bluuebunny/crossref_metadata_2025 huggingface dataset:
Three‐Dimensional Nitrogen‐Doped Graphene Frameworks from Electrochemical Exfoliation of Graphite as Efficient Supercapacitor Electrodes
Authors: Xiao Xiang , Zeng Yinxiang , Feng Haobin , Xu Kaiqi , Zhong Guobin , Wu Shijia , Wang Chao , Zhao Wei , Su Wei , Wei Zengfu , Lu Xihong
Published: October 2018

A facile, low‐cost, and efficient electrochemical exfoliation method is demonstrated to prepare three‐dimensional nitrogen‐doped graphene frameworks on a large scale. Benefiting from the enhanced specific surface area, increased conductivity and enriched active sites, the nitrogen‐doped graphene framework electrode exhibits remarkable capacitance, good cyclic stability, and superior rate capability (65.3% capacitance retention), outperforming most of the reported graphene‐based electrodes.
Topology and Nesting of the Zero Set Components of Monochromatic Random Waves
Authors: Canzani Yaiza , Sarnak Peter
Published: October 2018

This paper is dedicated to the study of the topologies and nesting configurations of the components of the zero set of monochromatic random waves. We prove that the probability of observing any diffeomorphism type and any nesting arrangement among the zero set components is strictly positive for waves of large enough frequencies. Our results are a consequence of building Laplace eigenfunctions in euclidean space whose zero sets have a component with prescribed topological type or an arrangement of components with prescribed nesting configuration. © 2018 Wiley Periodicals, Inc.
Assessment of Altered Cholesterol Homeostasis by Xenobiotics Using Ultra‐High Performance Liquid Chromatography–Tandem Mass Spectrometry
Authors: Herron Josi , Hines Kelly M. , Xu Libin
Published: October 2018

Cholesterol and cholesterol‐derived oxysterols are critical for embryonic development, synapse formation and function, and myelination, among other biological functions. Indeed, alterations in levels of cholesterol, sterol precursors, and oxysterols result in a variety of developmental disorders, emphasizing the importance of cholesterol homeostasis. The ability of xenobiotics to reproduce similar phenotypes by altering cholesterol homeostasis has increasingly become of interest. Therefore, the ability to quantitatively assess alterations in cholesterol homeostasis resulting from exposure to xenobiotics is of value. This unit describes methods for the quantitative assessment of altered post‐squalene cholesterol biosynthesis and subsequent oxysterol formation in various sample types using ultra‐high performance liquid chromatography‐tandem mass spectrometry (UHPLC‐MS/MS). Understanding alterations in cholesterol homeostasis resulting from xenobiotic exposure can provide key insight into the toxicant's mechanism of action and resulting phenotype. © 2018 by John Wiley & Sons, Inc.
Organic Functionalization of Polyoxovanadate–Alkoxide Clusters: Improving the Solubility of Multimetallic Charge Carriers for Nonaqueous Redox Flow Batteries
Authors: VanGelder Lauren E. , Petel Brittney E. , Nachtigall Olaf , Martinez Gabriel , Brennessel William W. , Matson Ellen M.
Published: October 2018

The success of nonaqueous redox flow battery technology requires synthetic advances in charge carrier design to increase compatibility with organic solvents. Herein, previous discoveries related to the development of multimetallic charge carriers are built upon with the high‐yielding syntheses of ether‐ functionalized polyoxovanadate–alkoxide clusters, [V6O7(OR)9(OCH2)3CR′] (R=CH3, C2H5; R′=CH3, CH2OCH3, CH2OC2H4OCH3). Like their homoleptic congeners [V6O7(OR)12] (R=CH3, C2H5), these clusters exhibit four redox events, spanning nearly a two‐volt window, and demonstrate rapid electron‐transfer kinetics. The ethoxide derivatives can reversibly cycle two electrons at each electrode in symmetric charging schematics, demonstrating long‐term solution stability. Furthermore, ether functionalization yields a twelvefold increase in solubility, a factor which directly dictates the energy density of a redox flow battery.
Complex long‐term dynamics of pollinator abundance in undisturbed Mediterranean montane habitats over two decades
Authors: Herrera Carlos M.
Published: October 2018

Current notions of “pollinator decline” and “pollination crisis” mainly arose from studies on pollinators of economic value in anthropogenic ecosystems of mid‐latitude temperate regions. Comprehensive long‐term pollinator data from biologically diverse, undisturbed communities are needed to evaluate the actual extent of the so‐called “global pollination crisis.” This paper analyzes the long‐term dynamics of pollinator abundance in undisturbed Mediterranean montane habitats using pollinator visitation data for 65 plant species collected over two decades. Objectives are (1) to elucidate patterns of long‐term changes in pollinator abundance from the perspectives of individual plant species, major pollinator groups, and the whole plant community and (2) to propose a novel methodological implementation based on combining a planned missing data design with the analytical strength of mixed effects models, which allows one to draw community‐wide inferences on long‐term pollinator trends in species‐rich natural habitats. Probabilistic measurements (“patch visitation probability” and “flower visitation probability” per time unit) were used to assess pollinator functional abundance for each plant species on two separate, randomly chosen years. A total of 13,054 pollinator censuses accounting for a total watching effort of 2,877,039 flower‐min were carried out on 299 different dates. Supra‐annual unstability in pollinator functional abundance was the rule, with visitation probability to flowering patches and/or individual flowers exhibiting significant heterogeneity between years in the majority of plant species (83%). At the plant‐community level, there was a significant linear increase in pollinator functional abundance over the study period. Probability of pollinator visitation to flowering patches and individual flowers increased due to increasing visitation by small solitary bees and, to a lesser extent, small beetles. Visitation to different plant species exhibited contrasting changes, and insect orders and genera differed widely in sign and magnitude of linear abundance trends, thus exemplifying the complex dynamics of community‐wide changes in pollinator functional abundance. Results of this investigation indicate that pollinator declines are not universal beyond anthropogenic ecosystems; stress the need for considering broader ecological scenarios and comprehensive samples of plants and pollinators; and illustrate the crucial importance of combining ambitious sampling designs with powerful analytical schemes to draw reliable inferences on pollinator trends at the plant community level.
The emergence of environmental taxes in Ghana—A public choice analysis
Authors: Kombat Alex Moyem , Wätzold Frank
Published: October 2018

Environmental pollution has become a huge problem in many parts of Africa. Until a few years ago, the prevalent response of African governments was the introduction of command and control instruments. This trend has changed and some African countries are now turning their attention to the use of economic instruments including taxes. One of the countries that has introduced environmental taxes is Ghana. This paper analyzes the policy processes related to the emergence and implementation of three environmental taxes in Ghana, namely, taxes on plastics, overaged vehicles, and petroleum applying a public choice approach as the framework of analysis. Overall, we find that all actors behaved as proposed by public choice resulting in environmental tax designs that do not follow what economists consider optimal. Nevertheless, the taxes contributed to mitigate environmental problems, partly because a share of the tax revenue was used for this purpose. Thus, environmental taxes have the potential to mitigate environmental problems in Africa provided functioning administrations are in place. This is, however, currently not the case in many African countries.
Two New, Metastable Polymorphs of Lithium Pyrophosphate Li4P2O7
Authors: Raguž Branimir , Wittich Knut , Glaum Robert
Published: October 2018

By quenching a melt of Li4P2O7 two new, thermodynamically metastable polymorphs are obtained as biphasic mixtures. The crystal structure of one polymorph was determined from single‐crystal X‐ray diffraction data {Li4P2O7‐trig*: colorless, trigonal, P3212 (no. 153), Z = 3, a = 5.1699(2) Å, c = 18.9722(8) Å, 60 parameters, R1 = 0.018, wR2 = 0.051, 1265 unique reflections with Fo > 4σ(Fo)}. For the second polymorph a structure model was derived, using direct space methods followed by Rietveld refinement {Li4P2O7‐pseudomono*: P1, a = 7.88468(5) Å, b = 10.30394(6) Å, c = 7.54581(4) Å, α = 89.8142(6)°, β = 115.26(2)°, γ = 90.2015(5)°, RI = 7.62}. 31P‐MAS‐NMR measurements show δiso = –2.9 ppm for Li4P2O7‐pseudomono* and δiso = –6.6 ppm for the trigonal polymorph. Substitution of about 10 % lithium by copper(I) is possible in the trigonal as well as in the long known triclinic polymorph as is evidenced by the results of SXRD, XRPD, and 31P‐MAS‐NMR measurements.
Exposure and cognitive‐behavioural therapy for chronic back pain: An RCT on treatment processes
Authors: Schemer Lea , Schroeder Andreas , Ørnbøl Eva , Glombiewski Julia Anna
Published: October 2018

Background

To improve treatment outcomes, it is essential to understand the processes involved in therapeutic change. The aim of this study was to investigate the processes involved in treatment of individuals with chronic lower back pain (CLBP) and high fear‐avoidance. Graded in vivo exposure (Exposure), a specific treatment, and cognitive‐behavioural therapy (CBT), a general treatment, were compared.

Methods

Our study used data from a three‐arm randomized controlled trial. The sample comprised 61 CLBP patients (pain duration >3 months; sufficient level of fear‐avoidance). Assessments of session‐by‐session processes were done weekly for a maximum 14 weeks. The primary outcome, functional disability, was assessed at pre‐treatment, post‐treatment and 6‐months follow‐up. First, two‐level models were used to test for treatment‐related similarities and differences in the changes in session‐by‐session measures (i.e., common and unique treatment processes respectively). Second, we analysed treatment processes as predictors of treatment outcome.

Results

Contrary to our expectations, we found no evidence of unique treatment processes. Our results indicate that Exposure and CBT share some treatment processes. Specifically, patients reported a reduction in fear of movement and improvements in their ability to relax, to distract themselves, to manage their pain, to confront feared movements, to be active and to enjoy things despite their pain. Changes in fear of movement, relaxation, distraction, confrontation, activity and pain‐related self‐efficacy were also related to disability reduction.

Conclusions

Despite conceptual differences, Exposure and CBT may share common treatment processes. Future research needs to address, however, whether these processes need to be targeted directly or can be supported indirectly.

Significance

We identified several treatment processes (e.g., reduction of fear of movement, enhancement of self‐efficacy), which were associated with disability reduction during the management of chronic pain and fear‐avoidance. These processes appeared to be equally important for Exposure and CBT. Practitioners should optimize these processes to improve their patients’ functioning.
Why mu‐opioid agonists have less analgesic efficacy in neuropathic pain?
Authors: Martínez‐Navarro Miriam , Maldonado Rafael , Baños Josep‐E.
Published: October 2018

Injury to peripheral nerves often leads to abnormal pain states (hyperalgesia, allodynia and spontaneous pain), which can remain long after the injury heals. Although opioid agonists remain the gold standard for the treatment of moderate to severe pain, they show reduced efficacy against neuropathic pain. In addition to analgesia, opioid use is also associated with hyperalgesia and analgesia tolerance, whose underlying mechanisms share some commonalities with nerve injury‐induced hypersensitivity. Here, we reviewed up‐to‐day research exploring the contribution of mu‐opioid receptor (MOR) on the pathophysiology of neuropathic pain and on analgesic opioid actions under these conditions. We focused on the specific contributions of MOR populations at peripheral, spinal and supraspinal level. Moreover, evidences of neuroplastic changes that may underlie the low efficacy of MOR agonists under neuropathic pain conditions are reviewed and discussed. Sensitization processes leading to pain hypersensitivity, molecular changes in signalling pathways triggered by MOR and glial activation are some of these mechanisms elicited by both nerve injury and opioid exposure. Nerve injury‐induced pain hypersensitivity might be masking the initial analgesic effects of opioid agonists, and alternatively, sustained opioid treatment to individuals already suffering from neuropathic pain could aggravate their pathophysiological state. Finally, some combined therapies that can increase opioid analgesic effectiveness in neuropathic pain treatment are highlighted.

Significance

This review provides evidence of the low benefit of opioid monotherapy in neuropathic pain and analyses the reasons of this reduced effectiveness. Opioid agonists along with drugs targeted to block the sensitization processes induced by MOR stimulation might result in a better management of neuropathic pain.
The association of adverse childhood experiences and of resilience with chronic noncancer pain in the German adult population – A cross‐sectional survey
Authors: Häuser Winfried , Brähler Elmar , Schmutzer Gabriele , Glaesmer Heide
Published: October 2018

Background

Adverse childhood experiences (ACE) might predispose to and resilience might protect against chronic noncancer pain (CNCP). We studied whether ACE are positively associated with CNCP, whether resilience was negatively associated with CNCP and whether resilience buffered a potential association of ACE with CNCP.

Methods

A cross‐sectional survey (N = 2,425) representative for the adult German general population was conducted in 2013. The following questionnaires were used: Chronic Pain Grade Questionnaire for CNCP stages; Childhood Trauma Screener for ACE; Brief Resilient Coping Scale for resilience; Patient Health Questionnaire 4 for psychological symptom burden; Giessen Subjective Complaints List for somatic symptom burden. To test the association of ACE and resilience with CNCP stages, logistic regression analyses including sociodemographic variables and psychological and somatic symptom burden as possible confounders were calculated.

Results

No statistically significant associations between any CNCP and disabling CNCP respectively with physical, emotional, and sexual abuse; emotional and physical neglect if compared to no chronic pain were found in uni‐ and multivariate analyses. There was a small effect of combined ACE and a small attenuating effect of resilience on any and disabling CNCP in univariate, but not in multivariate analysis. Large associations were found between age > 65 years with any CNCP (OR 6.51 [95% confidence interval 3.38 to 12.51)] and disabling CNCP (OR 9.33 [95% confidence interval 2.39 to 36.41]), respectively, if compared to no pain.

Conclusions

There was no pain‐proneness by single and combined ACE for and no protection by resilience for any and for disabling CNCP in the general adult German population.

Significance

There is no pain‐proneness due to adverse childhood experiences for any and disabling chronic noncancer pain. Resilience does not protect against any and disabling chronic noncancer pain. Older age is the strongest predictor of any and disabling chronic noncancer pain.
Combination of Entecavir/Peginterferon Alfa‐2a in Children With Hepatitis B e Antigen–Positive Immune Tolerant Chronic Hepatitis B Virus Infection
Authors: Rosenthal Philip , Ling Simon C. , Belle Steven H. , Murray Karen F. , Rodriguez‐Baez Norberto , Schwarzenberg Sarah J. , Teckman Jeffrey , Lin Hsing‐Hua S. , Schwarz Kathleen B. ,   for the Hepatitis B Research Network (HBRN)
Published: October 2018

The optimal management strategy for children with immune‐tolerant chronic hepatitis B virus (HBV) infection remains unknown. The purpose of this clinical trial was to determine the safety and efficacy of therapy with entecavir and peginterferon in a group of children in the immune‐tolerant phase of HBV infection. Children with immune‐tolerant features of chronic hepatitis B (CHB) received entecavir once‐daily in a dose of 0.015 mg/kg (0.5 mg maximum) for 48 weeks; peginterferon alfa‐2a (180 µg/1.73m2 subcutaneously) once‐weekly was added at the end of week 8 and continued until week 48. The primary endpoint was lack of detectable hepatitis B e antigen (HBeAg) with HBV DNA levels ≤1,000 IU/mL 48 weeks after stopping therapy. Sixty children (75% female), median age 10.9 (range, 3.4‐17.9) years, were enrolled. All were positive for hepatitis B surface antigen (HBsAg) and HBeAg and had high levels of HBV DNA with normal or minimally elevated levels of alanine aminotransferase (ALT). Fifty‐five children completed the entire 48‐week course of therapy. At 48 weeks after treatment ended (week 96), 2 children (3%) achieved the primary endpoint and were also HBsAg negative and anti–hepatitis B surface antigen antibody (anti‐HBs) positive. One child was HBeAg positive but HBsAg negative at week 60; another was HBeAg negative but HBsAg positive at week 72, which were their last clinic visits. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty‐seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). Conclusion: The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune‐tolerant phase of HBV infection, and treatment was associated with frequent AEs.
ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training
Authors: Sinha Neha , Reagh Zachariah M. , Tustison Nicholas J. , Berg Chelsie N. , Shaw Ashlee , Myers Catherine E. , Hill Diane , Yassa Michael A. , Gluck Mark A.
Published: October 2018

Using high‐resolution resting state functional magnetic resonance imaging (fMRI), the present study tested the hypothesis that ABCA7 genetic risk differentially affects intra‐medial temporal lobe (MTL) functional connectivity between MTL subfields, versus internetwork connectivity of the MTL with the medial prefrontal cortex (mPFC), in nondemented older African Americans. Although the association of ABCA7 risk variants with Alzheimer's disease (AD) has been confirmed worldwide, its effect size on the relative odds of being diagnosed with AD is significantly higher in African Americans. However, little is known about the neural correlates of cognitive function in older African Americans and how they relate to AD risk conferred by ABCA7. In a case–control fMRI study of 36 healthy African Americans, we observed ABCA7 related impairments in behavioral generalization that was mediated by dissociation in entorhinal cortex (EC) resting state functional connectivity. Specifically, ABCA7 risk variant was associated with EC‐hippocampus hyper‐synchronization and EC‐mPFC hypo‐synchronization. Carriers of the risk genotype also had a significantly smaller anterolateral EC, despite our finding no group differences on standardized neuropsychological tests. Our findings suggest a model where impaired cortical connectivity leads to a more functionally isolated EC at rest, which translates into aberrant EC‐hippocampus hyper‐synchronization resulting in generalization deficits. While we cannot identify the exact mechanism underlying the observed alterations in EC structure and network function, considering the relevance of Aβ in ABCA7 related AD pathogenesis, the results of our study may reflect the synergistic reinforcement between amyloid and tau pathology in the EC, which significantly increases tau‐induced neuronal loss and accelerates synaptic alterations. Finally, our results add to a growing literature suggesting that generalization of learning may be a useful tool for assessing the mild cognitive deficits seen in the earliest phases of prodromal AD, even before the more commonly reported deficits in episodic memory arise.
Quantitative assessment of optical clearing methods in various intact mouse organs
Authors: Xu Jianyi , Ma Yilin , Yu Tingting , Zhu Dan
Published: October 2018

Various tissue optical clearing techniques have sprung up for large volume imaging. However, there are few methods showed clearing and imaging data on different organs while most of them were focused on mouse brain, and as a result, it is difficult to select the suitable method for organs in practical applications due to lack of quantitative evaluation and comprehensive comparison. Therefore, it is necessary to evaluate and compare the performances of clearing methods for different organs. In this paper, several typical optical clearing methods were applied, including 3DISCO, uDISCO, SeeDB, FRUIT, CUBIC, ScaleS and PACT to clear intact brain, heart, kidney, liver, spleen, stomach, lung, small intestine, skin and muscle. The clearing efficiency, sample deformation, fluorescence preservation and imaging depth of these methods were quantitatively evaluated. Finally, based on the systemic evaluation of various parameters described above, the appropriate clearing method for specific organ including kidney or intestine was screened out. This paper will provide important references for selection of appropriate clearing methods in related researches.
Automated assessment of breast cancer margin in optical coherence tomography images via pretrained convolutional neural network
Authors: Singla Neeru , Dubey Kavita , Srivastava Vishal
Published: October 2018

The benchmark method for the evaluation of breast cancers involves microscopic testing of a hematoxylin and eosin (H&E)‐stained tissue biopsy. Resurgery is required in 20% to 30% of cases because of incomplete excision of malignant tissues. Therefore, a more accurate method is required to detect the cancer margin to avoid the risk of recurrence. In the recent years, convolutional neural networks (CNNs) has achieved excellent performance in the field of medical images diagnosis. It automatically extracts the features from the images and classifies them. In the proposed study, we apply a pretrained Inception‐v3 CNN with reverse active learning for the classification of healthy and malignancy breast tissue using optical coherence tomography (OCT) images. This proposed method attained the sensitivity, specificity and accuracy is 90.2%, 91.7% and 90%, respectively, with testing datasets collected from 48 patients (22 normal fibro‐adipose tissue and 26 Invasive ductal carcinomas cancerous tissues). The trained network utilizes for the breast cancer margin assessment to predict the tumor with negative margins. Additionally, the network output is correlated with the corresponding histology image. Our results lay the foundation for the future that the proposed method can be used to perform automatic intraoperative identification of breast cancer margins in real‐time and to guide core needle biopsies.
Effect of oxidation on intrinsic residual stress in amorphous silicon carbide films
Authors: Deku Felix , Mohammed Shakil , Joshi‐Imre Alexandra , Maeng Jimin , Danda Vindhya , Gardner Timothy J. , Cogan Stuart F.
Published: October 2018

The change in residual stress in plasma enhanced chemical vapor deposition amorphous silicon carbide (a‐SiC:H) films exposed to air and wet ambient environments is investigated. A close relationship between stress change and deposition condition is identified from mechanical and chemical characterization of a‐SiC:H films. Evidence of amorphous silicon carbide films reacting with oxygen and water vapor in the ambient environment are presented. The effect of deposition parameters on oxidation and stress variation in a‐SiC:H film is studied. It is found that the films deposited at low temperature or power are susceptible to oxidation and undergo a notable increase in compressive stress over time. Furthermore, the films deposited at sufficiently high temperature (≥325 C) and power density (≥0.2 W cm−2) do not exhibit pronounced oxidation or temporal stress variation. These results serve as the basis for developing amorphous silicon carbide based dielectric encapsulation for implantable medical devices. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1654–1661, 2019.
miR-219a-5p Regulates Rorβ During Osteoblast Differentiation and in Age-related Bone Loss
Authors: Aquino-Martinez Ruben , Farr Joshua N , Weivoda Megan M , Negley Brittany A , Onken Jennifer L , Thicke Brianne S , Fulcer McKenzie M , Fraser Daniel G , van Wijnen Andre J , Khosla Sundeep , Monroe David G
Published: October 2018

Developing novel approaches to treat skeletal disorders requires an understanding of how critical molecular factors regulate osteoblast differentiation and bone remodeling. We have reported that (1) retinoic acid receptor-related orphan receptor beta (Rorβ) is upregulated in bone samples isolated from aged mice and humans in vivo; (2) Rorβ expression is inhibited during osteoblastic differentiation in vitro; and (3) genetic deletion of Rorβ in mice results in preservation of bone mass during aging. These data establish that Rorβ inhibits osteogenesis and that strict control of Rorβ expression is essential for bone homeostasis. Because microRNAs (miRNAs) are known to play important roles in the regulation of gene expression in bone, we explored whether a predicted subset of nine miRNAs regulates Rorβ expression during both osteoblast differentiation and aging. Mouse osteoblastic cells were differentiated in vitro and assayed for Rorβ and miRNA expression. As Rorβ levels declined with differentiation, the expression of many of these miRNAs, including miR-219a-5p, was increased. We further demonstrated that miR-219a-5p was decreased in bone samples from old (24-month) mice, as compared with young (6-month) mice, concomitant with increased Rorβ expression. Importantly, we also found that miR-219a-5p expression was decreased in aged human bone biopsies compared with young controls, demonstrating that this phenomenon also occurs in aging bone in humans. Inhibition of miR-219a-5p in mouse calvarial osteoblasts led to increased Rorβ expression and decreased alkaline phosphatase expression and activity, whereas a miR-219a-5p mimic decreased Rorβ expression and increased osteogenic activity. Finally, we demonstrated that miR-219a-5p physically interacts with Rorβ mRNA in osteoblasts, defining Rorβ as a true molecular target of miR-219a-5p. Overall, our findings demonstrate that miR-219a-5p is involved in the regulation of Rorβ in both mouse and human bone. © 2018 American Society for Bone and Mineral Research.
A Novel Rhein Derivative Modulates Bone Formation and Resorption and Ameliorates Estrogen-Dependent Bone Loss
Authors: Jiang Min , Wang Tianqi , Yan Xueming , Liu Zhuochao , Yan Yufei , Yang Kai , Qi Jin , Zhou Hanbing , Qian Niandong , Zhou Qi , Chen Bo , Xu Xing , Xi Xiaobing , Yang Chunhao , Deng Lianfu
Published: October 2018

Osteoporosis, an osteolytic disease that affects millions of people worldwide, features a bone remodeling imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Identifying dual target-directed agents that inhibit excessive bone resorption and increase bone formation is considered an efficient strategy for developing new osteoporosis treatments. Rhein, a natural anthraquinone, can be isolated from various Asian herbal medicines. Rhein and its derivatives have been reported to have various beneficial pharmacological effects, especially their bone-targeting ability and anti-osteoclastogenesis activity. Moreover, hydrogen sulfide (H2S) was reported to prevent ovariectomy- (OVX-) induced bone loss by enhancing bone formation, and sulfur replacement therapy has been considered a novel and plausible therapeutic option. Based on this information, we synthesized a rhein-derived thioamide (RT) and investigated its effects on bone resorption and bone formation in vitro and in vivo. It has been found that the RT-inhibited receptor activator of the nuclear factor-κB (NF-κB) ligand- (RANKL-) induced osteoclastogenesis and bone resorption in a dose-dependent manner. The expression of osteoclast marker genes was also suppressed by RT treatment. Furthermore, exploration of signal transduction pathways indicated that RT markedly blocked RANKL-induced osteoclastogenesis by attenuating MAPK pathways. However, RT treatment in an osteoblastic cell line, MC3TE-E1, indicated that RT led to an increase in the deposition of minerals and the expression of osteoblast marker genes, as demonstrated by Alizarin Red staining and alkaline phosphatase activity. Importantly, an OVX mouse model showed that RT could attenuate the bone loss in estrogen deficiency-induced osteoporosis in vivo with a smart H2S-releasing property and that there was a considerable improvement in the biomechanical properties of bone. Accordingly, our current work highlights the dual regulation of bone remodeling by the rhein-derived molecule RT. This may be a highly promising approach for a new type of anti-osteoporosis agent. © 2018 American Society for Bone and Mineral Research.
Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies
Authors: Baird Denis A , Evans Daniel S , Kamanu Frederick K , Gregory Jennifer S , Saunders Fiona R , Giuraniuc Claudiu V , Barr Rebecca J , Aspden Richard M , Jenkins Deborah , Kiel Douglas P , Orwoll Eric S , Cummings Steven R , Lane Nancy E , Mullin Benjamin H , Williams Frances MK , Richards J Brent , Wilson Scott G , Spector Tim D , Faber Benjamin G , Lawlor Deborah A , Grundberg Elin , Ohlsson Claes , Pettersson-Kymmer Ulrika , Capellini Terence D , Richard Daniel , Beck Thomas J , Evans David M , Paternoster Lavinia , Karasik David , Tobias Jonathan H
Published: October 2018

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10−9, adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
Preventing and Repairing Myeloma Bone Disease by Combining Conventional Antiresorptive Treatment With a Bone Anabolic Agent in Murine Models
Authors: Paton-Hough Julia , Tazzyman Simon , Evans Holly , Lath Darren , Down Jenny M , Green Alanna C , Snowden John A , Chantry Andrew D , Lawson Michelle A
Published: October 2018

Multiple myeloma is a plasma cell malignancy, which develops in the bone marrow and frequently leads to severe bone destruction. Current antiresorptive therapies to treat the bone disease do little to repair damaged bone; therefore, new treatment strategies incorporating bone anabolic therapies are urgently required. We hypothesized that combination therapy using the standard of care antiresorptive zoledronic acid (Zol) with a bone anabolic (anti-TGFβ/1D11) would be more effective at treating myeloma-induced bone disease than Zol therapy alone. JJN3 myeloma-bearing mice (n = 8/group) treated with combined Zol and 1D11 resulted in a 48% increase (p ≤ 0.001) in trabecular bone volume (BV/TV) compared with Zol alone and a 65% increase (p ≤ 0.0001) compared with 1D11 alone. Our most significant finding was the substantial repair of U266-induced osteolytic bone lesions with combination therapy (n = 8/group), which resulted in a significant reduction in lesion area compared with vehicle (p ≤ 0.01) or Zol alone (p ≤ 0.01). These results demonstrate that combined antiresorptive and bone anabolic therapy is significantly more effective at preventing myeloma-induced bone disease than Zol alone. Furthermore, we demonstrate that combined therapy is able to repair established myelomatous bone lesions. This is a highly translational strategy that could significantly improve bone outcomes and quality of life for patients with myeloma. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Silencing of FOXO6 inhibits the proliferation, invasion, and glycolysis in colorectal cancer cells
Authors: Li Quanying , Tang Hongna , Hu Fangfang , Qin Changjiang
Published: October 2018

Forkhead box class O6 (FOXO6) is an important member of FOXO family, which has been demonstrated to be implicated in tumor development. However, the role of FOXO6 in colorectal cancer (CRC) is still unclear. The study aimed to investigate the potential roles of FOXO6 in the development of CRC. Our results showed that FOXO6 was overexpressed in CRC tissues and cell lines. FOXO6 knockdown inhibited cell proliferation, as well as repressed the migration and invasion of CRC cells. Additionally, we found that FOXO6 knockdown altered cellular metabolism by inhibiting glycolysis and promoting mitochondrial respiration. Furthermore, FOXO6 knockdown inhibited the activation of PI3K/Akt/mTOR pathway in CRC cells. The results herein indicated that FOXO6 knockdown inhibited cell proliferation, migration, invasion, and glycolysis in CRC cells. PI3K/Akt/mTOR pathway was involved in the effects of FOXO6 on CRC cells. These findings suggested that FOXO6 might be a potential target for the CRC therapy.
Protein translation associated to PERK arm is a new target for regulation of metainflammation: A connection with hepatocyte cholesterol
Authors: Galindo‐Hernández Octavio , Córdova‐Guerrero Iván , Díaz‐Rubio Laura Janeth , Pulido‐Capiz Ángel , Díaz‐Villanueva José Fernando , Castañeda‐Sánchez César Yahel , Serafín‐Higuera Nicolás , García‐González Víctor
Published: October 2018

Endoplasmic reticulum stress is a cellular phenomenon that has been associated with metabolic disorders, contributing to the development of obesity, fatty liver disease, and dyslipidemias. Under metabolic overload conditions, in cells with a high protein‐secretory activity, such as hepatocytes and Langerhans β cells, the unfolded protein response (UPR) is critical in to maintain protein homeostasis (proteostasis). UPR integrated by a tripartite signaling system, through activating transcription factor 6, protein kinase R‐like endoplasmic reticulum kinase (PERK), and inositol‐requiring enzyme 1, regulates gene transcription and translation to resolve stress and conserve proteostasis. In the current study, we demonstrated in hepatocytes under metabolic overload by saturated palmitic and stearic fatty acids, through activation of PERK signaling and CCAAT‐enhancer‐binding protein homologous protein (CHOP) transcription factor, an association with the expression of cyclooxygenase 2. More important, isolated exosomes from supernatants of macrophages exposed to lipopolysaccharides can also induce a metainflammation phenomenon, and when treated on hepatocytes, induced a rearrangement in cholesterol metabolism through sterol regulatory element‐binding protein 2 (SREBP2), low‐density lipoprotein receptor (LDLR), apolipoprotein A‐I, and ABCA1. Moreover, we demonstrate the cellular effect of terpene‐derived molecules, such as cryptotanshinone, isolated of plant Salvia brandegeei, regulating metainflammatory conditions through PERK pathway in both hepatocytes and β cells. Our data suggest the presence of a modulatory mechanism on specific protein translation process. This effect could be mediated by eukaryotic initiation factor‐4A, evaluating salubrinal as a control molecule. Likewise, the protective mechanisms of unsaturated fatty acids, such as oleic and palmitoleic acid were confirmed. Therefore, modulation of metainflammation suggests a new target through PERK signaling in cells with a high secretory activity, and possibly the regulation of cholesterol in hepatocytes is promoted via exosomes.
Starvation‐induced autophagy promotes the invasion and migration of human bladder cancer cells via TGF‐β1/Smad3‐mediated epithelial‐mesenchymal transition activation
Authors: Tong Hang , Yin Hubin , Hossain Mohammad Arman , Wang Yiyang , Wu Feixiang , Dong Xiaoyong , Gao Shun , Zhan Kai , He Weiyang
Published: October 2018

The biological characteristics of bladder cancer include enhanced invasion and migration, which are the main causes of death in patients. Starvation is a typical feature of the bladder cancer microenvironment and can induce autophagy. Autophagy has an important relationship with the invasion and migration of tumors. However, the role of autophagy in the invasion and migration of bladder cancer cells remains unclear. Hence, the aim of the current study was to clarify this role and underlying mechanism. In this study, we found that starvation enhanced the epithelial‐mesenchymal transition (EMT)‐mediated invasion and migration of T24 and 5637 cells while inducing autophagy. The inhibition of autophagy with chloroquine (CQ) or 3‐methyladenine (3MA) decreased EMT‐mediated invasion and migration. In addition, the expression of transforming growth factor 1 (TGF‐β1) and phosphorylated Smad3 (p‐Smad3) increased after starvation. The inhibition of autophagy with CQ or 3MA also decreased the expression of TGF‐β1 and p‐Smad3. The inhibitor of TGF‐β receptor sb431542 also inhibited the invasion, migration, and EMT of T24 and 5637 cells during starvation. Furthermore, recombinant TGF‐β1 induced autophagy and inhibition of the TGF‐β/Smad signaling pathway with sb431542 suppressed autophagy. In summary, our results suggested that autophagy promotes the invasion and migration of bladder cancer cells by inducing EMT through the TGF‐β1/Smad3 signaling pathway. Moreover, autophagy and TGF‐β1 can form a positive feedback loop to synergistically promote invasion and migration. Thus, our findings may provide a theoretical basis for the prevention of invasion and migration in bladder cancer.
Status of topoisomerase‐2β protein in all‐trans retinoic acid–treated human neuroblastoma (SK‐N‐SH) cells
Authors: Bhanothu Venkanna , Kondapi Anand Kumar
Published: October 2018

Of the mammalian topoisomerase (Topo)‐2 isozymes (α and β), Topo‐2β protein has been reported to regulate neuronal development and differentiation. However, the status of Topo‐2β in all‐trans retinoic acid (ATRA)‐treated human neuroblastoma (SK‐N‐SH) cells is not understood. More information about the effects of ATRA on SK‐N‐SH cells is needed to reveal the role of ATRA in the regulation of Topo‐2β levels and spontaneous regression of SK‐N‐SH cells to predict the clinical activity. This study was proposed to investigate the status and role of Topo‐2β protein in ATRA‐induced survival and neuronal differentiation of SK‐N‐SH cells. Microscopic, sodium dodecyl sulfate polyacrylamide gel electrophoresis after immunoprecipitations and Western blot analysis were used to study and compare Topo‐2β protein among 10 µM ATRA‐treated SK‐N‐SH cells and controls at different time points. The level of Topo‐2β protein increased in the initial days of treatment but markedly decreased upon induction of differentiation by ATRA in later stages. Upon ATRA treatment, SK‐N‐SH cells stretched, exhibited neurite extensions, and acquired a neuronal phenotype. Both treated and untreated SK‐N‐SH cells were able to migrate, occupy the scratched area, and completely recolonized 24 hours later. These results suggest an indirect role of Topo‐2β protein in regulation of genes involved in cell migration and differentiation of ATRA‐treated SK‐N‐SH cells. This study suggests that Topo‐2β may be part of activation/repression of protein complexes activated by epigenetic modifying agents, differentiating signals, and inducible locus. However, detailed studies are needed to explore the ATRA‐downstream genes leading to Topo‐2β regulation and regulatory proteins of neuronal differentiation.
MicroRNA‐129‐1‐3p regulates cyclic stretch–induced endothelial progenitor cell differentiation by targeting Runx2
Authors: Li Na , Wang Wen‐Bin , Bao Han , Shi Qian , Jiang Zong‐Lai , Qi Ying‐Xin , Han Yue
Published: October 2018

Endothelial progenitor cells (EPCs) are vital to the recovery of endothelial function and maintenance of vascular homeostasis. EPCs mobilize to sites of vessel injury and differentiate into mature endothelial cells (ECs). Locally mobilized EPCs are exposed to cyclic stretch caused by blood flow, which is important for EPC differentiation. MicroRNAs (miRNAs) have emerged as key regulators of several cellular processes. However, the role of miRNAs in cyclic stretch–induced EPC differentiation remains unclear. Here, we investigate the effects of microRNA‐129‐1‐3p (miR‐129‐1‐3p) and its novel target Runt‐related transcription factor 2 (Runx2) on EPC differentiation induced by cyclic stretch. Bone marrow‐derived EPCs were exposed to cyclic stretch with a magnitude of 5% (which mimics physiological mechanical stress) at a constant frequency of 1.25 Hz for 24 hours. The results from a miRNA array revealed that cyclic stretch significantly decreased miR‐129‐1‐3p expression. Furthermore, we found that downregulation of miR‐129‐1‐3p during cyclic stretch–induced EPC differentiation toward ECs. Meanwhile, expression of Runx2, a putative target gene of miR‐129‐1‐3p, was increased as a result of cyclic stretch. A 3′UTR reporter assay validated Runx2 as a direct target of miR‐129‐1‐3p. Furthermore, small interfering RNA (siRNA)‐mediated knockdown of Runx2 inhibited EPC differentiation into ECs and attenuated EPC tube formation via modulation of vascular endothelial growth factor (VEGF) secretion from EPCs in vitro. Our findings demonstrated that cyclic stretch suppresses miR‐129‐1‐3p expression, which in turn activates Runx2 and VEGF to promote endothelial differentiation of EPCs and angiogenesis. Therefore, targeting miR‐129‐1‐3p and Runx2 may be a potential therapeutic strategy for treating vessel injury.
Cell‐free microRNA‐148a is associated with renal allograft dysfunction: Implication for biomarker discovery
Authors: Nariman‐Saleh‐Fam Ziba , Bastami Milad , Ardalan Mohammadreza , Sharifi Simin , Hosseinian Khatib Seyed Mahdi , Zununi Vahed Sepideh
Published: October 2018

Background

Chronic allograft dysfunction (CAD), the foremost cause of renal graft loss worldwide, is a serious challenge for most of the recipients. As the epigenetic era is emerging, epigenetic biomarkers especially microRNAs (miRNAs) may reflect the current stage of the disease and patient’s therapy response. The current study investigated the potential significance of circulating miRNA‐148a in predicting the renal graft function.

Design and Methods

Circulating miRNAs were isolated from 53 plasma samples of recipients with histologically validated interstitial fibrosis and tubular atrophy (IFTA, n = 26), and recipients with stable graft function (SGF,
n = 27), and also healthy individuals (
n = 15). The level of miRNA‐148a was evaluated by the quantitative polymerase chain reaction (qPCR) and correlated with clinical and histological parameters.

Results

Significantly, miRNA‐148a decreased in IFTA compared with SGF subjects (P < 0.001). MiRNA‐148a levels indicated a significant association with serum creatinine levels (
r = 0.451,
P = 0.021) and glomerular filtration rate (
r = −0.520,
P = 0.006). MiRNA‐148a expression levels could discriminate IFTA cases from SGF individuals with an area under the curve of 0.89 (
P < 0.001), 97% sensitivity, and 72% specificity. A number of predicted targets that might be involved in CAD by miRNA‐148a were predicted.

Conclusion

Plasma cell‐free miRNA‐148a correlated with renal function and histological grades; therefore, it may be further investigated as a novel noninvasive molecular marker of the progression to IFTA in renal transplant recipients; moreover, the emerging biomarker may become a therapeutic target in the future clinic.
Effects of phospholipase D during cultured osteoblast mineralization and bone formation
Authors: Abdallah Dina , Skafi Najwa , Hamade Eva , Borel Mathieu , Reibel Sophie , Vitale Nicolas , El Jamal Alaeddine , Bougault Carole , Laroche Norbert , Vico Laurence , Badran Bassam , Hussein Nader , Magne David , Buchet Rene , Brizuela Leyre , Mebarek Saida
Published: October 2018

Mammalian phospholipase D (PLD) mostly hydrolyzes phosphatidylcholine producing phosphatidic acid. PLD activity was previously detected in different osteoblastic cell models, and was increased by several growth factors involved in bone homeostasis. To confirm possible actions of PLD isoforms during mineralization process, we analyzed their effects in osteoblastic cell models and during bone formation. PLD1 expression, along with PLD activity, increased during differentiation of primary osteoblasts and Saos‐2 cells, and peaked at the onset of mineralization. Subsequently, both PLD1 expression and PLD activity decreased, suggesting that PLD1 function is regulated during osteoblast maturation. In contrast, PLD2 expression was not significantly affected during differentiation of osteoblasts. Overexpression of PLD1 in Saos‐2 cells improved their mineralization potential. PLD inhibitor Halopemide or PLD1‐selective inhibitor, led to a decrease in mineralization in both cell types. On the contrary, the selective inhibitor of PLD2, did not affect the mineralization process. Moreover, primary osteoblasts isolated from PLD1 knockout (KO) mice were significantly less efficient in mineralization as compared with those isolated from wild type (WT) or PLD2 KO mice. In contrast, bone formation, as monitored by high‐resolution microcomputed tomography analysis, was not impaired in PLD1 KO nor in PLD2 KO mice, indicating that the lack of PLD1 or that of PLD2 did not affect the bone structure in adult mice. Taken together, our findings indicate that PLD activity, especially which of PLD1 isoform, may enhance the mineralization process in osteoblastic cells. Nonetheless, the lack of PLD1 or PLD2 do not seem to significantly affect bone formation in adult mice.