bluuebunny/crossref_metadata_2025_split huggingface dataset:
FSTL3 Promotes Tumor Cell Proliferation, Invasion, Survival and Associates with Poor Prognosis in Colorectal Cancer Patients
Authors: Fang Chih-Yeu , Hsiao Michael 
Published: April 2020

Follistatin like‐3 (FSTL3) is a potent inhibitor that antagonizes TGF‐β family ligands including activin, myostatin and bone morphogenetic proteins. Though usually a secreted glycoprotein, nuclear FSTL3 expression had been noted in several cell types, suggesting the existence of specific intracellular functions of this protein. Colorectal cancer (CRC) is one of the leading malignant tumors worldwide. Its strong metastatic ability and chemoresistance tendency is a major obstacle in clinical treatment. In large cohort survival analyses, we have found that FSTL3 has a significant prognostic predictive power in colorectal cancer at both RNA and protein level. Immunohistochemistry staining of CRC specimens revealed that patients with high FSTL3 expression are significantly associated with poor survival. Our study further showed that knockdown of FSTL3 inhibited the migration and invasion of colon cancer cells and reduced tumorigenesis in vivo. Conversely, ectopic over‐expression of FSTL3 elicited the opposite effects in CRC cells. In addition, the overexpression of FSTL3 was found to confer the resistance to 5‐fluorouracil in CRC cells. mRNA profiling analyses suggested that FSTL3 drives CRC tumorigenesis through various carcinogenesis‐related pathways. Our results unveil the significance of FSTL3 in the oncogenesis of CRC, with implications for its potential use as a diagnostic or prognostic biomarker and also a candidate for therapeutic target in this disease.Support or Funding InformationThis research was supported by Academia Sinica [AS‐SUMMIT‐108].
Physiome: Encouraging Reproducible and FAIR Computational Modelling
Authors: Nickerson David Phillip , Lundengård Karin , Watts Jared , Porter Simon , Yu Tommy , Nielsen Poul , Hunter Peter 
Published: April 2020

Computational modelling is a commonly used tool in the physiological sciences. For these models to be useful, it is essential that the model is reproducible and is available for other scientists to reuse. Despite development of standards and supporting software, widespread adoption of publishing reproducible and reusable computer models of biological systems is still lacking.Physiome is a new journal committed to reproducibility and reusability of mathematical models of physiological processes. Every article published in Physiome is connected to a curated and permanent version of the model code with a persistent identifier. Through the Physiome paper, the code necessary to run the model is easily accessible by just clicking a link, to be reused as it is or as a module in a bigger model. It is also connected to a primary paper published in a domain‐appropriate journal, where the validation and scientific value of the model is evaluated and presented. A Physiome publication is a complement to your primary article that ensures reproducibility, reusability and discoverability of your model. The format encourages modularity that facilitates the combination of different models to develop the next level of systems understanding. And all the models are in one place, easy to Find, Access, Interoperable, and Reuse (FAIR).Reproducibility and confirmation of results is crucial for useful science and should be one of the supporting pillars of good research. Yet, publication of it is rarely incentivised, often treated as a secondary result at best, which undermines the quality of our work. With the strict formulation of equations and easily shared code, one would expect mathematical models to be reproducible by default, but in fact less than 10% of the models published in scientific journals work when implemented by another group. Physiome will save valuable time and effort on trying to implement models from papers that lack information, or having your results lost because others cannot use them. In doing so, Physiome encourages model authors to make their work available in a reproducible and FAIR manner.For more information visit:
https://journal.physiomeproject.org.Support or Funding InformationWe acknowledge the support of the International Union of Physiological Sciences, Digital Science, Figshare, Overleaf, and the University of Auckland.
MIF‐CD74 Signaling Protects against Endothelial Senescence in Chronic Obstructive Pulmonary Disease
Authors: Kim So-Jin , Wan Feng , Zhang Xuchen , Zhang Yi , Ifedigbo Emeka , Leng Lin , Bucala Richard , Sauler Maor , Lee Patty 
Published: April 2020

RATIONALEChronic obstructive pulmonary disease (COPD) is characterized by gradual destruction of alveolar architecture and subsequent airflow obstruction. Advancing age and significant exposure to cigarette smoke (CS) are common risk factors, yet the pathologic manifestations of COPD are heterogenous and the biologic risk factors for COPD are unclear. MIF is an important regulator of innate immunity, cellular homeostasis and survival. We previously reported that circulating MIF was lower in smokers with COPD compared with smokers without COPD. Others have confirmed these findings and correlated decreased MIF protein with greater radiologic/functional evidence of emphysema in patients.METHODSGene expression microarray analysis was performed on lung tissue from individuals with/without COPD (n=262), and endothelial cell (Ec) CD74 expression was analyzed in single‐cell RNA‐seq (control=19, COPD=29). CD74 expression was determined by immunohistochemistry in human lung. CS extract (CSE) treated to HUVEC along with the following recombinant‐MIF (rMIF), MIF‐siRNA, neutralizing anti‐MIF monoclonal antibody (anti‐MIF mAb), MIF098 (MIF antagonist), or MIF20 (MIF agonist). U0126 (ERK inhibitor) was treated 1 hour prior to MIF20 treatment. MIF‐KO mice were treated with a control or MIF expressing lentiviral‐vector. Ec were isolated via MACS sorting. AKR/J mice were exposed to CS (4 months), and MIF20 was administered orally (3 mg/mouse) to mice every day for the final 2 months of CS exposure. Pressure‐Volume (PV) loops were measured by FlexiVent.RESULTSCD74 expression was increased in COPD patients especially in lung Ec. CSE increased p16 and p21 mRNA expression in HUVEC. This increase was attenuated by rMIF or MIF20, while augmented by anti‐MIF mAb or MIF98. CSE increased SA‐β‐gal activity and MIF20 attenuated it. The protective effect of MIF20 against CS‐induced Ec senescence was abolished by ERK signaling inhibitor. MIF‐KO mice showed an upshift of PV loop and increased Ec p21 expression, which were attenuated by restoration of MIF expression. CS induced upshift of PV loop, increased p16 and p21 expression, which were attenuated by MIF20.CONCLUSIONSThe expression of CD74, the cognate receptor for MIF, was increased in COPD. Senescence was induced in Ec by CS, an important causative factor for COPD. MIF20, a novel small molecule MIF agonist, attenuated CS‐induced senescence via ERK signaling, which is known to support cell survival and proliferation. Furthermore, MIF20 prevented CS‐induced lung emphysema. These data suggest that therapeutic modulation of MIF targeting in lung Ec is feasible represents a novel strategy to protect against senescence‐induced COPD.Support or Funding InformationM.S. is supported by NIH/NHLBI K08HL135402 and FAMRI YCSA 142017. P.J.L. is supported by NIH/NHLBI R01 HL138386, VAORD11858595, US Department of Defense PR150809, and FAMRI 150074.
Contributing annotations of predicted intrinsic protein disorder to the RCSB Protein Data Bank
Authors: Bui Jonathan T. 
Published: April 2020

The Protein Data Bank (PDB) holds information about three‐dimensional (3D) structures of biological macromolecules. It’s a global resource used by industry, researchers, students and educators for various ends. To serve users with diverse needs, the RCSB PDB (accessible at rcsb.org) integrates additional information associated with each structure, among which are properties derived from sequence data. Predictions of highly dynamic disordered regions are available for PDB entries, calculated using JRONN, a Java port of RONN algorithm. The IUPred2A method for calculations of disordered protein regions is evaluated to replace the previously used JRONN method. Previously published benchmark studies show that IUPred2A is more accurate than JRONN. By pre‐computing disordered regions and serving this information with each protein sequence in the PDB, users gain additional reference information and adds context to solved protein structures without requiring users to derive property information on their own. Furthermore, the integration of disorder calculations can be combined with other reference data on the PDB. For example, many entries in the PDB are highly structured globular molecules, but the addition of predicted regions of disorder can reveal short unstructured regions that can be important for protein‐protein interactions. Calculations of intrinsically disordered regions in protein sequences contributes valuable reference information to the PDB and can serve diverse research needs.Support or Funding InformationNational Science Foundation (DBI‐1832184), the US Department of Energy (DE‐SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institute of Health under grant R01GM133198.
SPARC: Abundance, Chemical Content and Regional Distributions of Nerve Fibers in the Human Gastric Muscle and Mucosa
Authors: Stebbing Martin J. , Di Natale Madeleine , Fakhry Josiane , Hunne Billie L. , Ward Sean M. , Sasse Kent C. , Furness John B. 
Published: April 2020

Disorders of gastric motility and sensation, including gastroparesis, are common, debilitating and currently poorly treated. To develop new treatments for these disorders, a thorough understanding of the gastric innervation and its pathology in humans is required. We have developed methods to identify and quantify the density of different classes of nerve fibers to the gastric muscle and mucosa. To do this we employed immunohistochemistry using characterized antibodies and a grid‐based quantitation method combined with high resolution confocal microscopy in resection tissue and biopsies from the gastric fundus and corpus. In the muscle we have identified nerve fibers immunoreactive for a range of neurochemical markers including neuronal nitric oxide synthase (NOS), vasoactive inhibitory peptide (VIP), tachykinins (TK), gastrin releasing peptide (GRP), neuropeptide Y (NPY), vesicular acetylcholine transporter (VAChT) and tyrosine hydroxylase (TH). Neuronal NOS and VIP were commonly colocalized in putative inhibitory nerves innervating the external musculature. We saw extensive labelling for VAChT and TK, both markers of the excitatory fibers innervating the muscle. GRP and NPY were also present in subgroups of excitatory nerve fibers. The density of inhibitory fibers (NOS) was greater than excitatory fibers (TK) in all external muscle layers. TH was found in a proportion of fibers in the muscle, suggesting direct sympathetic innervation of the muscle occurs in human stomach. These TH fibers also contained NPY but were separate from NPY immunoreactive excitatory muscle motor nerves.Prominent in mucosal innervation were fibers immunoreactive for VIP and GRP and a separate population containing VAChT. Another population of fibers containing NPY and TH were found around mucosal glands and also around arteries supplying the mucosa. For all common fiber types in the mucosa there was a gradient of densities such that most fibers were found in the bottom third of the mucosa and few fibers were found in the top third of the glands near the lumen. Rare CGRP containing fibers were also seen in the mucosa but were not present in every section suggesting they are rare and unevenly distributed.We conclude that the signature chemistries of nerve fibers that innervate the gastric muscle and mucosa in human are similar to those present in other species, including rat. An exception is the prominent direct innervation of the gastric muscle by extrinsic sympathetic axons which is often absent in small mammals. This parallel chemistry will allow us to extrapolate circuits determined experimentally in rat to human and to identify cell body types in the myenteric ganglia.Support or Funding InformationThis work was supported by NIH (SPARC) grant ID # OT2OD023847 (PI Terry Powley) to John Furness and Martin Stebbing.
ADAM17 on glutamatergic neurons inhibits GABAergic signaling in a salt‐sensitive hypertension model
Authors: Xu Jiaxi , Lazartigues Eric 
Published: April 2020

The brain plays an important role in modulating sympathetic drive to individual organs, leading to changes in cardiac output, vascular resistance and blood pressure regulation. Within the central nervous system, A Disintegrin And Metalloprotease 17 (ADAM17) impairs the compensatory activity of angiotensin converting enzyme type 2 (ACE2) through ectodomain shedding during hypertension. We previously observed that activation of neuronal ADAM17, especially in excitatory neurons, contributes to the development of neurogenic hypertension through promoting sympatho‐excitation. It was also revealed that ADAM17 located on glutamatergic neurons plays a supportive role in Ang‐II‐induced neuronal activation. To investigate the contributing mechanism, deoxycorticosterone (DOCA)‐salt (1mg/g body weight sc + 1% saline po for 3 weeks) or sham treatment was given to mice harboring ADAM17 knockdown in glutamatergic neurons (A17G) and their control littermates (C57Bl6/J male mice, 14–16 week‐old, n=10). At the end of the treatment, mice were sacrificed and their brains were collected. Expression levels of NMDA receptors (Grin1), AMPA receptors (GluR1), as well as GABAa receptors and Gad67 was assessed by QRT‐PCR. Among these genes, mRNA levels for Grin1, GluR1, and GABAa receptors were shown to be unaffected in the hypothalamus of either A17G mice or controls. However, mRNA level of Gad67, a critical enzyme that catalyzes the formation of GABA, was found to be significantly reduced in DOCA‐salt‐treated control mice, while it was significantly upregulated in the hypothalamus of DOCA‐salt‐treated A17G mice, implying that activation of ADAM17 in glutamatergic neurons might have a negative impact on GABAergic signaling. It was reported previously that neuro‐inflammation, especially microglia activation, can increase glutamate activity and decrease GABA synthesis as well as its release. Through CD11b labeling, we observed that less microglia was activated by DOCA‐salt treatment in the hypothalamus of A17G mice, compared to controls. Meanwhile, the markedly reduced interleukin‐6 (IL‐6) level in the hypothalamus also suggested that DOCA‐salt‐induced neuro‐inflammation was blunted in mice lacking ADAM17 in glutamatergic neurons. In addition, the distribution of ADAM17 was also studied. Beyond glutamatergic neurons, assessment of ADAM17’s presence in other neuronal populations and brain regions revealed its expression in GABAergic neurons within the MnPO (median preoptic nucleus), PVN and BNST (bed nucleus of the stria terminalis). Although the mechanism still needs to be verified, ADAM17‐mediated shedding in glutamatergic neurons seems to blunt GABAergic inhibitory activity. This may support the increase of glutamatergic neuronal excitability and sympatho‐excitation during DOCA‐salt hypertension.Support or Funding InformationVeterans Affairs Merit Award (BX004294), National Institutes of Health (HL093178 and COBRE P30GM106392) and LSUHSC‐NO Research Enhancement Program.
Role of Peroxisome Proliferator‐activated Receptor‐gamma in Type 2 Diabetes‐induced Testicular DNA Damage and Repair in Leptin Receptor‐deficient Obese Mice
Authors: Kilarkaje Narayana , Alfarhan Muneera Waheed , Al-Hussaini Heba 
Published: April 2020

The DNA damage repair mechanisms under hyperglycemic conditions are a subject of intense research as unrepaired DNA damage may enhance the possibility of carcinogenicity in diabetic patients. In this study, we investigated the role of peroxisome proliferator‐activated receptor‐gamma (PPARγ) in diabetes‐induced alterations in testicular functions and DNA damage and repair. Leptin signaling intact lean (heterozygous; db+/db−) and leptin receptor‐mutant (db−/db−) obese male mice (7‐week‐old; n=10/group) received either pioglitazone (a PPARγ agonist) or 2‐chloro‐5‐nitro‐N‐phenylbenzamide (a PPARγ antagonist) for 84 days (12 weeks) to modulate the receptor activities. Semi‐quantification of 4‐hydroxynonenal and 8‐oxo‐dG levels meassured the oxidative stress, and the TUNEL assay measured apoptotic testicular cells. Western blotting technique quantified the levels of base‐excision repair (BER) pathway proteins‐8‐oxoguanine glycosylases 1&2, apurinic/apyrimidinic endonuclease, DNA polymerase δ, poly (ADP‐ribose) polymerase 1 and X‐ray repair cross‐complementing protein‐1. PPARγ activation increased the body weights and reduced the blood glucose levels, but inhibition of PPARγ activities did not significantly affect these parameters in obese diabetic mice. Inhibition of PPARγ activities improved testis and epididymis weights and sperm counts in obese diabetic mice. The obese diabetic mice showed seminiferous tubular degeneration, epithelial sloughing and tubular atrophy and, modulation of PPARγ activities did not significantly protect testicular structure and function. The lack of leptin signaling in obese diabetic mice increased oxidative stress and oxidative DNA damage, and stimulation of PPARγ activities reduced only lipid peroxidation, and inhibition of PPARγ activities inhibited both lipid peroxidation and oxidative DNA damage. The obese diabetic mice showed upregulated base excision repair proteins to repair the increased oxidative DNA damage. PPARγ stimulation inhibited the DNA damage repair indicating its detrimental effects, and the inhibition of PPARγ activities led to inhibition of DNA damage repair in conjunction with reduced oxidative DNA damage. However, regardless of these modulatory effects of PPARγ, the obese diabetic mice showed comparable levels of apoptosis in their testes. In conclusion, PPARγ activation although reduces blood glucose levels, in the absence of leptin signaling upregulates DNA damage and inhibits base excision repair mechanisms in the testis. The inhibited PPARγ activities in the absence of leptin signaling are beneficial to protect the testicular functions in obese diabetic mice.Support or Funding InformationSupported by Kuwait University grant # YM05/17 and CGS.
Role of arrestin1 in regulation of GPCR signaling in platelet activation
Authors: Chaudhary Preeti Kumari , Kim Sang Gu , Kim Soochong 
Published: April 2020

The arrestins are a class of soluble proteins that function in concert with the GPCR kinases to stop or arrest GPCR‐mediated intracellular signaling. Although β‐arrestins function in the desensitization of most GPCRs, the functional differences of β‐arrestin1 (arrestin2, BARR1) versus β‐arrestin2 (arrestin1, BARR2) in the regulation of GPCR signaling in platelets and the mechanisms of desensitization of platelets to GPCR agonists by β‐arrestins have not been understood. In this study, we identify the role of BARR2 in the regulation of platelet function and GPCR signaling in platelets. We used mice lacking BARR1 and BARR2 to evaluate the functional role of BARR2 in platelet activation. Platelet aggregation, dense‐granule secretion, and fibrinogen receptor activation induced by 2‐MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in BARR2 −/− platelets compared to WT platelets. In contrast to BARR2 −/− platelets, AYPGKF‐, thrombin‐, and U46619‐induced platelet aggregation and secretion were significantly inhibited in BARR1 −/− platelets compared to WT platelets, while 2‐MeSADP‐induced platelet aggregation and secretion were minimally affected in BARR1 −/−platelets. However, CRP‐induced platelet aggregation and secretion were not affected in both BARR1 −/− and BARR2 −/− platelets. These results suggest that BARR2 functions as the predominant regulator in the termination of GPCR signaling in platelets. In addition, platelet aggregation was restored in response to second challenge of 2‐MeSADP and AYPGKF in BARR2 −/− platelets whereas re‐stimulation of agonist failed to induce aggregation in WT and b‐arrestin1 −/− platelets, indicating BARR2 contributes to P2Y1, P2Y12, and PAR receptor desensitization. Furthermore, 2MeSADP‐ and AYPGKF‐induced Akt and ERK phosphorylations were significantly potentiated in BARR2 −/− platelets. Finally, BARR2 −/− mice show an enhanced and stable thrombus formation after FeCl3 injury to the carotid artery, indicating BARR2 is critical for thrombus formation in vivo. We conclude that BARR2 plays an important role in regulation of platelet function through selective GPCR desensitization.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) Grant of the Korean government (NRF‐2016R1D1A1B01010310) and the Global Research and Development Center (GRDC) Program through the NRF funded by the Ministry of Education, Science and Technology (2017K1A4A3014959).