bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Preparation of a Heteroleptic Cyclometallated Ruthenium Complex Capable of Undergoing Photosubstitution of a Bidentate Ligand
Authors: Cuello‐Garibo Jordi‐Amat , James Catriona C. , Siegler Maxime A. , Hopkins Samantha L. , Bonnet Sylvestre
Published: October 2018

Cyclometallated ruthenium complexes typically exhibit red‐shifted absorption bands and lower photolability compared to their polypyridyl analogues. They also have lower symmetry, which sometimes makes their synthesis challenging. In this work, the coordination of four N,S bidentate ligands, 3‐(methylthio)propylamine (mtpa), 2‐(methylthio)ethylamine (mtea), 2‐(methylthio)ethyl‐2‐pyridine (mtep), and 2‐(methylthio)methylpyridine (mtmp), to the cyclometallated precursor [Ru(bpy)(phpy)(CH3CN)2]+ (bpy=2,2′‐bipyridine, Hphpy=2‐phenylpyridine) has been investigated, furnishing the corresponding heteroleptic complexes [Ru(bpy)(phpy)(N,S)]PF6 ([2]PF6–[5]PF6, respectively). The stereoselectivity of the synthesis strongly depended on the size of the ring formed by the Ru‐coordinated N,S ligand, with [2]PF6 and [4]PF6 being formed stereoselectively, but [3]PF6 and [5]PF6 being obtained as mixtures of inseparable isomers. The exact stereochemistry of the air‐stable complex [4]PF6 was established by a combination of DFT, 2D NMR, and single‐crystal X‐ray crystallographic studies. Finally, [4]PF6 was found to be photosubstitutionally active under irradiation with green light in acetonitrile, which makes it the first cyclometallated ruthenium complex capable of undergoing selective photosubstitution of a bidentate ligand.
Inside Cover: Cobalt(II)‐Catalyzed Bis‐isocyanides Insertion Reactions with Boric Acids and Sulfonyl Azides via Nitrene Radical Coupling (Chin. J. Chem. 11/2018)
Authors: Gu Zheng‐Yang , Zhang Rong , Wang Shun‐Yi , Ji Shun‐Jun
Published: October 2018

The inside cover picture shows isocyanide is an important reactive reactant, which has been widely used in the construction of nitrogen‐containing compounds. In our previous works, we found that cobalt catalyzed reactions of sulfonyl azide with isocyanide can effectively synthesize guanidines and isoureas. Therefore, we envisaged the cobalt‐catalyzed cascade reaction of sulfonyl azide, isocyanide and boronic acid to construct sulfonyl amidinium imine derivatives. The background of the cover shows Soochow University's motto “unto a full grown man”, and the use of Suzhou's outstanding traditional handicrafts “nut‐carving” to present “isocyanide” has a wonderful effect, as meaningful as the chemical reaction in this article. More details are discussed in the article by Ji et al. on page 1011–1016.

image
Cost‐effectiveness of rapid on‐site evaluation of the adequacy of FNA cytology samples performed by nonpathologists
Authors: Pearson Lauren N. , Layfield Lester J. , Schmidt Robert L.
Published: October 2018

Background

Rapid on‐site evaluation (ROSE) can increase adequacy and reduce needle passes in fine‐needle aspiration cytology (FNAC) procedures. However, ROSE increases the cost of FNAC. Costs may be reduced if ROSE is performed by an alternate evaluator (AE), such as a cytotechnologist (CT), endoscopist, or pulmonologist, rather than a cytopathologist (CP). Studies have shown that AEs can perform ROSE with high accuracy but are generally not as accurate as CPs. The objective of this study was to evaluate the impact of AEs on the cost‐effectiveness of ROSE.

Methods

A cost model, based on a mathematical sampling model, was developed. The cost model was used to compare the impact of the evaluator type on overall costs.

Results

CTs were likely to be cost‐effective for simple procedures and were unlikely to be cost‐effective for only the most complex procedures. The model demonstrated the tradeoff in cost savings from using AEs and the potential costs associated with repeated procedures due to the lower accuracy of AEs.

Conclusions

The cost‐effectiveness of AEs is context‐dependent. AEs can be cost‐effective even if they are less accurate than CPs. AEs are likely to be cost‐effective in most contexts.
Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer's disease
Authors: Whitesell Jennifer D. , Buckley Alex R. , Knox Joseph E. , Kuan Leonard , Graddis Nile , Pelos Andrew , Mukora Alice , Wakeman Wayne , Bohn Phillip , Ho Anh , Hirokawa Karla E. , Harris Julie A.
Published: October 2018

A variety of Alzheimer's disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid β (Aβ) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Aβ deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of Aβ plaques across age in three APP‐overexpression mouse lines (APP/PS1, Tg2576, and hAPP‐J20) using in vivo labeling with methoxy‐X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two‐photon tomography and labeled plaques were detected using custom‐built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain‐wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP‐J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; for example, the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP‐J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional Aβ deposition patterns described in AD.
“Through‐Space” Relativistic Effects on NMR Chemical Shifts of Pyridinium Halide Ionic Liquids
Authors: Ariai Jama , Saielli Giacomo
Published: October 2018

We have investigated, using two‐component relativistic density functional theory (DFT) at ZORA‐SO‐BP86 and ZORA‐SO‐PBE0 level, the occurrence of relativistic effects on the 1H, 13C, and 15N NMR chemical shifts of 1‐methylpyridinium halides [MP][X] and 1‐butyl‐3‐methylpyridinium trihalides [BMP][X3] ionic liquids (ILs) (X=Cl, Br, I) as a result of a non‐covalent interaction with the heavy anions. Our results indicate a sizeable deshielding effect in ion pairs when the anion is I− and I3−. A smaller, though nonzero, effect is observed also with bromine while chlorine based anions do not produce an appreciable relativistic shift. The chemical shift of the carbon atoms of the aromatic ring shows an inverse halogen dependence that has been rationalized based on the little C‐2s orbital contribution to the σ‐type interaction between the cation and anion. This is the first detailed account and systematic theoretical investigation of a relativistic heavy atom effect on the NMR chemical shifts of light atoms in the absence of covalent bonds. Our work paves the way and suggests the direction for an experimental investigation of such elusive signatures of ion pairing in ILs.
Efficient CRISPR/Cas9‐Mediated Mutagenesis in Primary Murine T Lymphocytes
Authors: Huang Bonnie , Johansen Kristoffer Haurum , Schwartzberg Pamela L.
Published: October 2018

The ability to alter gene expression directly in T lymphocytes has provided a powerful tool for understanding T cell biology, signaling, and function. Manipulation of T cell clones and primary T cells has been accomplished primarily through overexpression or gene‐silencing studies using cDNAs or shRNAs, respectively, which are often delivered by retroviral or lentiviral transduction or direct transfection methods. The recent development of CRISPR/Cas9‐based mutagenesis has revolutionized genomic editing, allowing unprecedented genetic manipulation of many cell types with greater precision and ease. This article outlines a protocol for CRISPR/Cas9‐mediated mutagenesis in primary T lymphocytes from Cas9 transgenic mice using retroviral delivery of guide RNAs. © 2018 by John Wiley & Sons, Inc.
Production of 5‐Hydroxymethylfurfural from D‐Fructose in Low‐Transition‐Temperature Mixtures Enhanced by Chloride Anions and Low Amounts of Organic Acids
Authors: Istasse Thibaut , Bockstal Lauris , Richel Aurore
Published: October 2018

The use of safe and sustainable solvents able to solvate reagents and to catalyze their reactions at temperatures below 100 °C is an innovative strategy to develop future lignocellulosic biorefineries. Many low‐transition‐temperature mixtures (LTTMs) have been investigated for this purpose. Among them, natural deep eutectic solvents (NADESs) have been proposed as cheap and renewable alternatives to ionic liquids for the synthesis of bio‐based chemical building blocks. We compare herein the ability of several organic acids/choline chloride/water LTTMs to perform D‐fructose dehydration to 5‐hydroxymethylfurfural (5‐HMF). The addition of chloride salts as well as an increased proportion of choline chloride promotes 5‐HMF formation, which seems to indicate a beneficial effect of chloride anions on D‐fructose dehydration. Besides improving selectivity by at least 10 %, increasing the choline chloride/acid ratio could enhance the biodegradability of the LTTMs. Unlike other acidic components, maleic and citric acids are especially selective at early D‐fructose conversion. Maleic acid was the most selective acidic component among the tested chemicals, achieving an 80 % 5‐HMF molar yield in 1 h at 90 °C.
Surface Nonpolarization of g‐C3N4 by Decoration with Sensitized Quantum Dots for Improved CO2 Photoreduction
Authors: Feng Huajun , Guo Qiaoqi , Xu Yingfeng , Chen Ting , Zhou Yuyang , Wang Yigang , Wang Meizhen , Shen Dongsheng
Published: October 2018

Photocatalytic conversion of CO2 can provide a solution for simultaneously addressing global warming and solar fuel generation. However, its applicability is presently limited by the unsatisfactory photoconversion efficiency of the state‐of‐art photocatalysts. In this regard, enhancing CO2 adsorption through surface modification could be an efficient way to improve the photoconversion efficiency. Herein, doping of nonpolar carbon quantum dots (CQDs) onto g‐C3N4 is reported for the construction of a metal‐free heterojunction photocatalyst (CQDs/g‐C3N4). CQDs offer several advantages such as band‐gap reduction and electron‐withdrawing effect to improve light absorption and photocarrier separation efficiency. However, this study reveals that nonpolar CQDs could also improve CO2 adsorption, photoinduced H2 production, reaction kinetics, and alter CO2 photoreduction pathways to generate CH4. Consequently, the CQDs/g‐C3N4 could generate six times more CO and CH4 without detectable H2 compared to pristine g‐C3N4, under similar conditions. Therefore, this study demonstrates a promising strategy for efficient adsorption, activation, and subsequent photoreduction of CO2 by nonpolar surface modification of g‐C3N4.
Fast and lightweight detection and filtering method for low‐rate TCP targeted distributed denial of service (LDDoS) attacks
Authors: Şimşek Mehmet , Şentürk Arafat
Published: October 2018

Detection and filtering of low‐rate distributed denial of service (LDDoS) attacks is hard since their behavior is similar to legitimate users' behavior. In the literature, there are many filtering approaches and metrics for LDDoS attacks. However, most of the LDDoS detection methods in the literature only monitor congestion state. Actually, precongestion period that the attack has already started has valuable information about the attack. In this study, we proposed a method that uses precongestion period for metric calculation. Also, most of LDDoS filtering approaches have high false‐positive and false‐negative rates and also require long period of time for detection. Additionally, we developed an efficient method for detection and filtering of LDDoS attacks. According to the experimental results, the proposed LDDoS detection method has zero false‐positive and false‐negative rates under the scenarios; attack detection time is significantly reduced with using the proposed metric calculation approach. Also, the proposed method has a simple logic, and it requires simple calculations. This increases the applicability of the developed method.
Drug resistance in Mycobacterium tuberculosis and targeting the l,d‐transpeptidase enzyme
Authors: Gokulan Kuppan , Varughese Kottayil I.
Published: October 2018

Tuberculosis (TB) is a disease that has afflicted mankind for thousands of years, but in the last seven decades, much progress has been made in anti‐TB therapy. Early drugs, such as para‐aminosalicylic acid, streptomycin, isoniazid, and rifamycins were very effective in combatting the disease, giving rise to the hope that TB would be eradicated from the face of the earth by 2010. Despite that optimism, TB continues to kill more than a million people annually worldwide. A major reason for our inability to contain TB is the emergence drug resistance in Mycobacterium tuberculosis. This commentary is based on our recent publication on the structure of l,d‐transpeptidase enzyme, relevant to drug resistance. As a background, we briefly outline the history and development of anti‐TB therapy. Based on the crystal structure, we suggest a potential direction for designing more potent drugs against TB.
Pelagic food webs of humic lakes show low short‐term response to forest harvesting
Authors: Deininger A. , Jonsson A. , Karlsson J. , Bergström A.‐K.
Published: October 2018

Forest harvest in the boreal zone can increase the input of terrestrial materials such as dissolved organic carbon (DOC) and nitrate (NO3−) into nearby aquatic ecosystems, with potential effects on phytoplankton growth through enhanced nutrient (i.e., positive) or reduced light availability (i.e., negative), which may affect ecosystem productivity and consumer resource use. Here, we conducted forest clear‐cutting experiments in the catchments of four small, humic, and nitrogen‐limited unproductive boreal lakes (two controls and two clear‐cut, 18% and 44% of area cut) with one reference and two impact years. Our aim was to assess the effects of forest clear‐cutting on pelagic biomass production and consumer resource use. We found that pelagic biomass production did not change after two years of forest clear‐cutting: Pelagic primary and bacterial production (PP, BP), PP:BP ratio, chl a, and seston carbon (seston C) were unaffected by clear‐cutting; neither did tree harvest affect seston stoichiometry (i.e., N:phosphorus [P], C:P) nor induce changes in zooplankton resource use, biomass, or community composition. In conclusion, our findings suggest that pelagic food webs of humic lakes (DOC > 15 mg/L) might be resilient to a moderate form of forest clear‐cutting, at least two years after tree removal, before mechanical site preparation (e.g., mounding, plowing) and when leaving buffer strips along lakes and incoming streams. Thus, pelagic food web responses to forest clear‐cutting might not be universal, but could depend on factors such as the time scale, share of catchment logged, and the forest practices involved, including the application of buffer strips and site preparation.
Impact of an interatrial shunt device on survival and heart failure hospitalization in patients with preserved ejection fraction
Authors: Kaye David M. , Petrie Mark C. , McKenzie Scott , Hasenfuβ Gerd , Malek Filip , Post Martijn , Doughty Robert N. , Trochu Jean‐Noël , Gustafsson Finn , Lang Irene , Kolodziej Adam , Westenfeld Ralf , Penicka Martin , Rosenberg Mark , Hausleiter Jörg , Raake Philip , Jondeau Guillaume , Bergmann Martin W. , Spelman Tim , Aytug Huseyin , Ponikowski Piotr , Hayward Chris ,   on behalf of the REDUCE LAP‐HF study investigators
Published: October 2018

Aims

Impaired left ventricular diastolic function leading to elevated left atrial pressures, particularly during exertion, is a key driver of symptoms and outcomes in heart failure with preserved ejection fraction (HFpEF). Insertion of an interatrial shunt device (IASD) to reduce left atrial pressure in HFpEF has been shown to be associated with short‐term haemodynamic and symptomatic benefit. We aimed to investigate the potential effects of IASD placement on HFpEF survival and heart failure hospitalization (HFH).

Methods and results

Heart failure with preserved ejection fraction patients participating in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure study (Corvia Medical) of an IASD were followed for a median duration of 739 days. The theoretical impact of IASD implantation on HFpEF mortality was investigated by comparing the observed survival of the study cohort with the survival predicted from baseline data using the Meta‐analysis Global Group in Chronic Heart Failure heart failure risk survival score. Baseline and post‐IASD implant parameters associated with HFH were also investigated. Based upon the individual baseline demographic and cardiovascular profile of the study cohort, the Meta‐analysis Global Group in Chronic Heart Failure score‐predicted mortality was 10.2/100 pt years. The observed mortality rate of the IASD‐treated cohort was 3.4/100 pt years, representing a 33% lower rate (P = 0.02). By Kaplan–Meier analysis, the observed survival in IASD patients was greater than predicted (P = 0.014). Baseline parameters were not predictive of future HFH events; however, poorer exercise tolerance and a higher workload‐corrected exercise pulmonary capillary wedge pressure at the 6 months post‐IASD study were associated with HFH.

Conclusions

The current study suggests IASD implantation may be associated with a reduction in mortality in HFpEF. Large‐scale ongoing randomized studies are required to confirm the potential benefit of this therapy.
Impedance Detection of 3‐Phenoxybenzoic Acid Comparing Wholes Antibodies and Antibody Fragments for Biomolecular Recognition
Authors: Pali Madhavi , Suni Ian I.
Published: October 2018

Antibody fragments for detection of 3‐phenoxybenzoic acid (3‐PBA) are created by disulfide bond cleavage with tris(2‐carboxyethyl)phosphine (TCEP). These antibody fragments are employed to improve the sensitivity for 3‐PBA detection by electrochemical impedance spectroscopy (EIS). The sensitivity and detection limit are compared for biomolecular recognition by both polyclonal antibodies and antibody fragments immobilized through amide bond formation atop a self‐assembled monolayer (SAM) on an Au electrode, as well as antibody fragments directly attached to Au through Au−S covalent bond formation. The detection limit for 3‐PBA is dramatically improved (1.1×10−8 M) for direct immobilization of antibody fragments through Au−S covalent bond formation relative to immobilization of either polyclonal antibodies (2.1×10−5 M) or antibody fragments (1.7×10−5 M) through amide bond formation. This can be attributed primarily to the much lower charge transfer resistance (Rct) and higher ionic permeability obtained at biosensor interfaces that do not include an Au‐thiol SAM, allowing easier detection of further changes in Rct. In addition, the exponential dependence of the electron tunnelling rate on biomolecular film thickness increases the sensitivity of the antibody fragments modestly relative to polyclonal antibodies. This is the first quantitative comparison of the use of antibodies and antibody fragments for biomolecular recognition within impedance biosensors.
Early Paleogene strike‐slip transition of the Tan–Lu Fault Zone across the southeast Bohai Bay Basin: Constraints from fault characteristics in its adjacent basins
Authors: Wang Guangzeng , Li Sanzhong , Wu Zhiping , Suo Yanhui , Guo Lingli , Wang Pengcheng
Published: October 2018

The Tan–Lu Fault Zone (TLFZ) is the largest continental‐scale strike‐slip fault zone in East China. It experienced a complex Meso‐Cenozoic deformation and controlled the development and evolution of the Bohai Bay Basin (BBB). Though its Mesozoic sinistral and Cenozoic dextral motions have been well documented, its strike‐slip transition history and mechanism from sinistral to dextral motions in the Early Paleogene remain poorly understood. To investigate these issues, we made a thorough analysis on the fault geometry and kinematics as well as the response of depocentre in the Early Paleogene of the sags adjacent to the TLFZ across the southeast BBB. The results show that the WNW‐/NW‐, E‐W‐, and ENE‐/NE‐trending extensional faults developed in the Early Paleogene of those sags share almost the same geometrical and kinematic features. Such features indicate that the TLFZ is sinistral in Ek3‐Ek2 depositional stage, extension dominated in Ek1 depositional stage, and dextral in Es4L depositional stage. Such strike‐slip transition of the TLFZ is a comprehensive effect of the plate events around the Eurasian Plate. The NNW‐directed subduction of the Pacific to the Eurasian plates triggers the sinistral motion of the TLFZ during 65–55 Ma, but this sinistral motion is terminated by the far‐field effect of the NNE‐directed India–Eurasia collision initiating at 55 Ma. Then, the kinematic adjustment of the Pacific Plate from NNW to WNW breaks the stress balance exerted on the TLFZ by the subduction of the Pacific to Eurasian plates and the India–Eurasia collision and makes it turn into dextral motion gradually during 48–42 Ma.
Cluster failure revisited: Impact of first level design and physiological noise on cluster false positive rates
Authors: Eklund Anders , Knutsson Hans , Nichols Thomas E.
Published: October 2018

Methodological research rarely generates a broad interest, yet our work on the validity of cluster inference methods for functional magnetic resonance imaging (fMRI) created intense discussion on both the minutia of our approach and its implications for the discipline. In the present work, we take on various critiques of our work and further explore the limitations of our original work. We address issues about the particular event‐related designs we used, considering multiple event types and randomization of events between subjects. We consider the lack of validity found with one‐sample permutation (sign flipping) tests, investigating a number of approaches to improve the false positive control of this widely used procedure. We found that the combination of a two‐sided test and cleaning the data using ICA FIX resulted in nominal false positive rates for all data sets, meaning that data cleaning is not only important for resting state fMRI, but also for task fMRI. Finally, we discuss the implications of our work on the fMRI literature as a whole, estimating that at least 10% of the fMRI studies have used the most problematic cluster inference method (p = .01 cluster defining threshold), and how individual studies can be interpreted in light of our findings. These additional results underscore our original conclusions, on the importance of data sharing and thorough evaluation of statistical methods on realistic null data.
Differential responsivity of neurons in perirhinal cortex, lateral entorhinal cortex, and dentate gyrus during time‐bridging learning
Authors: Suter Eugénie E. , Weiss Craig , Disterhoft John F.
Published: October 2018

Many studies have focused on the function of hippocampal region CA1 as a critical site for associative memory, but much less is known about changes in the afferents to CA1. Here we report the activity of multiple single neurons from perirhinal and entorhinal cortex and from dentate gyrus during trace eyeblink conditioning as well as consolidated recall, and in pseudo‐conditioned control rabbits. We also report an analysis of theta activity filtered from the local field potential (LFP). Our results show early associative changes in single‐neuron firing rate as well as theta oscillations in lateral entorhinal cortex (EC) and dentate gyrus (DG), and increases in the number of responsive neurons in perirhinal cortex. In both EC and DG, a subset of neurons from conditioned animals exhibited an elevated baseline firing rate and large responses to the conditioned stimulus and trace period. A similar population of cells has been seen in DG and in medial, but not lateral, EC during spatial tasks, suggesting that lateral EC contains cells responsive to a temporal associative task. In contrast to recent studies in our laboratory that found significant CA1 contributions to long‐term memory, the activity profiles of neurons within EC and DG were similar for conditioned and pseudoconditioned rabbits during post‐consolidation sessions. Collectively these results demonstrate that individual subregions of medial temporal lobe differentially support new and remotely acquired memories. Neuron firing profiles were similar on training trials when conditioned responses were and were not exhibited, demonstrating that these temporal lobe regions represent the CS–US association and do not control the behavioral response. The analysis of theta activity revealed that theta power was modulated by the conditioning stimuli in both the conditioned and pseudoconditioned groups and that although both groups exhibited a resetting of phase to the corneal airpuff, only the conditioned group exhibited a resetting of phase to the whisker conditioned stimulus.
MicroRNA and Human Bone Health
Authors: Cheng Vincent Ka‐Fai , Au Philip Chun‐Ming , Tan Kathryn CB , Cheung Ching‐Lung
Published: October 2018

The small non‐coding microRNAs (miRNAs) are post‐transcription regulators that modulate diverse cellular process in bone cells. Because optimal miRNA targeting is essential for their function, single‐nucleotide polymorphisms (SNPs) within or proximal to the loci of miRNA (miR‐SNPs) or mRNA (PolymiRTS) could potentially disrupt the miRNA‐mRNA interaction, leading to changes in bone metabolism and osteoporosis. Recent human studies of skeletal traits using miRNA profiling, genomewide association studies, and functional studies started to decipher the complex miRNA regulatory network. These studies have indicated that miRNAs may be a promising bone marker. This review focuses on human miRNA studies on bone traits and discusses how genetic variants affect bone metabolic pathways. Major ex vivo investigations using human samples supported with animal and in vitro models have shed light on the mechanistic role of miRNAs. Furthermore, studying the miRNAs’ signatures in secondary osteoporosis and osteoporotic medications such as teriparatide (TPTD) and denosumab (DMab) have provided valuable insight into clinical management of the disease. © 2018 The Authors.JBMR PlusPublished by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research
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

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

Endophytic 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

A 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

Background

Oridonin 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.

Methods

The 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.

Results

The 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.

Conclusion

Our 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

Neuroblastoma 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

Ribosomal 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

Stress‐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

Background

Heterophilic 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.

Methods

Serum 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.

Results

The 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.

Conclusions

The 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

Drawing 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

Background

In daily routine, pincer femoroacetabular impingement (FAI) findings are often seen without a clinical diagnosis of pincer FAI.

Purpose

To assess the presence of pincer FAI MRI findings in asymptomatic volunteers with negative impingement test versus patients with clinically confirmed FAI.

Study Type

Case–control study.

Population

Sixty‐three asymptomatic volunteers and 63 matched patients with FAI were included.

Field Strength/ Sequence

A coronal T1‐weighted turbo spin‐echo sequence as well as a 3D oblique transverse water‐excitation true fast imaging sequence at 1.5T.

Assessment

The 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 Tests

Descriptive statistics, Mann–Whitney U‐test, Unpaired t‐test, receiver operating characteristics (ROC), Intraclass correlation coefficient (ICC).

Results

Forty‐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 Conclusion

There 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: 1

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2019;49:1296–1303.