bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gestational Vitamin D Supplementation Leads to Reduced Perinatal RXRA DNA Methylation: Results From the MAVIDOS Trial
Authors: Curtis Elizabeth M , Krstic Nevena , Cook Eloïse , D'Angelo Stefania , Crozier Sarah R , Moon Rebecca J , Murray Robert , Garratt Emma , Costello Paula , Cleal Jane , Ashley Brogan , Bishop Nicholas J , Kennedy Stephen , Papageorghiou Aris T , Schoenmakers Inez , Fraser Robert , Gandhi Saurabh V , Prentice Ann , Javaid M Kassim , Inskip Hazel M , Godfrey Keith M , Bell Christopher G , Lillycrop Karen A , Cooper Cyrus , Harvey Nicholas C ,   the MAVIDOS Trial Group
Published: October 2018

ABSTRACT

We have previously demonstrated inverse associations between maternal 25(OH)-vitamin D status and perinatal DNA methylation at the retinoid-X-receptor-alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at −80°C (n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol-supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was −1.98% (95% CI, −3.65 to −0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer-related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Secondary metabolite as therapeutic agent from endophytic fungi Alternaria longipes strain VITN14G of mangrove plant Avicennia officinalis
Authors: Ranganathan Nathiya , Mahalingam Gayathri 
Published: October 2018

AbstractEndophytic fungi, especially from mangrove plants, are rich source of secondary metabolites, which plays a major role in various pharmacological actions preferably in cancer and bacterial infections. To perceive its role in antidiabetic activity we isolated and tested the metabolites derived from a novel strain Alternaria longipes strain VITN14G obtained from mangrove plant Avicennia officinalis. The crude extract was analyzed for antidiabetic activity and subjected to column chromatography. The isolated fractions were screened in vitro for α‐glucosidase and α‐amylase inhibitory activities. The cytotoxicity of the isolated fractions was studied on L929 cell lines. Following which, the screened fraction 2 was allowed for structure elucidation using gas chromatography‐mass spectrometry, one‐dimensional, two‐dimensional nuclear magnetic resonance spectroscopy, ultraviolet, and Fourier‐transform infrared analysis. The binding energies of the isolated fraction 2 with glycolytic enzymes were calculated by molecular docking studies using AutoDock Vina. The isolated fraction 2 identified as 2,4,6‐triphenylaniline, showed no significant difference in α‐amylase inhibition rates and a significant difference of 10% in α‐glucosidase inhibition rates than that of the standard drug acarbose. Further, the cytotoxicity assay of the isolated fraction 2 resulted in a cell viability of 73.96%. Supportingly, in silico studies showed 2,4,6‐triphenylaniline to produce a stronger binding affinity toward the glycolytic enzyme targets. The compound 2,4,6‐triphenylaniline isolated from A. longipes strain VITN14G exhibited satisfactory antidiabetic activity for type 2 diabetes in vitro, which will further be confirmed by in vivo studies. Successful outcome of the study will result in a natural substitute for existing synthetic antidiabetic drugs.
MORC4 is a novel breast cancer oncogene regulated by miR‐193b‐3p
Authors: Yang Zi’ang , Zhuang Qiulin , Hu Guangfu , Geng Shengkai 
Published: October 2018

AbstractA better understanding of breast cancer pathogenesis would contribute to improved diagnosis and therapy and potentially decreased mortality rates. Here, we found that the MORC family CW‐type zinc finger 4 (MORC4) overexpression in breast cancer tissues is associated with poor survival, and the short‐interfering RNA knockdown of MORC4 suppresses the growth of breast cancer cells by promoting apoptosis. To investigate the mechanisms associated with MORC4 upregulation, microRNAs potentially targeting MORC4 were analyzed, with miR‐193b‐3p identified as the regulator and a negative correlation between miR‐193b‐3p and MORC4 expression determined in both breast cancer cell lines and tissues. Further analysis verified that MORC4 silencing did not affect miR‐193b‐3p expression, although altered miR‐193b‐3p expression attenuated MORC4 protein levels. Moreover, dual‐luciferase reporter assays verified miR‐193b‐3p binding to the 3′ untranslated region of MORC4. Furthermore, restoration of miR‐193b‐3p expression in breast cancer cells led to decreased growth and activation of apoptosis, which was consistent with results associated with MORC4 silencing in breast cancer cells. These results identified MORC4 as differentially expressed in breast cancer cells and tissues and its downregulation by miR‐193b‐3p, as well as its roles in regulating the growth of breast cancer cells via regulation of apoptosis. Our findings offer novel insights into potential mechanisms associated with breast cancer pathogenesis.
Synergistic antitumor activity of oridonin and valproic acid on HL‐60 leukemia cells
Authors: Li Wei , Ma LiEn 
Published: October 2018

AbstractBackgroundOridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activities. Valproic acid (VPA) is a recently emerged antineoplastic histone deacetylase inhibitor. The aim of the present study is to investigate the synergistic role of oridonin and VPA to inhibit the growth and metastasis of human leukemia cells.MethodsThe effect of oridonin and VPA on proliferation was evaluated by the MTT assay. Cell migration and invasion were evaluated by transwell and scratch assays, respectively. In addition, cell apoptosis was examined by flow cytometry. The inhibitive effects of oridonin and VPA in vivo were determined by using xenografted nude mice.ResultsThe results demonstrated that oridonin in combination with VPA synergistically inhibited the proliferation of HL‐60 cells, and induced obvious caspase‐dependent apoptosis through activation of the intrinsic apoptosis pathway, which is involved in the downregulation of Bcl‐2/Bax ratio. Furthermore, the combination treatment in vivo remarkably reduced the xenograft tumor size and triggered tumor cell apoptosis.ConclusionOur results suggested that the novel combination of oridonin plus VPA exerted synergistic antiproliferative and apoptosis‐inducing effects on human myeloid leukemia cells, and may serve as a potentially promising antileukemia strategy.
Retinoic acid–induced survival effects in SH‐SY5Y neuroblastoma cells
Authors: Waetzig Vicki , Haeusgen Wiebke , Andres Cordula , Frehse Sonja , Reinecke Kirstin , Bruckmueller Henrike , Boehm Ruwen , Herdegen Thomas , Cascorbi Ingolf 
Published: October 2018

AbstractNeuroblastoma is a malignant childhood cancer arising from the embryonic sympathoadrenal lineage of the neural crest. Retinoic acid (RA) is included in the multimodal therapy of patients with high‐risk neuroblastoma to eliminate minimal residual disease. However, the formation of RA‐resistant cells substantially lowers 5‐year overall survival rates. To examine mechanisms that lead to treatment failure, we chose human SH‐SY5Y cells, which are known to tolerate incubation with RA by activating the survival kinases Akt and extracellular signal‐regulated kinase 1/2. Characterization of downstream pathways showed that both kinases increased the phosphorylation of the ubiquitin ligase mouse double minute homolog 2 (Mdm2) and thereby enhanced p53 degradation. When p53 signaling was sustained by blocking complex formation with Mdm2 or enhancing c‐Jun N‐terminal kinase (JNK) activation, cell viability was significantly reduced. In addition, Akt‐mediated phosphorylation of the cell‐cycle regulator p21 stimulated complex formation with caspase‐3, which also contributed to cell protection. Thus, treatment with RA augmented survival signaling and attenuated basal apoptotic pathways in SH‐SY5Y cells, which increased cell viability.
The polyproline‐motif of S6K2: eIF5A translational dependence and importance for protein‐protein interactions
Authors: Meneguello Leticia , Barbosa Natália M. , Pereira Karina D. , Proença André R. G. , Tamborlin Leticia , Simabuco Fernando M. , Iwai Leo K. , Zanelli Cleslei F. , Valentini Sandro R. , Luchessi Augusto D. 
Published: October 2018

AbstractRibosomal S6 kinase 1 (S6K1) and S6K2 proteins are effectors of the mammalian target of rapamycin complex 1 pathway, which control the process of protein synthesis in eukaryotes. S6K2 is associated with tumor progression and has a conserved C‐terminus polyproline rich motif predicted to be important for S6K2 interactions. It is noteworthy that the translation of proteins containing sequential prolines has been proposed to be dependent of eukaryotic translation initiation factor 5A (eIF5A) translation factor. Therefore, we investigated the importance of polyproline‐rich region of the S6K2 for its intrinsic phosphorylation activity, protein‐protein interaction and eIF5A role in S6K2 translation. In HeLa cell line, replacing S6K2 polyproline by the homologous S6K1‐sequence did not affect its kinase activity and the S6K2 endogenous content was maintained after eIF5A gene silencing, even after near complete depletion of eIF5A protein. Moreover, no changes in S6K2 transcript content was observed, ruling out the possibility of compensatory regulation by increasing the mRNA content. However, in the budding yeast model, we observed that S6K2 production was impaired when compared with S6K2∆Pro, after reduction of eIF5A protein content. These results suggest that although the polyproline region of S6K2 is capable of generating ribosomal stalling, the depletion of eIF5A in HeLa cells seems to be insufficient to cause an expressive decrease in the content of endogenous S6K2. Finally, coimmunoprecipitation assays revealed that the replacement of the polyproline motif of S6K2 alters its interactome and impairs its interaction with RPS6, a key modulator of ribosome activity. These results evidence the importance of S6K2 polyproline motif in the context of S6Ks function.
Transcriptom analysis revealed regulation of dexamethasone induced microRNAs in chicken thymus
Authors: Zhou Yanting , Tian Weihua , Zhang Meng , Ren Tuanhui , Sun Guirong , Jiang Ruirui , Han Ruili , Kang Xiangtao , Yan Fengbin 
Published: October 2018

AbstractStress‐induced immunosuppression is one of the serious threats to the poultry industry, especially obvious for young chicken. However, the molecular mechanism of stress‐induced immunosuppression has not been clear in chicken. Here, we established an immunosuppression model of 7‐day‐old chickens with injecting dexamethasone (Dex) to analyze the molecular regulation in the chicken thymus. The microRNAs (miRNAs) transcripts profiles of thymuses from the model and control group were identified by the Solexa sequencing technology. The results showed 121 significantly differently expressed (SDE) miRNAs, including 119 known and two novel miRNAs (novel‐58 and novel‐350). A total of 391 target genes of the SDE miRNAs were predicted and annotated. We verified the potential negative correlation between gga‐miR‐103‐3p and TGM2 by quantitative real‐time polymerase chain reaction (qRT‐PCR), as well as between novel‐350 and PCBD2, and the results were positive. Gene ontology (GO) enrichment analysis showed that there was 298 significant enrichment GO terms, in which 31 were related to immune or stress, such as lymphocyte apoptotic process and response to stress. KEGG pathway analysis suggested that the SDE miRNAs were involved in autophagy regulation, cytokine‐cytokine receptor interaction, Toll‐like receptor signaling pathway, Jak‐STAT signaling pathway, and so on (although not significantly enriched). In these immune signaling pathways, the SDE miRNAs (such as gga‐miR‐2954, gga‐miR‐146b‐3p, gga‐miR‐106‐3p, and gga‐miR‐214) and the predicted target genes (such as IL11Ra, CSF3R, IFNGR1, CNTF, and MAP2K2) might affect the thymus immune function of chicken. The above results would provide a basis for uncovering the molecular regulation mechanism of immunosuppression in poultry.
What makes D‐dimer assays suspicious–heterophilic antibodies?
Authors: Wu Ying , Xiao Ying‐Xiu , Huang Teng‐Yi , Zhang Xian‐Yan , Zhou Huan‐Bing , Zhang Xue‐Xuan , Wu Ying‐E 
Published: October 2018

BackgroundHeterophilic antibodies are still an important source of interference in immunoassays, but reports of interference with D‐dimers are rare. Are D‐dimer level abnormalities, found in the clinic, caused by heterophilic antibodies as well, or are other mechanisms involved? We will elaborate on this issue through two different examples in this article.MethodsSerum from two patients with significantly elevated levels of D‐dimers were measured and compared by different methods, diluted, and dealt with heterophilic antibody blockers. At the same time, to retrieve the interference, we focused on the cause of D‐dimer false positives and made a systematic review of the literature.ResultsThe D‐dimer values were normal (0.49 and 0.15 μg/mL) detected with different testing method and decreased after addition of heterophilic antibody blocking reagent. According to literature data, there were 66.7% (4/6) references showed the interference were heterophilic antibody.ConclusionsThe influence of heterophilic antibodies on the measurement of D‐dimers remains a big challenge. Different measuring instruments and methods may have significant differences in the measurement of D‐dimers. By using a combination of instrumental methods for measuring, incorporating heterophilic antibody blockers, and combining with clinical performance and imaging data, most of the interference can be eliminated.
Psychological capital and life satisfaction of refugees in Canada: Evidence from a community‐based educational support program
Authors: Bajwa Jaswant , Abai Mulugeta , Couto Sidonia , Kidd Sean , Dibavar Aytak , McKenzie Kwame 
Published: October 2018

AbstractDrawing on a 2‐year community‐based participatory research project, and grounded in the theories of positive psychology, this article examines the effects of targeted educational support on refugee participants’ psychological capital (PsyCap)–hope, self‐efficacy, resilience, and optimism–as well as life satisfaction. Two groups of participants attended a 14‐week trauma‐informed, educational support program in 2 consecutive sessions. The program was designed in collaboration with George Brown College, the Centre for Addiction and Mental Health, Wellesley Institute, and the Canadian Centre for Victims of Torture. The study aimed to understand the link between psychological capital and life satisfaction among refugees. Findings show that the participants’ psychological capital–particularly PsyCap‐resilience and PsyCap‐optimism–improved consistently, which in turn was reflected in the participants’ improved life satisfaction. The result also indicated a relationship between the four main characteristics of psychological capital and life satisfaction. We conclude that these indications of a potential positive association between refugees’ psychological capital and life satisfaction should be further examined.
Pincer‐type MRI morphology seen in over a third of asymptomatic healthy volunteers without femoroacetabular impingement
Authors: Bensler Susanne , Dietrich Tobias J. , Zubler Veronika , Pfirrmann Christian W.A. , Sutter Reto 
Published: October 2018

BackgroundIn daily routine, pincer femoroacetabular impingement (FAI) findings are often seen without a clinical diagnosis of pincer FAI.PurposeTo assess the presence of pincer FAI MRI findings in asymptomatic volunteers with negative impingement test versus patients with clinically confirmed FAI.Study TypeCase–control study.PopulationSixty‐three asymptomatic volunteers and 63 matched patients with FAI were included.Field Strength/ SequenceA coronal T1‐weighted turbo spin‐echo sequence as well as a 3D oblique transverse water‐excitation true fast imaging sequence at 1.5T.AssessmentThe volunteers underwent standard MRI of the hip, and patients underwent MR arthrography of the symptomatic hip using the same MR sequences. Measurements of cranial acetabular version, acetabular depth, and lateral center‐edge angle were performed independently by three fellowship‐trained musculoskeletal radiologists.Statistical TestsDescriptive statistics, Mann–Whitney U‐test, Unpaired t‐test, receiver operating characteristics (ROC), Intraclass correlation coefficient (ICC).ResultsForty‐one percent (26/63, reader 1), 32% and 37% (20 and 23/63, reader 2/3) of asymptomatic volunteers had at least one positive MR finding for pincer‐FAI. Patients with pincer or mixed‐type FAI had cranial retroversion of the acetabulum of –0.2° ± 7.1 (mean ± standard deviation) for reader 1 and –0.3° ± 5.5/–0.2° ± 4.8 for reader 2 / reader 3, while asymptomatic volunteers had an anteversion of 6.2° ± 6.4 (reader 1) and 3.2° ± 4.9/3.1° ± 6.5 (readers 2/3): This difference was statistically significant (P ≤ 0.002), but there was a large overlap between the groups. Acetabular depth measurements were very similar for patients with either pincer or mixed‐type FAI (5.1–5.3 mm ± 3.1) and volunteers (5.2–6.1 mm ± 2.6), without a statistically significant difference (P ≤ 0.50). Lateral center‐edge angle was also similar in patients with either pincer or mixed‐type FAI (32.1–35.1° ± 9.1) and volunteers (30.7–33.2° ± 6.5), without a statistically significant difference (P ≤ 0.28).Data ConclusionThere is a large overlap in pincer‐type MRI findings between patients with symptomatic FAI and asymptomatic volunteers. More than a third of volunteers exhibited at least one positive pincer‐type MRI finding.Level of Evidence: 1Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2019;49:1296–1303.
Simultaneous fat‐free isotropic 3D anatomical imaging and T2 mapping of knee cartilage with lipid‐insensitive binomial off‐resonant RF excitation (LIBRE) pulses
Authors: Colotti Roberto , Omoumi Patrick , van Heeswijk Ruud B. , Bastiaansen Jessica A.M. 
Published: October 2018

BackgroundImproved knee cartilage morphological delineation and T2 mapping precision necessitates isotropic 3D high‐resolution and efficient fat suppression.PurposeTo develop and assess an isotropic 3D lipid‐insensitive T2 mapping technique of the knee for improved cartilage delineation and precise measurement of T2 relaxation times.Study TypeProspective.Phantom/SubjectsPhantoms (n = 6) used in this study were designed to mimic the T1 and T2 relaxation times of cartilage and fat. The study cohort comprised healthy volunteers (n = 7) for morphometry and T2 relaxation time measurements.Field Strength/SequenceA high‐resolution isotropic 3D T2 mapping technique that uses sequential T2‐prepared segmented gradient‐recalled echo (Iso3DGRE) images and lipid‐insensitive binomial off‐resonant radiofrequency (RF) excitation (LIBRE) at 3T.AssessmentNumerical simulations and phantom experiments were performed to optimize the LIBRE pulse. Phantom studies were carried out to test the accuracy of the technique against reference standard spin‐echo (SE) T2 mapping. Subsequently, T2 maps with and without LIBRE pulses were acquired in knees of healthy volunteers and the T2 relaxation time values in different cartilage compartments were compared.Statistical TestsA two‐tailed paired Student's t‐test was used to compare the average T2 values and the relative standard deviations (inverse measurement of the precision) obtained with and without LIBRE pulses.ResultsA LIBRE pulse of 1 msec suppressed fat with an RF excitation frequency offset of 1560 Hz and optimal RF excitation angle of 35°. These results were corroborated by phantom and knee experiments. Robust and homogeneous fat suppression was obtained (a fat signal‐to‐noise ratio (SNR) decrease of 86.4 ± 2.4%). In phantoms, T2 values were found in good agreement when comparing LIBRE‐Iso3DGRE with SE (slope 0.93 ± 0.04, intercept 0.11 ± 1.6 msec, R2 >0.99). In vivo, LIBRE excitation resulted in more precise T2 estimation (23.7 ± 7.4%) than normal excitation (30.5 ± 9.9%, P < 0.0001).Data ConclusionHomogeneous LIBRE fat signal suppression was achieved with a total RF pulse duration of 1 msec, allowing for the removal of chemical shift artifacts and resulting in improved cartilage delineation and precise T2 values.Level of Evidence: 2Technical Efficacy: Stage 1J. Magn. Reson. Imaging 2019;49:1275–1284.
Therapeutic spectrum of interferon‐β in ischemic stroke
Authors: Wanve Madhuri , Kaur Harpreet , Sarmah Deepaneeta , Saraf Jackson , Pravalika Kanta , Vats Kanchan , Kalia Kiran , Borah Anupom , Yavagal Dileep R. , Dave Kunjan R. , Bhattacharya Pallab 
Published: October 2018

AbstractIschemic stroke is devastating and a major cause of morbidity and mortality worldwide. To date, only clot retrieval devices and/or intravenous tissue plasminogen activators (tPA) have been approved by the US‐FDA for the treatment of acute ischemic stroke. Therefore, there is an urgent need to develop an effective treatment for stroke that can have limited shortcomings and broad spectrum of applications. Interferon‐beta (IFN‐β), an endogenous cytokine and a key anti‐inflammatory agent, contributes toward obviating deleterious stroke outcomes. Therefore, exploring the role of IFN‐β may be a promising alternative approach for stroke intervention in the future. In the present review, we have discussed about IFN‐β along with its different mechanistic roles in ischemic stroke. Furthermore, therapeutic approaches targeting the inflammatory cascade with IFN‐β therapy that may be helpful in improving stroke outcome are also discussed.