bluuebunny/crossref_metadata_2025 huggingface dataset:
Fgf21 regulates T-cell development in the neonatal and juvenile thymus
Authors: Nakayama Yoshiaki , Masuda Yuki , Ohta Hiroya , Tanaka Tomohiro , Washida Miwa , Nabeshima Yo-ichi , Miyake Ayumi , Itoh Nobuyuki , Konishi Morichika
Published: March 2017

We have previously shown that Fibroblast growth factor 21 (Fgf21) is expressed in the thymus as well as in the liver. In line with this expression profile, Fgf21 was recently reported to protect against ageing-related thymic senescence by improving the function of thymic epithelial cells (TECs). However, the function of Fgf21 in the juvenile thymus remained to be elucidated. We investigated the physiological roles of Fgf21 in the juvenile thymus and found that young Fgf21 knockout mice, but not β-Klotho knockout mice nor adult Fgf21 knockout mice, showed a significant reduction in the percentage of single-positive CD4+ and CD8+ thymocytes without obvious alteration in TECs. Furthermore, treatment with recombinant FGF21 protein rescued the impairment in fetal thymus organ culture (FTOC) of Fgf21 knockout mice. Annexin V staining revealed FGF21 protein enhanced apoptosis of immature thymocytes undergoing selection process in FTOC, suggesting that FGF21 may facilitate the selection of developing T cells. Endocrine Fgf21 from the liver induced by metabolic stimulation did not affect juvenile thymocyte development. Our data suggest that Fgf21 acts as one of intrathymic cytokines in the neonatal and juvenile thymus, involving thymocyte development in a β-Klotho-independent manner.
Expression of canine distemper virus receptor nectin-4 in the central nervous system of dogs
Authors: Pratakpiriya Watanyoo , Ping Teh Angeline Ping , Radtanakatikanon Araya , Pirarat Nopadon , Thi Lan Nguyen , Takeda Makoto , Techangamsuwan Somporn , Yamaguchi Ryoji
Published: March 2017

Canine distemper virus (CDV) exhibits lymphotropic, epitheliotropic, and neurotropic nature, and causes a severe systemic infection in susceptible animals. Initially, signaling lymphocyte activation molecule (SLAM) expressed on immune cells has been identified as a crucial cellular receptor for CDV. Currently, nectin-4 expressed in epithelia has been shown to be another receptor for CDV. Our previous study demonstrated that neurons express nectin-4 and are infected with CDV. In this study, we investigated the distribution pattern of nectin-4 in various cell types in the canine central nervous system and showed its relation to CDV infection to further clarify the pathology of disease. Histopathological, immunohistochemical and immunofluorescent analyses were done using formalin-fixed paraffin-embedded tissues of CDV-infected dogs. Dual staining of nectin-4 and CDV antigen or nectin-4 and brain cell markers was performed. Nectin-4 was detected in ependymal cells, epithelia of choroid plexus, meningeal cells, neurons, granular cells, and Purkinje’s cells. CDV antigens were detected in these nectin-4-positive cells, further suggesting contribution of nectin-4 for the CDV neurovirulence. On the other hand, astrocytes did not express nectin-4, although they were frequently infected with CDV. Since astrocytes are negative for SLAM expression, they must express an unidentified CDV receptor, which also contributes to CDV neurovirulence.
A Novel Method of Evaluating Knee Joint Stability of Patients with Knee Osteoarthritis: Multiscale Entropy Analysis with A Knee-Aiming Task
Authors: Zhou Diange , Zhang Shijie , Zhang Hui , Jiang Long , Zhang Jue , Fang Jing
Published: March 2017

Deteriorating knee stability is a local risk factor that reflects the occurrence and aggregative of osteoarthritis (OA). Despite the many biomechanics-based methods for assessing the structural stability of knee joints in clinics, these methods have many limitations. The stability of the knee joint relies on not only biomechanical factors, but also proprioception and the central nervous system. In this study, we attempt to depict the stability of knee joint from a holistic viewpoint, and a novel index of knee joint stability (IKJS) was thus extracted. We compared the differences of IKJS in 57 healthy volunteers and 55 patients with OA before and after total knee replacement (TKR). Analysis of Variance results demonstrated that there existed significant differences in IKJS among the three participating groups (<0.0001). Also, the IKJS of the operated leg in patients with knee OA increased remarkably after TKR (p < 0.0001). Furthermore, the results of the experiment suggested that the IKJS has sufficient reproducibility (ICC = 0.80). In conclusion, the proposed IKJS that employs the knee-aiming task is feasible for quantitatively determining knee stability. It can provide a potentially valuable and convenient tool to evaluate the effect of postoperative rehabilitation for patients with knee OA.
Optomechanically induced transparency of x-rays via optical control
Authors: Liao Wen-Te , Pálffy Adriana
Published: March 2017

The search for new control methods over light-matter interactions is one of the engines that advances fundamental physics and applied science alike. A specific class of light-matter interaction interfaces are setups coupling photons of distinct frequencies via matter. Such devices, nontrivial in design, could be endowed with multifunctional tasking. Here we envisage for the first time an optomechanical system that bridges optical and robust, high-frequency x-ray photons, which are otherwise notoriously difficult to control. The x-ray-optical system comprises of an optomechanical cavity and a movable microlever interacting with an optical laser and with x-rays via resonant nuclear scattering. We show that optomechanically induced transparency of a broad range of photons (10 eV–100 keV) is achievable in this setup, allowing to tune nuclear x-ray absorption spectra via optomechanical control. This paves ways for metrology applications, e.g., the detection of the 229Thorium clock transition, and an unprecedentedly precise control of x-rays using optical photons.
Real-time observational evidence of changing Asian dust morphology with the mixing of heavy anthropogenic pollution
Authors: Pan Xiaole , Uno Itsushi , Wang Zhe , Nishizawa Tomoaki , Sugimoto Nobuo , Yamamoto Shigekazu , Kobayashi Hiroshi , Sun Yele , Fu Pingqing , Tang Xiao , Wang Zifa
Published: March 2017

Natural mineral dust and heavy anthropogenic pollution and its complex interactions cause significant environmental problems in East Asia. Due to restrictions of observing technique, real-time morphological change in Asian dust particles owing to coating process of anthropogenic pollutants is still statistically unclear. Here, we first used a newly developed, single-particle polarization detector and quantitatively investigate the evolution of the polarization property of backscattering light reflected from dust particle as they were mixing with anthropogenic pollutants in North China. The decrease in observed depolarization ratio is mainly attributed to the decrease of aspect ratio of the dust particles as a result of continuous coating processes. Hygroscopic growth of Calcium nitrate (Ca(NO3)2) on the surface of the dust particles played a vital role, particularly when they are stagnant in the polluted region with high RH conditions. Reliable statistics highlight the significant importance of internally mixed, ‘quasi-spherical’ Asian dust particles, which markedly act as cloud condensation nuclei and exert regional climate change.
Exposure to an acute hypoxic stimulus during early life affects the expression of glucose metabolism-related genes at first-feeding in trout
Authors: Liu Jingwei , Plagnes-Juan Elisabeth , Geurden Inge , Panserat Stéphane , Marandel Lucie
Published: March 2017

Rainbow trout (Oncorhynchus mykiss) is considered a “glucose-intolerant” species. With the aim of programming trout to improve their metabolic use of dietary carbohydrates, we hypothesised that a hypoxic stimulus applied during embryogenesis could later affect glucose metabolism at the first-feeding stage. An acute hypoxic stimulus (2.5 or 5.0 mg·L−1 O2) was applied for 24 h to non-hatched embryos or early hatched alevins followed by a challenge test with a high carbohydrate diet at first-feeding. The effectiveness of the early hypoxic stimulus was confirmed by the induction of oxygen-sensitive markers such as egln3. At first-feeding, trout previously subjected to the 2.5 mg·L−1 O2 hypoxia displayed a strong induction of glycolytic and glucose transport genes, whereas these glucose metabolism-related genes were affected much less in trout subjected to the less severe (5.0 mg·L−1 O2) hypoxia. Our results demonstrate that an acute hypoxic stimulus during early development can affect glucose metabolism in trout at first-feeding.
Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice
Authors: Yang Dan , Shao Junjie , Hu Ruifeng , Chen Haimei , Xie Ping , Liu Chang
Published: March 2017

Rivaroxaban is an oral direct factor Xa inhibitor approved for the treatment of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation. Despite its efficacy, rivaroxaban therapy results in adverse effects and complications, such as bleeding. Angiotensin II (AngII) is implicated in many cardiovascular conditions, such as hypertension and heart failure. In this study, we investigate whether AngII influences anticoagulant effects of rivaroxaban by using an experimental mouse model with type 2 diabetes mellitus and advanced glycation end product (AGE)-exposed human umbilical vein endothelial cells (HUVECs). We found that AngII promoted the anticoagulant effects of rivaroxaban in KKAy mice. The combination of rivaroxaban and AngII enhanced in vivo tissue factor pathway inhibitor (TFPI) activity and induced TFPI expression and activity in AGE-exposed HUVECs. Angiotensin type 2 receptor (AT2R) and Mas antagonists attenuated the AngII-enhanced anticoagulant action of rivaroxaban in vivo, and abolished the increased endothelial TFPI expression and activity. However, angiotensin type 1 receptor (AT1R) antagonist exerted no effects. Additionally, combination of rivaroxaban and AngII induced aortic AT2R and Mas expression. Our data suggest that the anticoagulant effects of rivaroxaban are promoted by AngII via AT2R and Mas signaling. These findings are significant for the clinical administration of rivaroxaban.
Low-frequency stimulation of the primary focus retards positive transfer of secondary focus
Authors: Kuang Yifang , Xu Cenglin , Zhang Yinxi , Wang Yi , Wu Xiaohua , Wang Ying , Liu Yao , Zhong Kai , Cheng Hui , Guo Yi , Wang Shuang , Ding Meiping , Chen Zhong
Published: March 2017

Positive transfer of secondary focus (PTS) refers to new epileptogenesis outside the primary focus and is minimally controlled by existing treatments. Low-frequency stimulation (LFS) has benefits on the onset of epilepsy and epileptogenesis. However, it’s unclear whether LFS can retard the PTS in epilepsy. Here we found that PTS at both contralateral amygdala and ipsilateral hippocampus were promoted after the primary focus was fully kindled in rat kindling model. The promotion of PTS at the mirror focus started when the primary kindling acquisition reached focal seizures. LFS retarded the promotion of PTS when it was applied at the primary focus during its kindling acquisition, while it only slightly retarded the promotion of PTS when applied after generalized seizures. Meanwhile, we found the expression of potassium chloride cotransporter 2 (KCC2) decreased during PTS, and LFS reversed this. Further, the decreased expression of KCC2 was verified in patients with PTS. These findings suggest that LFS may be a potential therapeutic approach for PTS in epilepsy.
Preservation of organic matter in marine sediments by inner-sphere interactions with reactive iron
Authors: Barber Andrew , Brandes Jay , Leri Alessandra , Lalonde Karine , Balind Kathryn , Wirick Sue , Wang Jian , Gélinas Yves
Published: March 2017

Interactions between organic matter and mineral matrices are critical to the preservation of soil and sediment organic matter. In addition to clay minerals, Fe(III) oxides particles have recently been shown to be responsible for the protection and burial of a large fraction of sedimentary organic carbon (OC). Through a combination of synchrotron X-ray techniques and high-resolution images of intact sediment particles, we assessed the mechanism of interaction between OC and iron, as well as the composition of organic matter co-localized with ferric iron. We present scanning transmission x-ray microscopy images at the Fe L3 and C K1 edges showing that the organic matter co-localized with Fe(III) consists primarily of C=C, C=O and C-OH functional groups. Coupling the co-localization results to iron K-edge X-ray absorption spectroscopy fitting results allowed to quantify the relative contribution of OC-complexed Fe to the total sediment iron and reactive iron pools, showing that 25–62% of total reactive iron is directly associated to OC through inner-sphere complexation in coastal sediments, as much as four times more than in low OC deep sea sediments. Direct inner-sphere complexation between OC and iron oxides (Fe-O-C) is responsible for transferring a large quantity of reduced OC to the sedimentary sink, which could otherwise be oxidized back to CO2.
Xiaoyaosan exerts anxiolytic-like effects by down-regulating the TNF-α/JAK2-STAT3 pathway in the rat hippocampus
Authors: Li Xiao-Juan , Ma Qing-Yu , Jiang You-Ming , Bai Xiao-Hui , Yan Zhi-Yi , Liu Qun , Pan Qiu-Xia , Liu Yue-Yun , Chen Jia-Xu
Published: March 2017

Although the anxiolytic-like effects of Xiaoyaosan, a Chinese herbal formula, have been described in many previous studies, its underlying mechanism remains undefined. The cytokine tumour necrosis factor-α (TNF-α) and its closely associated janus kinase 2 (JAK2)-signal transducer and activator of transcription (STAT3) signalling pathway regulate the neuro-inflammatory response in the brain, thus participating in the development of anxiety. Our purpose was to investigate whether the anxiolytic-like effects of Xiaoyaosan are related to the TNF-α/JAK2-STAT3 pathway in the hippocampus. We examined the effects of Xiaoyaosan on behaviours exhibited in the elevated plus maze test, open field test and novelty-suppressed feeding test as well as hippocampal neuron damage and changes in the TNF-α/JAK2-STAT3 pathway in a rat model of chronic immobilization stress (CIS)-induced anxiety. Xiaoyaosan exerts anxiolytic-like effects on CIS-induced anxiety, with a significant alleviation of anxiety-like behaviours, an attenuation of hippocampal neuron damage, and a reversal of the activation of the TNF-α/JAK2-STAT3 pathway in the hippocampus that are similar to the effects of the JAK2 antagonist AG490. However, Xiaoyaosan and AG490 failed to effectively regulate apoptosis-related factors, including Bax and Caspase-3. These results suggest that Xiaoyaosan attenuates stress-induced anxiety behaviours by down-regulating the TNF-α/JAK2-STAT3 pathway in the rat hippocampus.
Novel and traditional lipid-related biomarkers and their combinations in predicting coronary severity
Authors: Li Sha , Guo Yuan-Lin , Zhao Xi , Zhang Yan , Zhu Cheng-Gang , Wu Na-Qiong , Xu Rui-Xia , Qing Ping , Gao Ying , Li Xiao-Lin , Sun Jing , Liu Geng , Dong Qian , Li Jian-Jun
Published: March 2017

We investigated simultaneously traditional and novel lipid indices, alone or in combination, in predicting coronary severity assessed by Gensini score (GS) in 1605 non-lipid-lowering-drug-treated patients undergoing coronary angiography. Firstly, levels of triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), non high density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, lipoprotein (a) [Lp(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoC3, small dense LDL (sdLDL) and large HDL were increased, while HDL-C and apoA1 levels were decreased as GS status (all p for trend <0.05). However, gender stratification analyses showed similar associations between lipids and GS in men but not in women. Secondly, multiple logistic regression analyses indicated that the 12 indices were predictive for high GS (≥24) but not for low GS (1–23) compared with normal coronary (GS = 0) except for TG (neither) and apoB (both). Finally, we found that interactions between two indices with mutually exclusive composition were positively associated with GS status except for couples of TC + apoC3, apoB/PCSK9/apoC3 + sdLDL-C. Concordant elevations in the two showed the highest predictive values for high GS (all p for trend <0.05). Therefore, lipid biomarkers were associated with coronary severity and their adverse changes in combination emerged greater risks in men but not in women.
Locating the Human Cardiac Conduction System Using a 3D Model of Its Nutritious Arteries
Authors: Xu Yu , Peng Yukun , Qu Rongmei , Zheng Guorong , Feng Feiyan , Feng Yan , He Linying , He Shanli , Li Zeyu , Liu Chang , Xiao Zhaoming , Ouyang Jun , Dai Jingxing
Published: March 2017

It is difficult for anatomists to dissect the human cardiac conduction system (CCS) on specimens as well as for cardiovascular clinicians to locate the CCS during cardiac operations. Here, we demonstrate a new method for locating the CCS using a 3D model of its nutritious arteries. First, we perfused the coronary arteries with contrast material and then acquired a set of data of thin computer tomography (CT) scans. Then, we generated a 3D model of the coronary artery and distinguished the arteries that supply the CCS. We then located the CCS on the 3D model via its nutritious arteries and dissected the CCS. Finally, the structures that were dissected were removed for histological and immunofluorescent staining. The results of histological and immunofluorescence examination proved the structure to be the CCS. Thus, we successfully located the CCS using a 3D model of its nutritious arteries. We suggest that with this new method, cardiac surgeons can locate a patient’s CCS during cardiac surgeries such as transcatheter aortic valve implantation (TAVI) or radiofrequency catheter ablation (RFCA).
Crystal structure of a raw-starch-degrading bacterial α-amylase belonging to subfamily 37 of the glycoside hydrolase family GH13
Authors: Liu Yanhong , Yu Jigang , Li Fudong , Peng Hui , Zhang Xuecheng , Xiao Yazhong , He Chao
Published: March 2017

Subfamily 37 of the glycoside hydrolase family GH13 was recently established on the basis of the discovery of a novel α-amylase, designated AmyP, from a marine metagenomic library. AmyP exhibits raw-starch-degrading activity and consists of an N-terminal catalytic domain and a C-terminal starch-binding domain. To understand this newest subfamily, we determined the crystal structure of the catalytic domain of AmyP, named AmyPΔSBD, complexed with maltose, and the crystal structure of the E221Q mutant AmyPΔSBD complexed with maltotriose. Glu221 is one of the three conserved catalytic residues, and AmyP is inactivated by the E221Q mutation. Domain B of AmyPΔSBD forms a loop that protrudes from domain A, stabilizes the conformation of the active site and increases the thermostability of the enzyme. A new calcium ion is situated adjacent to the -3 subsite binding loop and may be responsible for the increased thermostability of the enzyme after the addition of calcium. Moreover, Tyr36 participates in both stacking and hydrogen bonding interactions with the sugar motif at subsite -3. This work provides the first insights into the structure of α-amylases belonging to subfamily 37 of GH13 and may contribute to the rational design of α-amylase mutants with enhanced performance in biotechnological applications.
An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes
Authors: Huang Xiao-Ting , Li Chen , Peng Xiang-Ping , Guo Jia , Yue Shao-Jie , Liu Wei , Zhao Fei-Yan , Han Jian-Zhong , Huang Yan-Hong , Yang-Li  , Cheng Qing-Mei , Zhou Zhi-Guang , Chen Chen , Feng Dan-Dan , Luo Zi-Qiang
Published: March 2017

In the nervous system, excessive activation of NMDA receptors causes neuronal injury. Although activation of NMDARs has been proposed to contribute to the progress of diabetes, little is known about the effect of excessive long-term activation of NMDARs on β-cells, especially under the challenge of hyperglycemia. Here we thoroughly investigated whether endogenous glutamate aggravated β-cell dysfunction under chronic exposure to high-glucoseviaactivation of NMDARs. The glutamate level was increased in plasma of diabetic mice or patients and in the supernatant of β-cell lines after treatment with high-glucose for 72 h. Decomposing the released glutamate improved GSIS of β-cells under chronic high-glucose exposure. Long-term treatment of β-cells with NMDA inhibited cell viability and decreased GSIS. These effects were eliminated byGluN1knockout. The NMDAR antagonist MK-801 orGluN1knockout prevented high-glucose-induced dysfunction in β-cells. MK-801 also decreased the expression of pro-inflammatory cytokines, and inhibited I-κB degradation, ROS generation and NLRP3 inflammasome expression in β-cells exposed to high-glucose. Furthermore, another NMDAR antagonist, Memantine, improved β-cells function in diabetic mice. Taken together, these findings indicate that an increase of glutamate may contribute to the development of diabetes through excessive activation of NMDARs in β-cells, accelerating β-cells dysfunction and apoptosis induced by hyperglycemia.
A novel toolbox to investigate tissue spatial organization applied to the study of the islets of Langerhans
Authors: Tran Thi Nhu Hoa , Arrojo E. Drigo Rafael , Berggren Per-Olof , Boudier Thomas
Published: March 2017

Thanks to the development of new 3D Imaging techniques, volumetric data of thick samples, especially tissues, are commonly available. Several algorithms were proposed to analyze cells or nuclei in tissues, however these tools are limited to two dimensions. Within any given tissue, cells are not likely to be organized randomly and as such have specific patterns of cell-cell interaction forming complex communication networks. In this paper, we propose a new set of tools as an approach to segment and analyze tissues in 3D with single cell resolution. This new tool box can identify and compute the geographical location of single cells and analyze the potential physical interactions between different cell types and in 3D. As a proof-of-principle, we applied our methodology to investigation of the cyto-architecture of the islets of Langerhans in mice and monkeys. The results obtained here are a significant improvement in current methodologies and provides new insight into the organization of alpha cells and their cellular interactions within the islet’s cellular framework.
Discrete call types referring to predation risk enhance the efficiency of the meerkat sentinel system
Authors: Rauber R. , Manser M. B.
Published: March 2017

Sentinel behaviour, a form of coordinated vigilance, occurs in a limited range of species, mostly in cooperative breeders. In some species sentinels confirm their presence vocally by giving a single sentinel call type, whereby the rate and subtle acoustic changes provide graded information on the variation of perceived predation risk. In contrast, meerkat (Suricata suricatta) sentinels produce six different sentinel call types. Here we show that manipulation of perception of danger has different effects on the likelihood of emitting these different call types, and that these call types affect foraging individuals differently. Increasing the perceived predation risk by playing back alarm calls decreased the production rate of the common short note calls and increased the production rate of the rare long calls. Playbacks of short note calls increased foraging behaviour and decreased vigilance in the rest of the group, whereas the opposite was observed when playing long calls. This suggests that the common call types act as all-clear signals, while the rare call types have a warning function. Therefore, meerkats increase the efficiency of their sentinel system by producing several discrete call types that represent changes in predation risk and lead to adjustments of the group’s vigilance behaviour.
Copper transporters are responsible for copper isotopic fractionation in eukaryotic cells
Authors: Cadiou Jean-Loup , Pichat Sylvain , Bondanese Victor P. , Soulard Alexandre , Fujii Toshiyuki , Albarède Francis , Oger Philippe
Published: March 2017

Copper isotopic composition is altered in cancerous compared to healthy tissues. However, the rationale for this difference is yet unknown. As a model of Cu isotopic fractionation, we monitored Cu uptake in Saccharomyces cerevisiae, whose Cu import is similar to human. Wild type cells are enriched in 63Cu relative to 65Cu. Likewise, 63Cu isotope enrichment in cells without high-affinity Cu transporters is of slightly lower magnitude. In cells with compromised Cu reductase activity, however, no isotope fractionation is observed and when Cu is provided solely in reduced form for this strain, copper is enriched in 63Cu like in the case of the wild type. Our results demonstrate that Cu isotope fractionation is generated by membrane importers and that its amplitude is modulated by Cu reduction. Based on ab initio calculations, we propose that the fractionation may be due to Cu binding with sulfur-rich amino acids: methionine and cysteine. In hepatocellular carcinoma (HCC), lower expression of the STEAP3 copper reductase and heavy Cu isotope enrichment have been reported for the tumor mass, relative to the surrounding tissue. Our study suggests that copper isotope fractionation observed in HCC could be due to lower reductase activity in the tumor.
Sex differences in DNA methylation of the cord blood are related to sex-bias psychiatric diseases
Authors: Maschietto Mariana , Bastos Laura Caroline , Tahira Ana Carolina , Bastos Elen Pereira , Euclydes Veronica Luiza Vale , Brentani Alexandra , Fink Günther , de Baumont Angelica , Felipe-Silva Aloísio , Francisco Rossana Pulcineli Vieira , Gouveia Gisele , Grisi Sandra Josefina Ferraz Ellero , Escobar Ana Maria Ulhoa , Moreira-Filho Carlos Alberto , Polanczyk Guilherme Vanoni , Miguel Euripedes Constantino , Brentani Helena
Published: March 2017

Sex differences in the prevalence of psychiatric disorders are well documented, with exposure to stress during gestation differentially impacting females and males. We explored sex-specific DNA methylation in the cord blood of 39 females and 32 males born at term and with appropriate weight at birth regarding their potential connection to psychiatric outcomes. Mothers were interviewed to gather information about environmental factors (gestational exposure) that could interfere with the methylation profiles in the newborns. Bisulphite converted DNA was hybridized to Illumina HumanMethylation450 BeadChips. Excluding XYS probes, there were 2,332 differentially methylated CpG sites (DMSs) between sexes, which were enriched within brain modules of co-methylated CpGs during brain development and also differentially methylated in the brains of boys and girls. Genes associated with the DMSs were enriched for neurodevelopmental disorders, particularly for CpG sites found differentially methylated in brain tissue between patients with schizophrenia and controls. Moreover, the DMS had an overlap of 890 (38%) CpG sites with a cohort submitted to toxic exposition during gestation. This study supports the evidences that sex differences in DNA methylation of autosomes act as a primary driver of sex differences that are found in psychiatric outcomes.
Identification of novel chemotherapeutic strategies for metastatic uveal melanoma
Authors: Fagone Paolo , Caltabiano Rosario , Russo Andrea , Lupo Gabriella , Anfuso Carmelina Daniela , Basile Maria Sofia , Longo Antonio , Nicoletti Ferdinando , De Pasquale Rocco , Libra Massimo , Reibaldi Michele
Published: March 2017

Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS2 web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma.
Eosinophils are key regulators of perivascular adipose tissue and vascular functionality
Authors: Withers Sarah B. , Forman Ruth , Meza-Perez Selene , Sorobetea Daniel , Sitnik Kasia , Hopwood Thomas , Lawrence Catherine B. , Agace William W. , Else Kathryn J. , Heagerty Anthony M. , Svensson-Frej Marcus , Cruickshank Sheena M.
Published: March 2017

Obesity impairs the relaxant capacity of adipose tissue surrounding the vasculature (PVAT) and has been implicated in resultant obesity-related hypertension and impaired glucose intolerance. Resident immune cells are thought to regulate adipocyte activity. We investigated the role of eosinophils in mediating normal PVAT function. Healthy PVAT elicits an anti-contractile effect, which was lost in mice deficient in eosinophils, mimicking the obese phenotype, and was restored upon eosinophil reconstitution. Ex vivo studies demonstrated that the loss of PVAT function was due to reduced bioavailability of adiponectin and adipocyte-derived nitric oxide, which was restored after eosinophil reconstitution. Mechanistic studies demonstrated that adiponectin and nitric oxide are released after activation of adipocyte-expressed β3 adrenoceptors by catecholamines, and identified eosinophils as a novel source of these mediators. We conclude that adipose tissue eosinophils play a key role in the regulation of normal PVAT anti-contractile function.
Effects of matrix stiffness on epithelial to mesenchymal transition-like processes of endometrial epithelial cells: Implications for the pathogenesis of endometriosis
Authors: Matsuzaki Sachiko , Darcha Claude , Pouly Jean-Luc , Canis Michel
Published: March 2017

Endometriosis is defined as the presence of endometrial glands and stroma within extrauterine sites. Our previous study revealed an epithelial to mesenchymal transition (EMT)-like process in red peritoneal endometriosis, whereas membrane localization of E-cadherin was well maintained in epithelial cells of deep infiltrating endometriosis (DIE). Here we show that endometrial epithelial cells (EEE) grown on polyacrylamide gel substrates (PGS) of 2 kilopascal (kPa), a soft matrix, initiate a partial EMT-like process with transforming growth factor-β1 (TGF-β1) stimulation. Increasing matrix stiffness with TGF-β1 stimulation reduced the number of cell-cell contacts. Cells that retained cell-cell contacts showed decreased expression of E-cadherin and zonula occludens 1 (ZO-1) to cell-cell junctions. Few deep endometriotic epithelial cells (DEE) grown on 30-kPa PGS, which may mimic in vivo tissue compliance of DIE, retained localization of E-cadherin to cell-cell junctions with TGF-β1 treatment. Immunohistochemical analysis showed no phosphorylated Smad 2/3 nuclear localization in E-cadherin+ epithelial cells of DIE. We hypothesize that EEE may undergo an EMT-like process after attachment of endometrium to peritoneum in a TGF-β1–rich microenvironment. However, TGF-β1 signaling may be absent in DIE, resulting in a more epithelial cell-like phenotype in a rigid microenvironment.
Associations between genetic variants in mRNA splicing-related genes and risk of lung cancer: a pathway-based analysis from published GWASs
Authors: Pan Yongchu , Liu Hongliang , Wang Yanru , Kang Xiaozheng , Liu Zhensheng , Owzar Kouros , Han Younghun , Su Li , Wei Yongyue , Hung Rayjean J. , Brhane Yonathan , McLaughlin John , Brennan Paul , Bickeböller Heike , Rosenberger Albert , Houlston Richard S. , Caporaso Neil , Teresa Landi Maria , Heinrich Joachim , Risch Angela , Wu Xifeng , Ye Yuanqing , Christiani David C. , Amos Christopher I. , Wei Qingyi
Published: March 2017

mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) ≤0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer.
TNF-α stimulates endothelial palmitic acid transcytosis and promotes insulin resistance
Authors: Li Wenjing , Yang Xiaoyan , Zheng Tao , Xing Shasha , Wu Yaogong , Bian Fang , Wu Guangjie , Li Ye , Li Juyi , Bai Xiangli , Wu Dan , Jia Xiong , Wang Ling , Zhu Lin , Jin Si
Published: March 2017

Persistent elevation of plasma TNF-α is a marker of low grade systemic inflammation. Palmitic acid (PA) is the most abundant type of saturated fatty acid in human body. PA is bound with albumin in plasma and could not pass through endothelial barrier freely. Albumin-bound PA has to be transported across monolayer endothelial cells through intracellular transcytosis, but not intercellular diffusion. In the present study, we discovered that TNF-α might stimulate PA transcytosis across cardiac microvascular endothelial cells, which further impaired the insulin-stimulated glucose uptake by cardiomyocytes and promoted insulin resistance. In this process, TNF-α-stimulated endothelial autophagy and NF-κB signaling crosstalk with each other and orchestrate the whole event, ultimately result in increased expression of fatty acid transporter protein 4 (FATP4) in endothelial cells and mediate the increased PA transcytosis across microvascular endothelial cells. Hopefully the present study discovered a novel missing link between low grade systemic inflammation and insulin resistance.
Inhibition of cathepsin K promotes osseointegration of titanium implants in ovariectomised rats
Authors: Yi Chun , Hao Ke-Yi , Ma Ting , Lin Ye , Ge Xi-Yuan , Zhang Yu
Published: March 2017

The bone mineral deficiency in osteoporosis poses a threat to the long-term outcomes of endosseous implants. The inhibitors of cathepsin K (CatK) significantly affect bone turnover, bone mineral density (BMD) and bone strength in the patients with osteoporosis. Therefore, we hypothesised that the application of a CatK inhibitor (CatKI) could increase the osseointegration of endosseous implants under osteoporotic conditions. Odanacatib (ODN), a highly selective CatKI, was chosen as the experimental drug. Sixteen rats were randomised into 4 groups: sham, ovariectomy (OVX) with vehicle, OVX with low-dose ODN (5 mg/kg) and OVX with high-dose ODN (30 mg/kg). Titanium implants were placed into the distal metaphysis of bilateral femurs of each OVX rat. After 8 weeks of gavaging, CatKI treatment increased the removal torque, BMD and bone-to-implant contact (BIC). Moreover, high-dose CatKI exerted a better influence than low-dose CatKI. Furthermore, CatKI treatment not only robustly suppressed CatK gene (CTSK) expression, but also moderately reduced expression of the osteoblast-related genes Runx2, Collagen-1, BSP, Osterix, OPN, SPP1 and ALP. Thus, CatKI could affect the osteoblast-related genes, although the balance of bone turnover was achieved mainly by CatK inhibition. In conclusion, CatKI prevented bone loss and aided endosseous implantation in osteoporotic conditions.
Development of bioluminescent chick chorioallantoic membrane (CAM) models for primary pancreatic cancer cells: a platform for drug testing
Authors: Rovithi Maria , Avan Amir , Funel Niccola , Leon Leticia G. , Gomez Valentina E. , Wurdinger Thomas , Griffioen Arjan W. , Verheul Henk M. W. , Giovannetti Elisa
Published: March 2017

The aim of the present study was to develop chick-embryo chorioallantoic membrane (CAM) bioluminescent tumor models employing low passage cell cultures obtained from primary pancreatic ductal adenocarcinoma (PDAC) cells. Primary PDAC cells transduced with lentivirus expressing Firefly-luciferase (Fluc) were established and inoculated onto the CAM membrane, with >80% engraftment. Fluc signal reliably correlated with tumor growth. Tumor features were evaluated by immunohistochemistry and genetic analyses, including analysis of mutations and mRNA expression of PDAC pivotal genes, as well as microRNA (miRNA) profiling. These studies showed that CAM tumors had histopathological and genetic characteristic comparable to the original tumors. We subsequently tested the modulation of key miRNAs and the activity of gemcitabine and crizotinib on CAM tumors, showing that combination treatment resulted in 63% inhibition of tumor growth as compared to control (p < 0.01). These results were associated with reduced expression of miR-21 and increased expression of miR-155. Our study provides the first evidence that transduced primary PDAC cells can form tumors on the CAM, retaining several histopathological and (epi)genetic characteristics of original tumors. Moreover, our results support the use of these models for drug testing, providing insights on molecular mechanisms underlying antitumor activity of new drugs/combinations.
Tuning Coupling Behavior of Stacked Heterostructures Based on MoS2, WS2, and WSe2
Authors: Wang Fang , Wang Junyong , Guo Shuang , Zhang Jinzhong , Hu Zhigao , Chu Junhao
Published: March 2017

The interlayer interaction of vertically stacked heterojunctions is very sensitive to the interlayer spacing, which will affect the coupling between the monolayers and allow band structure modulation. Here, with the aid of density functional theory (DFT) calculations, an interesting phenomenon is found that MoS2-WS2, MoS2-WSe2, and WS2-WSe2 heterostructures turn into direct-gap semiconductors from indirect-gap semiconductors with increasing the interlayer space. Moreover, the electronic structure changing process with interlayer spacing of MoS2-WS2, MoS2-WSe2, and WS2-WSe2 is different from each other. With the help of variable-temperature spectral experiment, different electronic transition properties of MoS2-WS2, MoS2-WSe2, and WS2-WSe2 have been demonstrated. The transition transformation from indirect to direct can be only observed in the MoS2-WS2 heterostructure, as the valence band maximum (VBM) at the Γ point in the MoS2-WSe2 and WS2-WSe2 heterostructure is less sensitive to the interlayer spacing than those from the MoS2-WS2 heterostructure. The present work highlights the significance of the temperature tuning in interlayer coupling and advance the research of MoS2-WS2, MoS2-WSe2, and WS2-WSe2 based device applications.
Sophisticated Clean Air Strategies Required to Mitigate Against Particulate Organic Pollution
Authors: Grigas T. , Ovadnevaite J. , Ceburnis D. , Moran E. , McGovern F. M. , Jennings S. G. , O’Dowd C.
Published: March 2017

Since the 1980’s, measures mitigating the impact of transboundary air pollution have been implemented successfully as evidenced in the 1980–2014 record of atmospheric sulphur pollution over the NE-Atlantic, a key region for monitoring background northern-hemisphere pollution levels. The record reveals a 72–79% reduction in annual-average airborne sulphur pollution (SO4 and SO2, respectively) over the 35-year period. The NE-Atlantic, as observed from the Mace Head research station on the Irish coast, can be considered clean for 64% of the time during which sulphate dominates PM1 levels, contributing 42% of the mass, and for the remainder of the time, under polluted conditions, a carbonaceous (organic matter and Black Carbon) aerosol prevails, contributing 60% to 90% of the PM1 mass and exhibiting a trend whereby its contribution increases with increasing pollution levels. The carbonaceous aerosol is known to be diverse in source and nature and requires sophisticated air pollution policies underpinned by sophisticated characterisation and source apportionment capabilities to inform selective emissions-reduction strategies. Inauspiciously, however, this carbonaceous concoction is not measured in regulatory Air Quality networks.
Signature of an aggregation-prone conformation of tau
Authors: Eschmann Neil A. , Georgieva Elka R. , Ganguly Pritam , Borbat Peter P. , Rappaport Maxime D. , Akdogan Yasar , Freed Jack H. , Shea Joan-Emma , Han Songi
Published: March 2017

The self-assembly of the microtubule associated tau protein into fibrillar cell inclusions is linked to a number of devastating neurodegenerative disorders collectively known as tauopathies. The mechanism by which tau self-assembles into pathological entities is a matter of much debate, largely due to the lack of direct experimental insights into the earliest stages of aggregation. We present pulsed double electron-electron resonance measurements of two key fibril-forming regions of tau, PHF6 and PHF6*, in transient as aggregation happens. By monitoring the end-to-end distance distribution of these segments as a function of aggregation time, we show that the PHF6(*) regions dramatically extend to distances commensurate with extended β-strand structures within the earliest stages of aggregation, well before fibril formation. Combined with simulations, our experiments show that the extended β-strand conformational state of PHF6(*) is readily populated under aggregating conditions, constituting a defining signature of aggregation-prone tau, and as such, a possible target for therapeutic interventions.
Lentiviral vectors can be used for full-length dystrophin gene therapy
Authors: Counsell John R. , Asgarian Zeinab , Meng Jinhong , Ferrer Veronica , Vink Conrad A. , Howe Steven J. , Waddington Simon N. , Thrasher Adrian J. , Muntoni Francesco , Morgan Jennifer E. , Danos Olivier
Published: March 2017

Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors. Lentiviral vectors can package larger transgenes than adeno-associated viruses, yet lentiviral vectors remain largely unexplored for full-length dystrophin delivery. In our work, we have demonstrated that lentiviral vectors can package and deliver inserts of a similar size to dystrophin. We report a novel approach for delivering large transgenes in lentiviruses, in which we demonstrate proof-of-concept for a ‘template-switching’ lentiviral vector that harnesses recombination events during reverse-transcription. During this work, we discovered that a standard, unmodified lentiviral vector was efficient in delivering full-length dystrophin to target cells, within a total genomic load of more than 15,000 base pairs. We have demonstrated gene therapy with this vector by restoring dystrophin expression in DMD myoblasts, where dystrophin was expressed at the sarcolemma of myotubes after myogenic differentiation. Ultimately, our work demonstrates proof-of-concept that lentiviruses can be used for permanent full-length dystrophin gene therapy, which presents a significant advancement in developing an effective treatment for DMD.
Fabrication of calix[4]arene-attached mesoporous ammonium molybdophosphate–silica hybrid and its application as an adsorbent for cesium ions
Authors: Ahn Junho , Lim Na Young , Park Jeong Su , Choi Yeonweon , Jung Jong Hwa
Published: March 2017

The cesium cation is a common contaminant in medical and industrial products as well as in nuclear wastes, and it can present a serious risk to human health.
Selective and efficient synthesis of trans-arylvinylboronates and trans-hetarylvinylboronates using palladium catalyzed cross-coupling
Authors: Liu Zhihao , Wei Wei , Xiong Lu , Feng Qiang , Shi Yaojie , Wang Ningyu , Yu Luoting
Published: March 2017

A versatile method of palladium catalyzed cross-coupling between pinacol vinylboronate and (het)arylbromides to obtain trans-(het)arylvinylboronates in excellent yields and selectivity.
A novel Cu+-doped Li[Fe0.9Cu0.1Li0.1]PO4/C cathode material with enhanced electrochemical properties
Authors: Zhu Jian-Min , Xia Tian , Yan Kang-Kang , Chang Wei-Jui , Chen Xue-Gang , Ye Ying , Zhang Ping-Ping
Published: March 2017

LiFePO4 is an effective battery material which has gained global focus.
LncRNA-MALAT1 as a novel biomarker of cadmium toxicity regulates cell proliferation and apoptosis
Authors: Huang Qinhai , Lu Qian , Chen Baoxin , Shen Huanyu , Liu Qun , Zhou Zhiheng , Lei Yixiong
Published: March 2017

Cadmium (Cd) and its compounds are well-known human carcinogens, but the mechanisms underlying the carcinogenesis are not well understood.
Peptide-functionalized gold nanoparticles: versatile biomaterials for diagnostic and therapeutic applications
Authors: Zong Jingyi , Cobb Steven L. , Cameron Neil R.
Published: March 2017

This review provides an overview of the current methods used for preparing peptide-functionalized GNPs, and discusses the key properties of this class of biomaterial. In particular, their potential application in areas of sensing, targeted drug delivery, anti-cancer therapeutics and oligonucleotide delivery are discussed.
SMI-Ribosome inactivating protein conjugates selectively inhibit tumor cell growth
Authors: Roy Saumya , Axup Jun Y. , Forsyth Jane S. , Goswami Rajib K. , Hutchins Benjamin M. , Bajuri Krishna M. , Kazane Stephanie A. , Smider Vaughn V. , Felding Brunhilde H. , Sinha Subhash C.
Published: March 2017

Cell-targeting conjugates of Saporin 6, prepared using a small molecule inhibitor of integrins αvβ3 and αvβ5 and the Saporin A157C mutant, selectively and potently inhibited proliferation of tumor cells expressing the target integrins.
The smallest cucurbituril analogue with high affinity for Ag+
Authors: Wu Yufan , Xu Lixi , Shen Yenan , Wang Yang , Zou Lei , Wang Qiaochun , Jiang Xiaoqing , Liu Jiansen , Tian He
Published: March 2017

The smallest cucurbituril analogue with four repeated bi-uredio units was firstly synthesized and it binds selectively towards Ag+.
A catalytic scalable Pauson–Khand reaction in a plug flow reactor
Authors: García-Lacuna Jorge , Domínguez Gema , Blanco-Urgoiti Jaime , Pérez-Castells Javier
Published: March 2017

Scalable, safe, highly efficient and broad-scope PKR in a plug flow reactor.
The aromaticity of dicupra[10]annulenes
Authors: Grande-Aztatzi Rafael , Mercero Jose M. , Matito Eduard , Frenking Gernot , Ugalde Jesus M.
Published: March 2017

The aromaticity of dicupra[10]annulenes closely resembles that of naphthalene.