bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption
Authors: Thumbigere-Math Vivek , Foster Brian L , Bachu Mahesh , Yoshii Hiroaki , Brooks Stephen R. , Coulter Alyssa , Chavez Michael B , Togi Sumihito , Neely Anthony L , Deng Zuoming , Mansky Kim C , Ozato Keiko , Somerman Martha J 
Published: March 2019

ABSTRACT

This is the first study to our knowledge to report a novel mutation in the interferon regulatory factor 8 gene (IRF8G388S) associated with multiple idiopathic tooth root resorption, a form of periodontal disease. The IRF8G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. Functional assays demonstrated that the IRF8G388S mutant promoted osteoclastogenesis and failed to inhibit NFATc1-dependent transcriptional activation when compared with IRF8WT control. Further, similar to subjects with heterozygous IRF8G388S mutation, Irf8+/– mice exhibited increased osteoclast activity in the mandibular alveolar bone surrounding molar teeth. Immunohistochemistry illustrated increased NFATc1 expression in the dentoalveolar region of Irf8–/– and Irf8+/– mice when compared with Irf8+/+ controls. Genomewide analyses revealed that IRF8 constitutively bound to regulatory regions of several thousand genes in osteoclast precursors, and genetic aberration of IRF8 significantly enhanced many osteoclast-specific transcripts. Collectively, this study delineates the critical role of IRF8 in defining osteoclast lineage and osteoclast transcriptional program, which may help in better understanding of various osteoclast-mediated disorders, including periodontal disease. © 2019 American Society for Bone and Mineral Research.
Integrated Model to Describe Morphine Pharmacokinetics in Humans
Authors: Liu Tao , Ivaturi Vijay , Gobburu Jogarao 
Published: March 2019

AbstractThe pharmacokinetics (PK) of morphine has been extensively investigated. Though different publications have focused on the various aspects of morphine PK, none have quantitatively interpreted morphine PK across different publications. The objective of this research is to summarize the current understanding of morphine PK in humans quantitatively. In this research, a parent‐metabolite compartmental PK modeling approach was used to summarize the current understanding of morphine PK in humans. Plasma concentration‐time profiles and cumulative urine recovery time profiles of morphine, morphine‐3‐glucuronide, and morphine‐6‐glucuronide were digitized from the previous publications to develop the parent‐metabolite PK model. The parent‐metabolite PK model successfully described the plasma concentration‐time profiles and cumulative urine recovery of morphine as well as its two major metabolites, morphine‐3‐glucuronide and morphine‐6‐glucuronide, after intravenous and oral administration of morphine. This research separated out the first‐pass effect on morphine metabolism after oral administration. By integrating these results with two mass balance studies of morphine, a clear picture of morphine absorption and disposition is given. Though the results are mainly based on data collected from healthy volunteers or patients whose disease is not expected to impact morphine PK, the parent‐metabolite model sets a framework to further evaluate morphine PK in special populations, such as pediatrics and patients with renal impairment.
Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis
Authors: Handa Priya , Thomas Sunil , Morgan-Stevenson Vicki , Maliken Bryan D , Gochanour Eric , Boukhar Sarag , Yeh Matthew M , Kowdley Kris V 
Published: March 2019

Abstract
We have previously demonstrated that iron overload in hepatic reticuloendothelial system cells (RES) is associated with severe nonalcoholic steatohepatitis (NASH) and advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Recruited myeloid-derived macrophages have gained a pivotal position as drivers of NASH progression and fibrosis. In this study, we used bone marrow-derived macrophages (BMDM) from C57Bl6 mice as surrogates for recruited macrophages and examined the effect of iron on macrophage polarization. Treatment with iron (ferric ammonium citrate, FAC) led to increased expression levels of M1 markers: CCL2, CD14, iNOS, IL-1β, IL-6, and TNF-α; it also increased protein levels of CD68, TNF-α, IL-1β, and IL-6 by flow cytometry. This effect could be reversed by desferrioxamine, an iron chelator. Furthermore, iron loading of macrophages in the presence of IL-4 led to the down-regulation of M2 markers: arginase-1, Mgl-1, and M2-specific transcriptional regulator, KLF4. Iron loading of macrophages with IL-4 also resulted in reduced phosphorylation of STAT6, another transcriptional regulator of M2 activation. Dietary iron overload of C57Bl6 mice led to hepatic macrophage M1 activation. Iron overload also stimulated hepatic fibrogenesis. Histologic analysis revealed that iron overload resulted in steatohepatitis. Furthermore, NAFLD patients with hepatic RES iron deposition had increased hepatic gene expression levels of M1 markers, IL-6, IL-1β, and CD40 and reduced gene expression of an M2 marker, TGM2, relative to patients with hepatocellular iron deposition pattern. We conclude that iron disrupts the balance between M1/M2 macrophage polarization and leads to macrophage-driven inflammation and fibrogenesis in NAFLD.
Synthetic CpG oligonucleotides as potential modulators of neutrophil survival in PAMP-associated inhibition of apoptosis
Authors: Golenkina Ekaterina A , Viryasova Galina M , Galkina Svetlana I , Arifulin Evgenii A , Gaponova Tatjana V , Romanova Yulia M , Sud’ina Galina F 
Published: March 2019

Abstract
We studied the effects of a synthetic CpG oligonucleotide (CpG ODN2006) on polymorphonuclear leukocyte (PMNL, neutrophil) survival and oxidant status. CpG ODN2006 showed a dose-dependent effect on the apoptosis of resting neutrophils. Without affecting the viability of resting cells, low concentrations of CpG ODN2006 interfered with Salmonella typhimurium-mediated viability prolongation and increased neutrophil apoptosis to control levels. CpG ODN2006 stimulated neutrophil apoptosis by enhancing ROS generation. Even small doses of ODN could induce the production of intracellular superoxide anions. The high superoxide reactogenicity, including with respect to nitrogen oxide, led to increased levels of intracellular ROS and RNS, which ultimately caused apoptosis. The pro-oxidant effect of low concentrations of CpG ODN2006 was not sufficient to trigger irreversible pro-apoptotic mechanisms. However, the sensitivity of PMNLs to ODN2006, a modulator of apoptosis, increased significantly under conditions of infectious inflammation. Inactivated S. typhimurium proved to be suitable for simulating inflammatory conditions in vitro.
Real-time deformability cytometry reveals sequential contraction and expansion during neutrophil priming
Authors: Bashant Kathleen R , Vassallo Arlette , Herold Christoph , Berner Reinhard , Menschner Leonhard , Subburayalu Julien , Kaplan Mariana J , Summers Charlotte , Guck Jochen , Chilvers Edwin R , Toepfner Nicole 
Published: March 2019

Abstract
It has become increasingly apparent that the biomechanical properties of neutrophils impact on their trafficking through the circulation and in particularly through the pulmonary capillary bed. The retention of polarized or shape-changed neutrophils in the lungs was recently proposed to contribute to acute respiratory distress syndrome pathogenesis. Accordingly, this study tested the hypothesis that neutrophil priming is coupled to morpho-rheological (MORE) changes capable of altering cell function. We employ real-time deformability cytometry (RT-DC), a recently developed, rapid, and sensitive way to assess the distribution of size, shape, and deformability of thousands of cells within seconds. During RT-DC analysis, neutrophils can be easily identified within anticoagulated “whole blood” due to their unique granularity and size, thus avoiding the need for further isolation techniques, which affect biomechanical cell properties. Hence, RT-DC is uniquely suited to describe the kinetics of MORE cell changes. We reveal that, following activation or priming, neutrophils undergo a short period of cell shrinking and stiffening, followed by a phase of cell expansion and softening. In some contexts, neutrophils ultimately recover their un-primed mechanical phenotype. The mechanism(s) underlying changes in human neutrophil size are shown to be Na+/H+ antiport-dependent and are predicted to have profound implications for neutrophil movement through the vascular system in health and disease.
Enhanced uniform data sampling for constrained data‐driven modeling of antenna input characteristics
Authors: Koziel Slawomir , Sigurðsson Ari T. , Pietrenko‐Dabrowska Anna , Szczepanski Stanislaw 
Published: March 2019

AbstractData‐driven surrogates are the most popular replacement models utilized in many fields of engineering and science, including design of microwave and antenna structures. The primary practical issue is a curse of dimensionality, which limits the number of independent parameters that can be accounted for in the modeling process. Recently, a performance‐driven modeling technique has been proposed where the constrained domain of the model is spanned by a set of reference designs optimized with respect to selected figures of interest. This approach allows for significant improvement of prediction power of the surrogates without the necessity of reducing the parameter ranges. Yet uniform allocation of the training data samples in the constrained domain remains a problem. Here, a novel design of experiments technique ensuring better sample uniformity is proposed. Our approach involves uniform sampling on the domain‐spanning manifold and linear transformation of the remaining sample vector components onto orthogonal directions with respect to the manifold. Two antenna examples are provided to demonstrate the advantages of the technique, including application case studies (antenna optimization).
Gender difference of CCAAT/enhancer binding protein homologous protein deficiency in susceptibility to osteopenia
Authors: Wu Cheng‐Tien , Chen Ya‐Wen , Su Yen‐Hao , Chiu Chen‐Yuan , Guan Siao‐Syun , Yang Rong‐Seg , Liu Shing‐Hwa 
Published: March 2019

ABSTRACTExpression of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) is induced during endoplasmic reticulum (ER) stress, which is related to apoptosis in several cell types. CHOP null mice have been exhibited to decrease bone formation. However, a study of transgenic mice overexpressing CHOP in the bone microenvironment showed that CHOP overexpression impairs the osteoblastic function leading to osteopenia. The regulatory role of CHOP in bone formation is controversial and still remains to be clarified. Here, we investigated the alterations in bone microstructure of CHOP knockout (Chop−/−) mice and tested the gender difference of CHOP deficiency in susceptibility to osteopenia. Adult female and male mice (WT) and Chop−/− mice were used. The microcomputed tomography (µCT) analysis in trabecular bone and cortical bone of tibia was determined. Trabecular bone volume fraction (BV/TV), trabecular number, and bone mineral density (BMD) in tibia are markedly decreased in both male and female Chop−/− mice compared to the control WT mice. Unexpectedly, the BMD and BV/TV in trabecular bone of tibia in female Chop−/− mice were significantly lower than in male Chop−/− mice. The similar results could also be observed in the cortical bone of tibia in Chop−/− mice. This gender difference was also observed in the decreased capacity of osteoblast differentiation of bone marrow cells isolated from Chop−/− mice. These results indicated that ER stress‐related CHOP signaling might play an important role in the bone formation in a mouse model, especially in females. There is the gender difference of CHOP deficiency in susceptibility to osteopenia. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res
Prospective application of stem cells to prevent post‐operative skeletal fibrosis
Authors: Li Xiaolei , Chen Song , Yan Lianqi , Wang Jingcheng , Pei Ming 
Published: March 2019

ABSTRACTPost‐operative skeletal fibrosis is considered one of the major complications causing dysfunction of the skeletal system and compromising the outcomes of clinical treatment. Limited success has been achieved using current therapies; more effective therapies to reduce post‐operative skeletal fibrosis are needed. Stem cells possess the ability to repair and regenerate damaged tissue. Numerous studies show that stem cells serve as a promising therapeutic approach for fibrotic diseases in tissues other than the skeletal system by inhibiting the inflammatory response and secreting favorable cytokines through activating specific signaling pathways, acting as so‐called medicinal signaling cells. In this review, current therapies are summarized for post‐operative skeletal fibrosis. Given that stem cells are used as a promising therapeutic approach for fibrotic diseases, little effort has been undertaken to use stem cells to prevent post‐operative skeletal fibrosis. This review aims at providing useful information for the potential application of stem cells in preventing post‐operative skeletal fibrosis in the near future. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1236–1245, 2019.
Gender and disease severity determine proximal femoral morphology in developmental dysplasia of the hip
Authors: Boughton Oliver R. , Uemura Keisuke , Tamura Kazunori , Takao Masaki , Hamada Hidetoshi , Cobb Justin P. , Sugano Nobuhiko 
Published: March 2019

ABSTRACTIn this computed tomography (CT) morphological study we describe the way the proximal femoral morphology differs with worsening degrees of developmental dysplasia of the hip (DDH) and describe gender differences in patients with DDH. Forty‐nine male patients with DDH were matched with 49 females with DDH, using age and the Crowe classification of DDH severity. The femoral length, anteversion, neck‐shaft angle, offset, neck length, canal‐calcar ratio, canal flare index, lateral center‐edge angle, alpha angle, pelvic tilt, and pelvic incidence were measured for each patient on their pre‐operative CT scans, prior to total hip arthroplasty surgery. Femoral anteversion and neck length were 16° and 47 mm, 25°and 36 mm, 26° and 43 mm, and 44° and 36 mm, for Crowe I and III males and Crowe I and III females, respectively. The mean male anteversion was 22° (±14), compared to 30° (±15.5) in females (p = 0.02, Confidence Interval: 1.6–14.9). Gender differences in femoral length, neck length and offset lost significance when height‐normalized and no other significant gender differences were found. In conclusion, femoral neck length reduces with increasing DDH severity, whilst anteversion tends to increase. Male patients with DDH have significantly less femoral anteversion, which has important implications for osteotomy and arthroplasty surgery in DDH. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res
Effect of trabecular metal on the elution of gentamicin from Palacos cement
Authors: Mooney Jake A. , Manasherob Robert , Smeriglio Piera , Bhutani Nidhi , Amanatullah Derek F. 
Published: March 2019

ABSTRACTPeriprosthetic joint infections continues to be a common complication in total joint arthroplasty, resulting in significant morbidity, mortality, and additional cost. Trabecular metal implants with an internal cemented interface may be customizable drug delivery devices with an ingrowth interface. Thirty‐six acetabular implants were assembled in vitro, half with a trabecular metal shell and half without. The antibiotic loaded bone cement was prepared via three different mixing techniques and at two different mixing times. Mixing time had a significant effect on the total amount of gentamicin eluted. The long mixing protocol eluted up to 126% (p = 0.001) more gentamicin than the short mixing protocol at 4 h and 192% (p < 0.001) more at 7 days. Hand or mechanical mixing technique had no significant effect on elution at 4 h. At 7 days, the mechanical mixing system under vacuum eluted over 50% (p = 0.031) more gentamicin than without a vacuum and nearly 60% (p = 0.040) more gentamicin than hand mixing. The use of a trabecular metal shell had no significant effect on the bulk elution of gentamicin at 4 h (p > 0.05) but significantly reduced total gentamicin elution under certain mixing protocols at 7 days. A possible optimization strategy to improve elution kinetics would be to use a long mixing time with a mechanical mixing system under vacuum. The establishment of trabecular metal as an effective delivery vehicle for antibiotics makes possible an entirely new class of drug eluting device designs. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res
Botox‐induced muscle paralysis alters intracortical porosity and osteocyte lacunar density in skeletally mature rats
Authors: Gatti Vittorio , Ghobryal Bishoy , Gelbs Michelle J. , Gerber Michael B. , Doty Stephen B. , Cardoso Luis , Fritton Susannah P. 
Published: March 2019

ABSTRACTReduced mechanical loading can lead to disuse osteoporosis, resulting in bone fragility. Disuse models report macroscopic bone loss due to muscle inactivity and immobilization, yet only recently has there been quantification of the effects of disuse on the vascular pores and osteocyte network, which are believed to play an important role in mechanotransduction via interstitial fluid flow. The goal of this study was to perform a high‐resolution analysis of the effects of muscle inactivity on intracortical porosity and osteocyte lacunar density in skeletally mature rats. Muscle paralysis was induced in 20‐week‐old female Sprague Dawley rats by injection of botulinum neurotoxin. Rats were injected in the right hindlimb muscles with either Botox (BTX, n = 8) or saline solution (CTRL, n = 8), with a third group used as baseline controls (n = 8). Four weeks after injection, Botox caused a ∼60% reduction in hindlimb muscle mass. High‐resolution micro‐CT analysis showed that Botox‐induced muscle paralysis increased vascular canal porosity and reduced osteocyte lacunar density within the tibial metaphysis cortex. Cortical thickness and other areal properties were diminished in the proximal tibial metaphysis, whereas no differences were found in the mid‐diaphysis. Within the BTX group, the injected limbs showed a lower cancellous bone volume fraction relative to the contralateral limb. These results indicate that diminished muscle activity alters the vascular canal porosity and osteocyte lacunar density in cortical bone, which could alter interstitial fluid flow, affecting molecular transport and the transmission of mechanical signals to osteocytes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res
Novel Near‐Infrared Fluorescence‐Guided Surgery With Vesicular Stomatitis Virus for Complete Surgical Resection of Osteosarcomas in Mice
Authors: Sakuda Tomohiko , Kubo Tadahiko , Johan Muhammad Phetrus , Furuta Taisuke , Sakaguchi Takemasa , Nakanishi Mahito , Ochi Mitsuo , Adachi Nobuo 
Published: March 2019

ABSTRACTAttempts have been made to visualize tumor cells intraoperatively with fluorescence guidance. However, the clear demarcation and complete tumor resection have always been a challenging task. To address this, we have developed a novel fluorescence bioimaging system with vesicular stomatitis virus (VSV) incorporating Katushka, near‐infrared fluorescent protein. VSV is tumor‐specific owing to the deficiency of antiviral interferon signaling pathways in tumor cells. We aimed to evaluate the tumor specificity of the recombinant VSV‐Katushka (rVSV‐K) in osteosarcoma cells and to assess the feasibility of complete tumor resection by the rVSV‐K fluorescence guidance. In in vitro experiments, mouse and human osteosarcoma cell lines and normal human mesenchymal stem cells were infected with rVSV‐K and observed by fluorescence microscopy. Near‐infrared fluorescence was observed only in osteosarcoma cells, even at a low‐concentration of virus infections. In in vivo experiments, mouse osteosarcoma (LM8) cells were transplanted subcutaneously into the back of immune‐competent mice to produce an osteosarcoma, which was then injected with rVSV‐K. The areas emitting fluorescence were resected using a bioimaging system. The distance between the surgical and tumor margins of the fluorescence‐guided resection with rVSV‐K group was significantly larger than that of the non‐guided resection groups. The local recurrence rate was significantly lower in the fluorescence‐guided resection with rVSV‐K group than in the non‐guided resection groups. The distant metastasis rate and average survival rate were not significantly different between all groups. These results suggest that the rVSV‐K is specific to osteosarcoma cells and enables complete tumor resection of osteosarcomas in mice. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res
Durable molybdenum oxide coated solid‐phase microextraction fiber for highly selective and efficient extraction of polycyclic aromatic hydrocarbons in water
Authors: Liu Hongmei , Wang Xiaoqi , Fan Hua , Dang Shihao 
Published: March 2019

AbstractA bonding method was developed for coating molybdenum oxides onto a steel wire substrate, which was used as a solid‐phase microextraction fiber, was coupled with gas chromatography. Based on the characterization, it is found that the as‐prepared molybdenum oxides material contained a nanobelt structure with a uniform size and good dispersibility. In addition, there were a large number of small protrusions on the surface of the nanobelts. These characteristics provided a large specific surface area for extraction. Molybdenum oxides exhibited a high extraction selectivity for polycyclic aromatic hydrocarbons owing to its moderate coordination. After the optimization of the factors, method detection limits of < 1.25 μg/L were achieved, and the calibration curves were linear within the range of 2–600 μg/L. In addition, repeatability was demonstrated, and the relative standard deviation < 6.4%. The molybdenum oxides coating had a high scratch resistance, which could effectively prevent coating wear and failure. Combined with the high thermal and chemical stability, the service life of the coating was improved and could be used 150 times without a significant reduction in the extraction performance. Finally, the as‐prepared fiber had a comparable extraction capacity and higher partition coefficients that those of commercial polyacrylate fibers.