bluuebunny/crossref_metadata_2025 huggingface dataset:
Coherent shuttle of electron-spin states
Authors: Fujita Takafumi , Baart Timothy Alexander , Reichl Christian , Wegscheider Werner , Vandersypen Lieven Mark Koenraad
Published: June 2017

We demonstrate a coherent spin shuttle through a GaAs/AlGaAs quadruple-quantum-dot array. Starting with two electrons in a spin-singlet state in the first dot, we shuttle one electron over to either the second, third, or fourth dot. We observe that the separated spin-singlet evolves periodically into the m = 0 spin-triplet and back before it dephases due to nuclear spin noise. We attribute the time evolution to differences in the local Zeeman splitting between the respective dots. With the help of numerical simulations, we analyze and discuss the visibility of the singlet-triplet oscillations and connect it to the requirements for coherent spin shuttling in terms of the inter-dot tunnel coupling strength and rise time of the pulses. The distribution of entangled spin pairs through tunnel coupled structures may be of great utility for connecting distant qubit registers on a chip.
Quantum ferromagnet in the proximity of the tricritical point
Authors: Opletal Petr , Prokleška Jan , Valenta Jaroslav , Proschek Petr , Tkáč Vladimír , Tarasenko Róbert , Běhounková Marie , Matoušková Šárka , Abd-Elmeguid Mohsen M. , Sechovský Vladimír
Published: June 2017

Echoes of quantum phase transitions at finite temperatures are theoretically and experimentally challenging and unexplored topics. Particularly in metallic quantum ferromagnets the experimental investigations are hampered by an intricate preparation of sufficiently pure samples and the access to the proper coordinates in parameter space. The present study shows that it is possible to tune a specific system at easily accessible conditions to the vicinity of its quantum phase transition. The physics is demonstrated on Ru-doped UCoAl, driven by pressure or substitution to and across the tricritical point and follows the first-order transition line to the theoretically presumed quantum phase transition. These findings open the possibilities for further in-depth studies of classical and quantum critical phenomena at easily reachable conditions.
Translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types
Authors: Cambria Elena , Pasqualini Francesco S. , Wolint Petra , Günter Julia , Steiger Julia , Bopp Annina , Hoerstrup Simon P. , Emmert Maximilian Y.
Published: June 2017

Acute myocardial infarction and chronic heart failure rank among the major causes of morbidity and mortality worldwide. Except for heart transplantation, current therapy options only treat the symptoms but do not cure the disease. Stem cell-based therapies represent a possible paradigm shift for cardiac repair. However, most of the first-generation approaches displayed heterogeneous clinical outcomes regarding efficacy. Stemming from the desire to closely match the target organ, second-generation cell types were introduced and rapidly moved from bench to bedside. Unfortunately, debates remain around the benefit of stem cell therapy, optimal trial design parameters, and the ideal cell type. Aiming at highlighting controversies, this article provides a critical overview of the translation of first-generation and second-generation cell types. It further emphasizes the importance of understanding the mechanisms of cardiac repair and the lessons learned from first-generation trials, in order to improve cell-based therapies and to potentially finally implement cell-free therapies.
Development and Evaluation of 18F-IRS for Molecular Imaging Mutant EGF Receptors in NSCLC
Authors: Song Yan , Xiao Zunyu , Wang Kai , Wang Xiance , Zhang Chongqing , Fang Fang , Sun Xilin , Shen Baozhong
Published: June 2017

To prepare and evaluate a new radiotracer 18F-IRS for molecular imaging mutant EGF Receptors in vitro and vivo. Uptake and efflux of 18F-IRS were performed with four NSCLC cell lines including HCC827, H1975, H358 and H520. In vivo tumor targeting and pharmacokinetics of the radiotracers were also evaluated in HCC827, H1975, H358 and H520 tumor-bearing nude mice by PET/CT imaging. Ex vivo biodistribution assays were performed to quantify the accumulation of 18F-IRS in vivo. We also performed 18F-IRS PET/CT imaging of three patients with NSCLC. We labeled this small molecule with QD620 for flow cytometry and confocal imaging analyses. The uptakes of 18F-IRS by HCC827 and HCC827 tumors were significantly higher than those of H358, H1975 and H520, and they were reduced by the addition of 100 μM of gefitinib. Biodistribution experiments showed an accumulation of 18F-IRS in tumors of HCC827 xenografts. Flow cytometry and confocal imaging with QD620-IRS further demonstrated that binding specifically to HCC827 cells. 18F-IRS accumulation was preferential in the tumor, which was NSCLC with responsive EGFR exon 19 deleted. 18F-IRS showed high binding stability and specificity to 19 exon deleted EGFR mutation in vitro and vivo.
An effective molecular approach for assessing cereal aphid-parasitoid-endosymbiont networks
Authors: Ye Zhengpei , Vollhardt Ines M. G. , Girtler Susanne , Wallinger Corinna , Tomanovic Zeljko , Traugott Michael
Published: June 2017

Molecular approaches are increasingly being used to analyse host-parasitoid food webs as they overcome several hurdles inherent to conventional approaches. However, such studies have focused primarily on the detection and identification of aphids and their aphidiid primary parasitoids, largely ignoring primary parasitoid-hyperparasitoid interactions or limiting these to a few common species within a small geographical area. Furthermore, the detection of bacterial secondary endosymbionts has not been considered in such assays despite the fact that endosymbionts may alter aphid-parasitoid interactions, as they can confer protection against parasitoids. Here we present a novel two-step multiplex PCR (MP-PCR) protocol to assess cereal aphid-primary parasitoid-hyperparasitoid-endosymbiont interactions. The first step of the assay allows detection of parasitoid DNA at a general level (24 primary and 16 hyperparasitoid species) as well as the species-specific detection of endosymbionts (3 species) and cereal aphids (3 species). The second step of the MP-PCR assay targets seven primary and six hyperparasitoid species that commonly occur in Central Europe. Additional parasitoid species not covered by the second-step of the assay can be identified via sequencing 16S rRNA amplicons generated in the first step of the assay. The approach presented here provides an efficient, highly sensitive, and cost-effective (~consumable costs of 1.3 € per sample) tool for assessing cereal aphid-parasitoid-endosymbiont interactions.
Flexible Indium–Tin Oxide Crystal on Plastic Substrates Supported by Graphene Monolayer
Authors: Lee Sang Jin , Kim Yekyung , Hwang Jun-Yeon , Lee Ju-Ho , Jung Seungon , Park Hyesung , Cho Seungmin , Nahm Sahn , Yang Woo Seok , Kim Hyeongkeun , Han Seung Ho
Published: June 2017

Flexible and crystallized indium–tin oxide (ITO) thin films were successfully obtained on plastic polyethylene terephthalate (PET) films with monolayered graphene as a platform. The highly crystalline ITO (c-ITO) was first fabricated on a rigid substrate of graphene on copper foil and it was subsequently transferred onto a PET substrate by a well-established technique. Despite the plasma damage during ITO deposition, the graphene layer effectively acted as a Cu-diffusion barrier. The c-ITO/graphene/PET electrode with the 60-nm-thick ITO exhibited a reasonable sheet resistance of ~45 Ω sq−1 and a transmittance of ~92% at a wavelength of 550 nm. The c-ITO on the monolayered graphene support showed significant enhancement in flexibility compared with the ITO/PET film without graphene because the atomically controlled monolayered graphene acted as a mechanically robust support. The prepared flexible transparent c-ITO/graphene/PET electrode was applied as the anode in a bulk heterojunction polymer solar cell (PSC) to evaluate its performance, which was comparable with that of the commonly used c-ITO/glass electrode. These results represent important progress in the fabrication of flexible transparent electrodes for future optoelectronics applications.
Deregulation of miRNAs in malignant pleural mesothelioma is associated with prognosis and suggests an alteration of cell metabolism
Authors: De Santi Chiara , Melaiu Ombretta , Bonotti Alessandra , Cascione Luciano , Di Leva Gianpiero , Foddis Rudy , Cristaudo Alfonso , Lucchi Marco , Mora Marco , Truini Anna , Tironi Andrea , Murer Bruno , Boldorini Renzo , Cipollini Monica , Gemignani Federica , Gasparini Pierluigi , Mutti Luciano , Landi Stefano
Published: June 2017

Malignant pleural mesothelioma (MPM) is an aggressive human cancer and miRNAs can play a key role for this disease. In order to broaden the knowledge in this field, the miRNA expression was investigated in a large series of MPM to discover new pathways helpful in diagnosis, prognosis and therapy. We employed nanoString nCounter system for miRNA profiling on 105 MPM samples and 10 healthy pleura. The analysis was followed by the validation of the most significantly deregulated miRNAs by RT-qPCR in an independent sample set. We identified 63 miRNAs deregulated in a statistically significant way. MiR-185, miR-197, and miR-299 were confirmed differentially expressed, after validation study. In addition, the results of the microarray analysis corroborated previous findings concerning miR-15b-5p, miR-126-3p, and miR-145-5p. Kaplan-Meier curves were used to explore the association between miRNA expression and overall survival (OS) and identified a 2-miRNA prognostic signature (Let-7c-5p and miR-151a-5p) related to hypoxia and energy metabolism respectively. In silico analyses with DIANA-microT-CDS highlighted 5 putative targets in common between two miRNAs. With the present work we showed that the pattern of miRNAs expression is highly deregulated in MPM and that a 2-miRNA signature can be a new useful tool for prognosis in MPM.
Permeability-driven selection in a semi-empirical protocell model: the roots of prebiotic systems evolution
Authors: Piedrafita Gabriel , Monnard Pierre-Alain , Mavelli Fabio , Ruiz-Mirazo Kepa
Published: June 2017

The origin-of-life problem has been traditionally conceived as the chemical challenge to find the type of molecule and free-solution reaction dynamics that could have started Darwinian evolution. Different autocatalytic and ‘self-replicative’ molecular species have been extensively investigated, together with plausible synthetic pathways that might have led, abiotically, to such a minimalist scenario. However, in addition to molecular kinetics or molecular evolutionary dynamics, other physical and chemical constraints (like compartmentalization, differential diffusion, selective transport, osmotic forces, energetic couplings) could have been crucial for the cohesion, functional integration, and intrinsic stability/robustness of intermediate systems between chemistry and biology. These less acknowledged mechanisms of interaction and molecular control might have made the initial pathways to prebiotic systems evolution more intricate, but were surely essential for sustaining far-from-equilibrium chemical dynamics, given their functional relevance in all modern cells. Here we explore a protocellular scenario in which some of those additional constraints/mechanisms are addressed, demonstrating their ‘system-level’ implications. In particular, an experimental study on the permeability of prebiotic vesicle membranes composed of binary lipid mixtures allows us to construct a semi-empirical model where protocells are able to reproduce and undergo an evolutionary process based on their coupling with an internal chemistry that supports lipid synthesis.
Innate And Adaptive Immunity are Progressively Activated in Parallel with Renal Injury in the 5/6 Renal Ablation Model
Authors: Fanelli Camilla , Arias Simone C. A. , Machado Flavia G. , Okuma Jessica K. , Malheiros Denise M. A. C. , Azevedo Hatylas , Moreira-Filho Carlos A. , Camara Niels O. S. , Fujihara Clarice K. , Zatz Roberto
Published: June 2017

The mechanisms triggering renal inflammation in chronic kidney disease (CKD) are unclear. We performed a detailed analysis of the time course of innate and adaptive immunity activation in the 5/6 renal ablation (Nx) model. Munich-Wistar rats undergoing Nx were studied 15, 60 and 120 days after ablation. Hypertension, albuminuria, creatinine retention, interstitial expansion and infiltration by macrophages and T-lymphocytes were already evident 15 days after Nx. PCR-array was used to screen for altered gene expression, whereas gene and protein expressions of TLR4, CASP1, IL-1β and NLRP3 were individually assessed. Tlr4, Tlr5, Lbp, Nlrp3, Casp1, Irf7 and Il1b were already upregulated 15 days after Nx, while activation of Tlr2, Tlr7, Tlr9, Nod2, Tnf and Il6 was seen after 60 days post-ablation. The number of genes related to innate or adaptive immunity grew steadily with time. These observations indicate that parallel activation of innate and adaptive immunity antecedes glomerular injury and involves a growing number of intricate signaling pathways, helping to explain the difficulty in detaining renal injury in Nx as CKD advances, and, stressing the need for early treatment. Additionally, these findings may contribute to the search of therapeutic targets specific for advanced phases of CKD.
Global temporal patterns of pancreatic cancer and association with socioeconomic development
Authors: Wong Martin C. S. , Jiang Johnny Y. , Liang Miaoyin , Fang Yuan , Yeung Ming Sze , Sung Joseph J. Y.
Published: June 2017

Pancreatic cancer induces a substantial global burden. We examined its global incidence/mortality rates and their correlation with socioeconomic development (Human Development Index [HDI] and Gross Domestic Product [GDP] in 2000 as proxy measures). Data on age-standardized incidence/mortality rates in 2012 were retrieved from the GLOBOCAN database. Temporal patterns in 1998–2007 were assessed for 39 countries according to gender. The Average Annual Percent Change (AAPC) of the incidence/mortality trends was evaluated using joinpoint regression analysis. The age-standardized incidence ranged between 0.8–8.9/100,000. When compared among countries, Brazil (AAPC = 10.4, 95%C.I. = 0.8,21) and France (AAPC = 4.7, 95%C.I. = 3.6,5.9) reported the highest incidence rise in men. The greatest increase in women was reported in Thailand (AAPC = 7, 95%C.I. = 2.1,12.1) and Ecuador (AAPC = 4.3, 95%C.I. = 1.3,7.3). For mortality, the Philippines (APCC = 4.3, 95%C.I. = 2,6.6) and Croatia (AAPC = 2, 95% C.I. = 0,3.9) reported the biggest increase among men. The Philippines (AAPC = 5.8, 95% C.I. 4.5,7.2) and Slovakia (AAPC = 3.1, 95% C.I. 0.9,5.3) showed the most prominent rise among women. Its incidence was positively correlated with HDI (men: r = 0.66; women: r = 0.70) and GDP (men: r = 0.29; women: r = 0.28, all p < 0.05), and similarly for mortality (men: r = 0.67; women: r = 0.72 [HDI]; men: r = 0.23; women: r = 0.28 [GDP]). In summary, the incidence and mortality of pancreatic cancer were rising in many countries, requiring regular surveillance.
Pwp2 mediates UTP-B assembly via two structurally independent domains
Authors: Boissier Fanny , Schmidt Christina Maria , Linnemann Jan , Fribourg Sébastien , Perez-Fernandez Jorge
Published: June 2017

The SSU processome constitutes a large ribonucleoprotein complex involved in the early steps of ribosome biogenesis. UTP-B is one of the first multi-subunit protein complexes that associates with the pre-ribosomal RNA to form the SSU processome. To understand the molecular basis of the hierarchical assembly of the SSU-processome, we have undergone a structural and functional analysis of the UTP-B subunit Pwp2p. We show that Pwp2p is required for the proper assembly of UTP-B and for a productive association of UTP-B with pre-rRNA. These two functions are mediated by two distinct structural domains. The N-terminal domain of Pwp2p folds into a tandem WD-repeat (tWD) that associates with Utp21p, Utp18p, and Utp6p to form a core complex. The CTDs of Pwp2p and Utp21p mediate the assembly of the heterodimer Utp12p:Utp13p that is required for the stable incorporation of the UTP-B complex in the SSU processome. Finally, we provide evidence suggesting a role of UTP-B as a platform for the binding of assembly factors during the maturation of 20S rRNA precursors.
Promoter hypermethylation inactivates CDKN2A, CDKN2B and RASSF1A genes in sporadic parathyroid adenomas
Authors: Arya Ashutosh Kumar , Bhadada Sanjay Kumar , Singh Priyanka , Sachdeva Naresh , Saikia Uma Nahar , Dahiya Divya , Behera Arunanshu , Bhansali Anil , Rao Sudhaker D.
Published: June 2017

Cyclin D1, a G1-S phase regulator, is upregulated in parathyroid adenomas. Since cyclin-dependent kinase (CDK) inhibitors, CDKN2A and CDKN2B, and RASSF1A (Ras-association domain family 1, isoform A) are involved in G1-S phase arrest and act as potential tumor suppressor genes, we aimed to study potential methylation-mediated inactivation of these genes in parathyroid adenomas. Gene expressions of cyclin D1 (CCND1) and regulatory molecules (CDKN2A, CDKN2B and RASSF1A) was analysed in parathyroid adenoma tissues (n = 30). DNA promoter methylation of cyclin D1 regulators were assessed and correlated with clinicopathological features of the patients. Gene expression analysis showed a relative fold reductions of 0.35 for CDKN2A (p = 0.01), 0.45 for CDKN2B (P = 0.02), and 0.39 for RASSF1A (p < 0.01) in adenomatous compared to normal parathyroid tissue. There was an inverse relationship between the expressions of CDKN2A and CDKN2B with CCND1. In addition, the promoter regions of CDKN2A, CDKN2B, and of RASSF1A were significantly hyper-methylated in 50% (n = 15), 47% (n = 14), and 90% (n = 27) of adenomas respectively. In contrast, no such aberrant methylation of these genes was observed in normal parathyroid tissue. So, promoter hypermethylation is associated with down-regulation of CCND1 regulatory genes in sporadic parathyroid adenomas. This dysregulated cell cycle mechanism may contribute to parathyroid tumorigenesis.
Action sequencing in the spontaneous swimming behavior of zebrafish larvae - implications for drug development
Authors: Palmér Tobias , Ek Fredrik , Enqvist Olof , Olsson Roger , Åström Kalle , Petersson Per
Published: June 2017

All motile organisms need to organize their motor output to obtain functional goals. In vertebrates, natural behaviors are generally composed of a relatively large set of motor components which in turn are combined into a rich repertoire of complex actions. It is therefore an experimental challenge to investigate the organizational principles of natural behaviors. Using the relatively simple locomotion pattern of 10 days old zebrafish larvae we have here characterized the basic organizational principles governing the swimming behavior. Our results show that transitions between different behavioral states can be described by a model combining a stochastic component with a control signal. By dividing swimming bouts into a limited number of categories, we show that similar types of swimming behavior as well as stand-stills between bouts were temporally clustered, indicating a basic level of action sequencing. Finally, we show that pharmacological manipulations known to induce alterations in the organization of motor behavior in mammals, mainly through basal ganglia interactions, have related effects in zebrafish larvae. This latter finding may be of specific relevance to the field of drug development given the growing importance of zebrafish larvae in phenotypic screening for novel drug candidates acting on central nervous system targets.
Effect of adapter duration on repetition suppression in inferior temporal cortex
Authors: Kuravi Pradeep , Vogels Rufin
Published: June 2017

Many inferior temporal (IT) cortical neurons reduce their response when a stimulus is repeated. Proposed mechanisms underlying this repetition suppression range from “fatigue” to top-down expectations of repetition. Here we examine a prediction from simple fatigue-based models of adaptation: prolonging adapter duration will increase the adapter response, leading to more repetition suppression. To test this, we varied adapter duration from 300 to 3000 ms, keeping the test stimulus duration constant. We observed no effect of adapter duration on repetition suppression when averaging responses across the test presentation. This was not because of a ceiling effect, since repeated presentations of a short adapter increased repetition suppression. Examination of test stimulus responses showed increased repetition suppression with longer adapter durations during the initial response phase, which reversed at a later phase. Across neurons, we found that the degree of repetition suppression covaried with the ratio of the response during the initial transient and later sustained phase of the response during the long adapter presentation, suggesting overlapping mechanisms that underlie adaptation during the adapter and the delayed test. We propose a fatigue-based account in which fatigue increases non-linearly with adapter duration to explain these unexpected findings.
HOTAIR rs7958904 polymorphism is associated with increased cervical cancer risk in a Chinese population
Authors: Jin Hua , Lu Xiaoyun , Ni Jing , Sun Jinfang , Gu Bin , Ding Bo , Zhu Haixia , Ma Chao , Cui Mengjing , Xu Yuling , Zhang Zhengdong , Lercher Martin , Chen Jian , Gao Na , Wang Shizhi
Published: June 2017

Previously, we have identified single nucleotide polymorphisms (SNPs) rs7958904 and rs4759314 in long non-coding RNA HOX transcript antisense RNA (HOTAIR) were significantly associated with risk of colorectal and gastric cancer, respectively. Here, we aimed to investigate the association between HOTAIR SNPs and cervical cancer (CC) susceptibility. A total of 1209 cases and 1348 controls were enrolled for association study and genotyped with TaqMan allelic discrimination method. The Cancer Genome Atlas (TCGA) database was utilized for in vivo analysis of allele-specific HOTAIR expression. MTT assay was employed for evaluation of allele-specific cell proliferation. The rs7958904 CC genotype was related to an increased risk of cervical cancer compared with the GG/GC genotypes (OR = 1.57, 95% CI = 1.10–2.25). TCGA database showed the CC tissues with rs7958904 CC genotype had higher HOTAIR expression than those with GG genotype (P = 0.046). MTT assay demonstrated a growth-promoting role of rs7958904 C allele on CC cells. Further functional studies on the effect of rs7958904 on biological behavior of CC cells are needed to confirm and extend our findings. In conclusion, HOTAIR rs7958904 might influence CC susceptibility through modulation of CC cell proliferation, and could serve as a diagnostic biomarker.
Evaluating the repeatability of corneal elevation through calculating the misalignment between Successive topography measurements during the follow up of LASIK
Authors: Zheng XiaoBo , Yang WeiHua , Huang LiFang , Wang JunJie , Cao Si , Geraghty Brendan , Zhao YiPing , Wang QinMei , Bao FangJun , Elsheikh Ahmed
Published: June 2017

The study aims to evaluate, using the Iterative Closest Point (ICP) algorithm, the repeatability of successive corneal elevation measurements taken post-LASIK. Two topography maps of 98 LASIK participants were recorded preoperatively (Pre), 1 month (Pos1M) and 3 months postoperatively (Pos3M). Elevation of the second measurement was fitted to the first measurement by calculating using ICP, and correcting for, both translational and rotational misalignment components. The RMS of elevation differences between anterior corneal measurements were statistically significant post-LASIK compared to preoperation (P < 0.05). A misalignment ratio used to describe the weighting of the elevation difference caused by misalignment relative to the total difference remained stable (0.40 and 0.23 for anterior and posterior corneal surfaces, respectively) in different periods. The study also considered the combined misalignment parameter (CM), which represents the total effect of all individual misalignment components on the repeatability of corneal topography maps. CM was significantly greater post-LASIK relative to pre-LASIK (P < 0.05). Overall, the contribution of misalignment to the total difference between successive corneal measurements remained stable pre and post operation, while the combined effect of refractive error correction and optical diameter appeared to have a significant influence on the elevation repeatability in the early stages of the follow up period.
REG3β modifies cell tumor function by impairing extracellular vesicle uptake
Authors: Bonjoch Laia , Gironella Meritxell , Iovanna Juan Lucio , Closa Daniel
Published: June 2017

Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-sized membrane vesicles containing proteins and nucleic acids, which act as intercellular messengers. They play an important role in a variety of physiological processes, as well as in pathological situations such as inflammation or cancer. Here, we show that in the case of pancreatic ductal adenocarcinoma (PDAC), the healthy pancreatic tissue surrounding the tumor releases REG3β, a lectin that binds to the glycoproteins present in the surface of EVs, thus interfering with their uptake and internalization by target cells. In vitro, the disruption of the signaling mediated by EVs due to the presence of REG3β, prevents the EV-induced phenotypic switch in macrophages, inhibits the increased cell migration of cancer cells and reverses a number of metabolomic changes promoted by EVs. In vivo, the uptake of REG3β+ EVs by tumor cells is significantly impaired. Furthermore, it results in an increase of circulating REG3β+ EVs in blood of pancreatic cancer patients. Our findings highlight the effect of a lectin released by the healthy pancreatic tissue surrounding the tumor in modulating the EV-mediated interactions between different cell types in PDAC.
Disruption of retinal pigment epithelial cell properties under the exposure of cotinine
Authors: Zhang Xiao-Yu , Ng Tsz Kin , Brelén Mårten Erik , Chan Kwok Ping , Wu Di , Yung Jasmine Sum Yee , Cao Di , Wang Yumeng , Zhang Shaodan , Chan Sun On , Pang Chi Pui
Published: June 2017

Cigarette smoking is a major risk factor for age-related macular degeneration (AMD), in which progressive retinal pigment epithelial (RPE) cell degeneration is a major pathological change. Nicotine is a major biologically active component in cigarette smoke. It is continuously catabolized into cotinine, which has longer half-life and higher concentration in tissue cells and fluids. Here we hypothesized that continuous exposure of cotinine has more potent effects on human RPE cell properties than nicotine. Human RPE cell line (ARPE-19) was treated continuously with 1–2 µM of nicotine and/or cotinine for 7 days. RPE cells treated with 2 μM cotinine and nicotine-cotinine mixture has lower MTT signals without significant changes in cell apoptosis or integrity. Moreover, RPE cell migration was retarded under cotinine treatments, but not nicotine. Both nicotine and cotinine treatments attenuated the phagocytotic activity of RPE cells. In addition, cotinine and nicotine-cotinine mixture suppressed VEGF and IL-8 expression and upregulated TIMP-2 expression. Expressions of autophagy genes were upregulated by the cotinine treatment, whereas expressions of epithelial-to-mesenchymal transition markers were downregulated. In conclusion, our study, for the first time, demonstrated that cotinine, rather than nicotine, affects the properties of RPE cells in vitro, which could explain the smoking-induced RPE pathology.
Direct competition between DNA binding factors highlights the role of Krüppel-like Factor 1 in the erythroid/megakaryocyte switch
Authors: Norton Laura J. , Hallal Samantha , Stout Elizabeth S. , Funnell Alister P. W. , Pearson Richard C. M. , Crossley Merlin , Quinlan Kate G. R.
Published: June 2017

The Krüppel-like factor (KLF) family of transcription factors play critical roles in haematopoiesis. KLF1, the founding member of the family, has been implicated in the control of both erythropoiesis and megakaryopoiesis. Here we describe a novel system using an artificial dominant negative isoform of KLF1 to investigate the role of KLF1 in the erythroid/megakaryocytic switch in vivo. We developed murine cell lines stably overexpressing a GST-KLF1 DNA binding domain fusion protein (GST-KLF1 DBD), as well as lines expressing GST only as a control. Interestingly, overexpression of GST-KLF1 DBD led to an overall reduction in erythroid features and an increase in megakaryocytic features indicative of a reduced function of endogenous KLF1. We simultaneously compared in vivo DNA occupancy of both endogenous KLF1 and GST-KLF1 DBD by ChIP qPCR. Here we found that GST-KLF1 DBD physically displaces endogenous KLF1 at a number of loci, providing novel in vivo evidence of direct competition between DNA binding proteins. These results highlight the role of KLF1 in the erythroid/megakaryocyte switch and suggest that direct competition between transcription factors with similar consensus sequences is an important mechanism in transcriptional regulation.
Conserved amino acid networks modulate discrete functional properties in an enzyme superfamily
Authors: Narayanan Chitra , Gagné Donald , Reynolds Kimberly A. , Doucet Nicolas
Published: June 2017

In this work, we applied the sequence-based statistical coupling analysis approach to characterize conserved amino acid networks important for biochemical function in the pancreatic-type ribonuclease (ptRNase) superfamily. This superfamily-wide analysis indicates a decomposition of the RNase tertiary structure into spatially distributed yet physically connected networks of co-evolving amino acids, termed sectors. Comparison of this statistics-based description with new NMR experiments data shows that discrete amino acid networks, termedsectors, control the tuning of distinct functional properties in different enzyme homologs. Further, experimental characterization of evolutionarily distant sequences reveals that sequence variation at sector positions can distinguish homologs with a conserved dynamic pattern and optimal catalytic activity from those with altered dynamics and diminished catalytic activities. Taken together, these results provide important insights into the mechanistic design of the ptRNase superfamily, and presents a structural basis for evolutionary tuning of function in functionally diverse enzyme homologs.
Intracranial Fluid Redistribution But No White Matter Microstructural Changes During a Spaceflight Analog
Authors: Koppelmans Vincent , Pasternak Ofer , Bloomberg Jacob J. , Dios Yiri E. De , Wood Scott J. , Riascos Roy , Reuter-Lorenz Patricia A. , Kofman Igor S. , Mulavara Ajitkumar P. , Seidler Rachael D.
Published: June 2017

The neural correlates of spaceflight-induced sensorimotor impairments are unknown. Head down-tilt bed rest (HDBR) serves as a microgravity analog because it mimics the headward fluid shift and axial body unloading of spaceflight. We investigated focal brain white matter (WM) changes and fluid shifts during 70 days of 6° HDBR in 16 subjects who were assessed pre (2x), during (3x), and post-HDBR (2x). Changes over time were compared to those in control subjects (n = 12) assessed four times over 90 days. Diffusion MRI was used to assess WM microstructure and fluid shifts. Free-Water Imaging was used to quantify distribution of intracranial extracellular free water (FW). Additionally, we tested whether WM and FW changes correlated with changes in functional mobility and balance measures. HDBR resulted in FW increases in fronto-temporal regions and decreases in posterior-parietal regions that largely recovered by two weeks post-HDBR. WM microstructure was unaffected by HDBR. FW decreases in the post-central gyrus and precuneus correlated negatively with balance changes. We previously reported that gray matter increases in these regions were associated with less HDBR-induced balance impairment, suggesting adaptive structural neuroplasticity. Future studies are warranted to determine causality and underlying mechanisms.
Hatching enzymes disrupt aberrant gonadal degeneration by the autophagy/apoptosis cell fate decision
Authors: Chakraborty Tapas , Mohapatra Sipra , Tobayama Megumi , Ohta Kayoko , Ryu Yong-Woon , Kazeto Yukinori , Ohta Kohei , Zhou Linyan , Nagahama Yoshitaka , Matsubara Takahiro
Published: June 2017

Environmental stressors, gonadal degenerative diseases and tumour development can significantly alter the oocyte physiology, and species fertility and fitness. To expand the molecular understanding about oocyte degradation, we isolated several spliced variants of Japanese anchovy hatching enzymes (AcHEs; ovastacin homologue) 1 and 2, and analysed their potential in oocyte sustenance. Particularly, AcHE1b, an ovary-specific, steroid-regulated, methylation-dependent, stress-responsive isoform, was neofunctionalized to regulate autophagic oocyte degeneration. AcHE1a and 2 triggered apoptotic degeneration in vitellogenic and mature oocytes, respectively. Progesterone, starvation, and high temperature elevated the total degenerating oocyte population and AcHE1b transcription by hyper-demethylation. Overexpression, knockdown and intracellular zinc ion chelation study confirmed the functional significance of AcHE1b in autophagy induction, possibly to mitigate the stress effects in fish, via ion-homeostasis. Our finding chronicles the importance of AcHEs in stress-influenced apoptosis/autophagy cell fate decision and may prove significant in reproductive failure assessments, gonadal health maintenance and ovarian degenerative disease therapy.
Imipramine Inhibits Chikungunya Virus Replication in Human Skin Fibroblasts through Interference with Intracellular Cholesterol Trafficking
Authors: Wichit Sineewanlaya , Hamel Rodolphe , Bernard Eric , Talignani Loïc , Diop Fodé , Ferraris Pauline , Liegeois Florian , Ekchariyawat Peeraya , Luplertlop Natthanej , Surasombatpattana Pornapat , Thomas Frédéric , Merits Andres , Choumet Valérie , Roques Pierre , Yssel Hans , Briant Laurence , Missé Dorothée
Published: June 2017

Chikungunya virus (CHIKV) is an emerging arbovirus of the Togaviridae family that poses a present worldwide threat to human in the absence of any licensed vaccine or antiviral treatment to control viral infection. Here, we show that compounds interfering with intracellular cholesterol transport have the capacity to inhibit CHIKV replication in human skin fibroblasts, a major viral entry site in the human host. Pretreatment of these cells with the class II cationic amphiphilic compound U18666A, or treatment with the FDA-approved antidepressant drug imipramine resulted in a near total inhibition of viral replication and production at the highest concentration used without any cytotoxic effects. Imipramine was found to affect both the fusion and replication steps of the viral life cycle. The key contribution of cholesterol availability to the CHIKV life cycle was validated further by the use of fibroblasts from Niemann-Pick type C (NPC) patients in which the virus was unable to replicate. Interestingly, imipramine also strongly inhibited the replication of several Flaviviridae family members, including Zika, West Nile and Dengue virus. Together, these data show that this compound is a potential drug candidate for anti-arboviral treatment.
Serum Lipid Levels and Risk Of Hand Osteoarthritis: The Chingford Prospective Cohort Study
Authors: Garcia-Gil M. , Reyes C. , Ramos R. , Sanchez-Santos M. T. , Prieto-Alhambra D. , Spector T. D. , Hart D. J. , Arden N. K.
Published: June 2017

The development of hand osteoarthritis (HOA) could be linked to hyperlipidaemia. No longitudinal studies have addressed the relationship between serum lipid profile and HOA. The study aim was to determine the association between serum lipid profile and the incidence of radiographic hand osteoarthritis (RHOA). All women in a prospective population-based cohort from the Chingford study with available baseline lipid measurements and without RHOA on a baseline were included. Study outcome was the incidence of RHOA in year 11 of follow-up. Serum lipid profile variables were analysed as continuous variables and categorised into quartiles. The association between serum lipid profile and RHOA was modeled using multivariable logistic regression. Overall RHOA incidence was 51.6% (45.7–57.4%). An inverse association between HDL cholesterol levels and the incidence of RHOA was observed by quartile: OR of 0.36 [95%CI 0.17–0.75], 0.52 [95%CI 0.26–1.06], and 0.48 [95%CI 0.22–1.03]. Triglycerides levels showed a significant trend. No relationship was found with total or LDL cholesterol. Higher levels of HDL cholesterol appear to protect against RHOA after 11 years of follow-up. More research is needed to elucidate HOA risk factors, the mechanisms related to the lipid pathway, and the effects of lipid-lowering agents on reducing the incidence of OA.
Design of Acquisition Schemes and Setup Geometry for Anisotropic X-ray Dark-Field Tomography (AXDT)
Authors: Sharma Y. , Schaff F. , Wieczorek M. , Pfeiffer F. , Lasser T.
Published: June 2017

Anisotropic X-ray Dark-field Tomography (AXDT) is a new imaging technique for reconstructing the three-dimensional scattering profile within a sample using the dark-field signal measured in an X-ray grating interferometry setup. As in any tomographic measurement, the acquisition geometry plays a key role in the accurate reconstruction of the scattering information. More- over, the anisotropic nature of the dark-field signal poses additional challenges for designing the acquisition protocols. In this work, we present an efficient approach to measure scattering orientations spread over the unit sphere and prove its efficacy using the knowledge from conventional tomography. In addition, we conclude (using analytical and experimental results) that placing the gratings such that the grating bars make an angle of 45 degrees with respect to the vertical direction is the optimal setup configuration for AXDT.
Clinical on-site monitoring of ß-lactam antibiotics for a personalized antibiotherapy
Authors: Bruch R. , Chatelle C. , Kling A. , Rebmann B. , Wirth S. , Schumann S. , Weber W. , Dincer C. , Urban G.
Published: June 2017

An appropriate antibiotherapy is crucial for the safety and recovery of patients. Depending on the clinical conditions of patients, the required dose to effectively eradicate an infection may vary. An inadequate dosing not only reduces the efficacy of the antibiotic, but also promotes the emergence of antimicrobial resistances. Therefore, a personalized therapy is of great interest for improved patients’ outcome and will reduce in long-term the prevalence of multidrug-resistances. In this context, on-site monitoring of the antibiotic blood concentration is fundamental to facilitate an individual adjustment of the antibiotherapy. Herein, we present a bioinspired approach for the bedside monitoring of free accessible ß-lactam antibiotics, including penicillins (piperacillin) and cephalosporins (cefuroxime and cefazolin) in untreated plasma samples. The introduced system combines a disposable microfluidic chip with a naturally occurring penicillin-binding protein, resulting in a high-performance platform, capable of gauging very low antibiotic concentrations (less than 6 ng ml−1) from only 1 µl of serum. The system’s applicability to a personalized antibiotherapy was successfully demonstrated by monitoring the pharmacokinetics of patients, treated with ß-lactam antibiotics, undergoing surgery.
Fluid viscoelasticity promotes collective swimming of sperm
Authors: Tung Chih-kuan , Lin Chungwei , Harvey Benedict , Fiore Alyssa G. , Ardon Florencia , Wu Mingming , Suarez Susan S.
Published: June 2017

From flocking birds to swarming insects, interactions of organisms large and small lead to the emergence of collective dynamics. Here, we report striking collective swimming of bovine sperm in dynamic clusters, enabled by the viscoelasticity of the fluid. Sperm oriented in the same direction within each cluster, and cluster size and cell-cell alignment strength increased with viscoelasticity of the fluid. In contrast, sperm swam randomly and individually in Newtonian (nonelastic) fluids of low and high viscosity. Analysis of the fluid motion surrounding individual swimming sperm indicated that sperm-fluid interaction was facilitated by the elastic component of the fluid. In humans, as well as cattle, sperm are naturally deposited at the entrance to the cervix and must swim through viscoelastic cervical mucus and other mucoid secretions to reach the site of fertilization. Collective swimming induced by elasticity may thus facilitate sperm migration and contribute to successful fertilization. We note that almost all biological fluids (e.g. mucus and blood) are viscoelastic in nature, and this finding highlights the importance of fluid elasticity in biological function.
Modeling Congenital Hyperinsulinism with ABCC8-Deficient Human Embryonic Stem Cells Generated by CRISPR/Cas9
Authors: Guo Dongsheng , Liu Haikun , Ruzi Aynisahan , Gao Ge , Nasir Abbas , Liu Yanli , Yang Fan , Wu Feima , Xu Guosheng , Li Yin-xiong
Published: June 2017

Congenital hyperinsulinism (CHI) is a rare genetic disorder characterized by excess insulin secretion, which results in hypoglycemia. Mutation of sulfonylurea receptor 1 (SUR1), encoded by the ABCC8 gene, is the main cause of CHI. Here, we captured the phenotype of excess insulin secretion through pancreatic differentiation of ABCC8-deficient stem cells generated by the CRISPR/Cas9 system. ABCC8-deficient insulin-producing cells secreted higher insulin than their wild-type counterparts, and the excess insulin secretion was rescued by nifedipine, octreotide and nicorandil. Further, we tested the role of SUR1 in response to different potassium levels and found that dysfunction of SUR1 decreased the insulin secretion rate in low and high potassium environments. Hence, pancreatic differentiation of ABCC8-deficient cells recapitulated the CHI disease phenotype in vitro, which represents an attractive model to further elucidate the function of SUR1 and to develop and screen for novel therapeutic drugs.
Antibacterial cellulose paper made with silver-coated gold nanoparticles
Authors: Tsai Tsung-Ting , Huang Tse-Hao , Chang Chih-Jung , Yi-Ju Ho Natalie , Tseng Yu-Ting , Chen Chien-Fu
Published: June 2017

In this study, we investigated the antibacterial activity of silver-coated gold nanoparticles (Au-Ag NPs) immobilized on cellulose paper. Ag NPs are known to have strong antibacterial properties, while Au NPs are biocompatible and relatively simple to prepare. We made the Au-Ag NPs using a facile process called Ag enhancement, in which Au NPs serve as the nuclei for precipitation of a Ag coating, the thickness of which can be easily controlled by varying the ratio of the reactants. After synthesis, electron microscopy showed that the Au-Ag NPs displayed a core-shell structure, and that they could be successfully immobilized onto a cellulose membrane by heat treatment. We then investigated the antibacterial properties of this NP-coated cellulose paper against E. coli JM109. The inhibition rate, growth curve, and AATCC 100 activity test showed that cellulose paper coated with 15 nm Au-Ag NPs possessed excellent antibacterial activity against E. coli JM109. These results suggest that Au-Ag NPs immobilized on cellulose paper could be a valuable antibacterial technology for applications such as food packaging, clothing, wound dressings, and other personal care products.
Variation in Tree Species Ability to Capture and Retain Airborne Fine Particulate Matter (PM2.5)
Authors: Chen Lixin , Liu Chenming , Zhang Lu , Zou Rui , Zhang Zhiqiang
Published: June 2017

Human health risks caused by PM2.5 raise awareness to the role of trees as bio-filters of urban air pollution, but not all species are equally capable of filtering the air. The objectives of this current study were: (1) to determine the foliar traits for effective PM2.5-capture and (2) explore species-to-species differences in foliar PM2.5-recapture capacity following a rain event. The study concluded that overall, the acicular needle shape made conifers more efficient with PM2.5 accumulation and post-rainfall recapture than broadleaved species. The foliar shape and venation of broadleaved species did not appear to influence the PM2.5 accumulation. However, the number of the grooves and trichomes of broadleaved species were positively related to foliar PM2.5 accumulation, suggesting that they could be used as indicators for the effectiveness of tree PM2.5 capture. Furthermore, the amount of PM2.5 removal by rainfall was determined by the total foliar PM2.5. Not all PM2.5 remained on the foliage. In some species, PM2.5 was resuspended during the growing season, and thus reduced the net particular accumulation for that species. These findings contribute to a better understanding of tree species potential for reducing PM2.5 in urban environments.
FPR2 promotes invasion and metastasis of gastric cancer cells and predicts the prognosis of patients
Authors: Hou Xi-Lu , Ji Cheng-Dong , Tang Jun , Wang Yan-Xia , Xiang Dong-Fang , Li Hai-Qing , Liu Wei-Wei , Wang Jiao-Xue , Yan He-Zhong , Wang Yan , Zhang Peng , Cui You-Hong , Wang Ji-Ming , Bian Xiu-Wu , Liu Wei
Published: June 2017

Formyl peptide receptor 2 (FPR2), a classical chemoattractant receptor of G-protein-coupled receptors, is reported to be involved in invasion and metastasis of some cancers, but the role of FPR2 in gastric cancer (GC) has not yet been elucidated. In this study, we found that the levels of FPR2 expression in GC were positively correlated with invasion depth, lymph node metastasis and negatively correlated with the patients’ overall survival. Multivariate analysis indicated that FPR2 expression was an independent prognostic marker for GC patients. FPR2-knockdown significantly abrogated the migration and invasion stimulated by Hp(2–20) and Ac(2–26), two well-characterized ligands for FPR2 in GC cells. FPR2 deletion also reduced the tumorigenic and metastatic capabilities of GC cells in vivo. Mechanistically, stimulation with FPR2 ligands resulted in down-regulation of E-cadherin and up-regulation of vimentin, which were reversed by FPR2 knock-down, implying the involvement of epithelial–mesenchymal transition (EMT). Moreover, the activation of FPR2 was accompanied with ERK1/2 phosphorylation, which could be attenuated by FPR2 silencing or treatment with MEK inhibitor, PD98059. Altogether, our results demonstrate that FPR2 is functionally involved in invasion and metastasis, and potentially acts as a novel prognostic marker as well as a potential therapeutic target in human GC.
Reference value of left and right atrial size and phasic function by SSFP CMR at 3.0 T in healthy Chinese adults
Authors: Li Weihao , Wan Ke , Han Yuchi , Liu Hong , Cheng Wei , Sun Jiayu , Luo Yong , Yang Dan , Chung Yiu-Cho , Chen Yucheng
Published: June 2017

The size and function of the left atrium (LA) and right atrium (RA) are related closely with the prognosis of cardiovascular diseases. However, their normal reference values, as measured by cardiac magnetic resonance (CMR), are not well established in Chinese populations. Healthy Chinese subjects (n = 135, 66 males, age 23–83 years) without cardiovascular risk factors were recruited. We imaged the LA and RA of all subjects using short axis and long axis slices by steady-state free precession (SSFP) sequences using a 3.0T scanner. The size and functional parameters were measured. Age and gender differences in LA were further explored. The normal reference values of atrial dimensions, volumes, and empty fractions (EFs) were provided by short axis (SAX) and area-length methods. Volumes and EFs derived by the area-length method showed correlated well with those derived by the by SAX method, but significantly underestimated the volumes (all P < 0.001) and overestimated the LA EFs (all P < 0.001). Atrial dimensions and volumes were generally larger in males. Conduit EFs and total EFs showed gender differences. Most atrial parameters correlated with age. In general, our results showed that gender and age have considerable impact on LA and RA size and function.