets, providing an important stepping‐stone for further characterization of these orphan GPCRs. Taken together, the VirD technology provides a high‐throughout platform for screening for drugs, affinity reagents, ligands, and beyond.Support or Funding InformationNCI IMAT R33 and CDI LabsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Expression of Sirpα Tailless Mutant in Mice Impairs Naïve CD4+ T Cell Adhesion to Immobilized ICAM‐1 and TCR Induced Proliferation.
Authors: Planas Francisco Esteban Velázquez , Autio Anu Esteban , Newton Gail , Parkos Charles , Luscinskas Francis William 
Published: June 2021

Signal Regulatory Protein alpha (SIRPα) interaction with its ligand CD47 plays an important role in immune cell homeostasis. CD47 is expressed by essentially all cell types, and acts as a “don't eat me signal” and a marker of self. We previously demonstrated that CD47 on both endothelium and T cells plays an important role in T cell adhesion and diapedesis in vivo and in vitro, and that CD47−/− CD4+ T cells had impaired antigen mediated proliferation in a model of Experimental Autoimmune Encephalomyelitis (EAE). In contrast to CD47, SIRPα has been reported as selectively expressed in the Central Nervous System (CNS), in most myeloid cells and at very low levels‐to‐absent in lymphoid cells in humans. To gain insight into the function of SIRPα in leukocyte recruitment, Sirpα truncated cytoplasmic, non‐signaling mutant (Sirpatm1Nog) transgenic mice and WT mice were studied in TNFα‐induced dermal air pouch model of inflammation. Unexpectedly, CD4+ T cells in Sirpatm1Nog mice, compared to WT mice, had significantly decreased recruitment into the air pouch (WT, 11.9 ± 2.9 ×103 vs Sirpatm1Nog, 7.8 ± 2.6 ×103, p<0.05), whereas no differences in CD8+ T cell or myeloid cell recruitment were observed. Interestingly, flow cytometric analysis using P84 monoclonal antibody showed that a low but significant fraction of CD4+ T cells in both WT and Sirpatm1Nog mice expressed SIRPα. Expression of Very Late Antigen‐4 (VLA‐4) and Lymphocyte Function Associated Antigen‐1 (LFA‐1) integrins, which are ligands of Vascular Cell Adhesion Molecule‐1 (VCAM‐1) and Intercellular Adhesion Molecule‐1 (ICAM‐1), respectively, were similar in T cells from WT and Sirpatm1Nog mice. Additional studies showed naïve CD4+ isolated from Sirpatm1Nog, compared to WT mice, had significantly blunted proliferation 48 hrs after T cell receptor crosslinking (TCR‐XL), and that CD4 T cells had impaired SDF‐1α induced arrest on immobilized ICAM‐1 under shear flow conditions. In summary, these studies demonstrate that SIRPα plays an unexpected and important role in T cell recruitment in vivo and in vitro and in TCR‐XL induced proliferation in vitro. These data suggest that loss of SIRPα signaling in SIRPα+ T cells leads to impaired LFA‐1 activation.Support or Funding InformationR01 HL125780 and T32HL007627.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Loss of local innervation induces lymph node expansion
Authors: Chen Chien‐Sin , Ince Louise , Scheiermann Christoph 
Published: June 2021

Peripheral lymphoid and non‐lymphoid tissues receive direct innervation via the nervous system but the relevance of neural input for the mounting of immune responses remains largely unknown. Ablating local innervation to popliteal lymph nodes (popLNs) by unilateral surgical ligation of the sciatic nerve led to footpad edema and dramatic expansion of popLNs due to an increase in cellularity in the ipsilateral side. In contrast, local surgeries leaving popLNs innervated, such as femoral denervation or sciatic denervation downstream of the popliteal fossa, did not generate nodal expansion. The increase in lymph node cellularity could be attributed to B cell proliferation and was associated with enhanced lymphocyte homing from the blood while leukocyte egress into efferent lymph remained unchanged. Homing was a critical factor in this process since blocking leukocyte entry into the lymph node with antibodies directed against L‐selectin or both α4‐ and αL‐integrins ablated denervation‐induced nodal expansion. Higher levels of TNF‐α, IL‐17 and IL‐4 were detected in denervated lymph nodes, the latter of which was also observed by systemic or local sympathectomy. Thus, loss of neural input to lymph nodes resulted in increased cellularity which was dependent on leukocyte homing. These data provide evidence for an important role of direct neural innervation in the control of immune responses.Support or Funding InformationFunded by the German Research Foundation (Emmy Noether SCHE 1645/2‐1 and SFB914 projects B09 and Z03) and the European Research Council (CIRCODE, 635872)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Surface glycocalyx and glypican‐1 mediate tumor cell metastasis
Authors: Qazi Henry , Moran Heriberto , Cancel Limary M. , Mayer Mariya , Roberge Sylvie , Huang Peigen , Munn Lance L. , Tarbell John M. 
Published: June 2021

The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive renal carcinoma cells (SN12L1) with high metastatic potential have enhanced invasion rates compared to low metastatic (SN12C) cells in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) and hyaluronic acid (HA) in the glycocalyx play an important role in this flow mediated mechanotransduction and upregulation of invasive and metastatic potential. In our recent study, SN12L1 cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chambers with defined interstitial flow, we showed that flow‐enhanced invasion is suppressed in HS deficient cells. We also examined two prominent HSPGs on renal carcinoma cells – glypican‐1 and syndecan‐1 and one prominent HA receptor – CD44. We observed higher glypican‐1 levels in flow dependent SN12L1 cells when compared to SN12C cells. Caki‐1 (highly metastatic) cells did not display flow‐dependent invasion in vitro and did not display elevated glypican‐1 compared to low metastatic Caki‐2 cells. However we did observe significantly increased HS, HA, syndecan‐1 and CD44 in Caki‐1 compared to Caki‐2 cells suggesting an alternative mechanism for reported higher metastatic rates in these cells. All of our data are consistent with the hypothesis that glypican‐1 is the core protein responsible for flow sensing in metastatic cancer cells. This is also consistent with observations in endothelial cells. To assess the ability of tumor cells to metastasize in vivo, parental or HS knockdown SN12L1 cells expressing fluorescent reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from knockdown cells compared to control cells with intact HS. The reduction was even greater (98%) in lungs where most of the metastases from the control cells were observed. The ability of these knockdown cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx and glypican‐1 in tumor progression.Support or Funding InformationGrant: RO1CA204949 Targeting glycocalyx mediated mechanisms of tumor metastsisThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dsg2 regulates intestinal epithelial cell adhesion and barrier function via EGFR
Authors: Ungewiß Hanna , Schlegel Nicolas , Waschke Jens 
Published: June 2021

Rapidly renewing epithelial tissues such as the intestinal epithelium require precise modulation of intercellular adhesion to preserve barrier integrity during cell division and differentiation. Previously, we have shown that Desmoglein 2 (Dsg2), an adhesion molecule of desmosomes, beside its adhesion function, regulates intestinal barrier properties via p38MAPK signaling. Here we show that Dsg2 and epidermal growth factor receptor (EGFR) co‐localize at the apical part of cell‐cell contacts in polarized enterocytes using confocal and stimulated emission depletion (STED) microscopy. DLD1 cells deficient for Dsg2 display EGFR mislocalization and reduced protein levels of activated as well as total EGFR. Atomic force microscopy (AFM) revealed EGFR‐Dsg2 interaction both under cell‐free conditions as well as on living enterocytes, which was confirmed by co‐immunoprecipitation. Moreover, EGFR inhibition reduced cell cohesion and barrier reformation. In line with this, we demonstrate that Src activity is required for barrier formation and localization of EGFR and Dsg2 to cell‐cell contacts. Thus, our study reveals a new mechanism by which Dsg2 regulates barrier properties via EGFR.Support or Funding InformationThis work was funded by grants of the Deutsche Forschungsgemeinschaft: the priority program DFG_SPP1782This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Antenatal exposure to secondhand smoke impacts growth and cardiopulmonary energetics in 4‐week‐old mice
Authors: Hirschi Kelsey M. , Egbert Kaleb , Clark Christian , Mella Nate , Plothow Edward , Mejia Juan F. , Arroyo Juan A. , Reynolds Paul R. 
Published: June 2021

Secondhand smoke (SHS) is a well‐established cause of respiratory illness in infants and children who live in environments where exposure is common. Recent studies examining potential effects of antenatal SHS exposure suggest that antenatal exposure to SHS impacts cardiovascular and respiratory function through childhood and may have lifelong ramifications. In the present study, we sought to determine effects of antenatal SHS exposure on 4‐week‐old mice. C57/Bl6 mice (n=8) were exposed to SHS or room air via a nose‐only delivery system (Scireq) beginning on gestational day (dGA) 14.5 to 17.5 dGA. At 4 weeks of age, mice were weighted and blood pressure and heart rate was determined with a tail occlusion cuff (Kent Scientific). Whole body, heart/body and liver/body weights were determined. Lastly, organ‐specific mitochondrial function tests were performed. At 4 weeks of age, antenatal exposure of SHS caused: 1) a significant reduction (p<0.03) in total body weight; 2) significantly elevated systolic (p<0.0002) and diastolic (p<0.004) blood pressure; 3) no differences in the animal's heart rate; 4) significantly decreased heart (p<0.004) and kidney (p<0.0006) weights when indexed to body weight; and 5) significantly decreased oxygen consumption related to cellular respiration in SHS‐exposed hearts and lungs when compared to room air exposed controls. Our results indicate that antenatal exposure to SHS has a detrimental effect on growth rates and cardiopulmonary energetics through the 4th week of age, or the equivalent of early adolescence. These results may be beneficial in understanding the long‐term effects of antenatal SHS exposure.Support or Funding InformationThis work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR and JAA) and a BYU Mentoring Environment Grant (JAA and PRR).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.