bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparing the sexual health workforce to deliver integrated services: is education the answer? A qualitative study exploring the impact of sexual health education on developing integrated policy and practice
Authors: Brook Judy , Salmon Debra , Knight Rachael-Anne
Published: March 2017

Aim

This study aimed to explore the ability of sexual health nurses working in the South West of England, to implement new learning within existing sexual health service delivery models. Drawing on Lipsky’s account of street-level bureaucracy to conceptualise policy implementation, the impact of workforce learning on the development of integrated services across this region of the United Kingdom was assessed.

Background

In order to achieve the United Nations’ goal of universal access to sexual health, it is essential for reproductive and sexual health, including HIV provision, to integrate into a single service. This integration requires a commitment to collaboration by service commissioners and an alignment of principles and values across sexual health and contraceptive services. UK health policy has embraced this holistic agenda but moves towards integrating historically separate clinical services, has presented significant workforce development challenges and influenced policy success.

Methods

Employing a qualitative approach, the study included data from semi-structured telephone interviews and focus groups, and longitudinal data from pre- and post-intervention surveys, collected between September 2013 and September 2015. Data were collected from 88 nurses undertaking a workforce development programme and six of their service managers. Data were analysed using thematic analysis to identify consistent themes.

Findings

Nurses confirmed the role of new learning in enabling them to negotiate the political landscape but expressed frustration at their lack of agency in the integration agenda, exposing a clear dichotomy between the intentions of policy and the reality of practice. Nevertheless, using high levels of professional judgement and discretion practitioners managed the incongruence between policy and practice in order to deliver integrated services in the interests of patients. Workforce education, while essential for the transition to the delivery of integrated services, was insufficient to fulfil the sexual health agenda without a strengthening of public health.
Familial and Special Twin Influences on Cigarette Use Initiation
Authors: Bares Cristina B. , Maes Hermine H. , Kendler Kenneth S.
Published: March 2017

Background: Shared experiences within families play an important role in the initiation of cigarette use among adolescents. Behavioral genetic studies using various samples have implicated that the shared environment that twins experience is an important source of influence on whether adolescents initiate cigarette use. Whether the special twin environment, in addition to the shared environment, contributes significantly to making twin siblings more similar in cigarette initiation, and whether the influence of the special twin environment persists into adulthood, is less clear. Methods: Data for this study came from the National Longitudinal Survey of Adolescent Health. Twin, full-, and half-sibling pairs between the ages of 12 and 33 were separated into three age groups, with about 3,000 individuals in each age group. The proportion of variance in cigarette use initiation explained by genetic, shared, special twin, and unique environmental factors were examined. Results: The results of separate age-moderated univariate variance decomposition models indicate that the special twin environment does not significantly contribute to the variance in cigarette use initiation in adolescence or young adulthood. Conclusion: Factors shared by individuals in a family, but that are not specific to being a twin, are important in determining whether adolescents will initiate the use of cigarettes.
Republican Resolution Urges Congress to Counter Climate Threat
Authors: Showstack Randy
Published: March 2017

The bill calls for using American ingenuity and innovation to find solutions to changes in global and regional climates but makes no mention of fossil fuel emissions.
Identification of dimethylamine monooxygenase in marine bacteria reveals a metabolic bottleneck in the methylated amine degradation pathway
Authors: Lidbury Ian , Mausz Michaela A , Scanlan David J , Chen Yin
Published: March 2017

Methylated amines (MAs) are ubiquitous in the marine environment and their subsequent flux into the atmosphere can result in the formation of aerosols and ultimately cloud condensation nuclei. Therefore, these compounds have a potentially important role in climate regulation. Using Ruegeria pomeroyi as a model, we identified the genes encoding dimethylamine (DMA) monooxygenase (dmmABC) and demonstrate that this enzyme degrades DMA to monomethylamine (MMA). Although only dmmABC are required for enzyme activity in recombinant Escherichia coli, we found that an additional gene, dmmD, was required for the growth of R. pomeroyi on MAs. The dmmDABC genes are absent from the genomes of multiple marine bacteria, including all representatives of the cosmopolitan SAR11 clade. Consequently, the abundance of dmmDABC in marine metagenomes was substantially lower than the genes required for other metabolic steps of the MA degradation pathway. Thus, there is a genetic and potential metabolic bottleneck in the marine MA degradation pathway. Our data provide an explanation for the observation that DMA-derived secondary organic aerosols (SOAs) are among the most abundant SOAs detected in fine marine particles over the North and Tropical Atlantic Ocean.
Hidden amorphous phase and reentrant supercooled liquid in Pd-Ni-P metallic glasses
Authors: Lan S. , Ren Y. , Wei X. Y. , Wang B. , Gilbert E. P. , Shibayama T. , Watanabe S. , Ohnuma M. , Wang X. -L.
Published: March 2017

An anomaly in differential scanning calorimetry has been reported in a number of metallic glass materials in which a broad exothermal peak was observed between the glass and crystallization temperatures. The mystery surrounding this calorimetric anomaly is epitomized by four decades long studies of Pd-Ni-P metallic glasses, arguably the best glass-forming alloys. Here we show, using a suite of in situ experimental techniques, that Pd-Ni-P alloys have a hidden amorphous phase in the supercooled liquid region. The anomalous exothermal peak is the consequence of a polyamorphous phase transition between two supercooled liquids, involving a change in the packing of atomic clusters over medium-range length scales as large as 18 Å. With further temperature increase, the alloy reenters the supercooled liquid phase, which forms the room-temperature glass phase on quenching. The outcome of this study raises a possibility to manipulate the structure and hence the stability of metallic glasses through heat treatment.
Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche
Authors: Yang Ting-Lin B. , Chen Qijun , Deng Jennifer T. , Jagannathan Geetha , Tobias John W. , Schultz David C. , Wang Shan , Lengner Christopher J. , Rustgi Anil K. , Lynch John P. , Johnson F. Brad
Published: March 2017

Critical telomere shortening (for example, secondary to partial telomerase deficiency in the rare disease dyskeratosis congenita) causes tissue pathology, but underlying mechanisms are not fully understood. Mice lacking telomerase (for example, mTR−/− telomerase RNA template mutants) provide a model for investigating pathogenesis. In such mice, after several generations of telomerase deficiency telomeres shorten to the point of uncapping, causing defects most pronounced in high-turnover tissues including intestinal epithelium. Here we show that late-generation mTR−/− mutants experience marked downregulation of Wnt pathway genes in intestinal crypt epithelia, including crypt base columnar stem cells and Paneth cells, and in underlying stroma. The importance of these changes was revealed by rescue of crypt apoptosis and Wnt pathway gene expression upon treatment with Wnt pathway agonists. Rescue was associated with reduced telomere-dysfunction-induced foci and anaphase bridges, indicating improved telomere capping. Thus a mutually reinforcing feedback loop exists between telomere capping and Wnt signalling, and telomere capping can be impacted by extracellular cues in a fashion independent of telomerase.
DNA methylation evidence against the accelerated aging hypothesis of schizophrenia
Authors: McKinney Brandon C. , Lin Huang , Ding Ying , Lewis David A. , Sweet Robert A.
Published: March 2017

The accelerated aging hypothesis of schizophrenia posits that physiological changes throughout the body that are associated with normal aging occur at an earlier age in individuals with schizophrenia. Testing this hypothesis has been limited by problems measuring biological age. Recently, a method using DNA methylation levels at 353 genomic sites to produce “DNA methylation age”, an estimate of tissue biological age, was described and validated. We used this method to test the hypothesis in the postmortem superior temporal gyrus of 22 non-psychiatric control and 22 schizophrenia subjects. DNA methylation age correlated with chronological age in both non-psychiatric control (r = 0.95, p < 0.0001) and schizophrenia subjects (r = 0.96, p < 0.0001). Age acceleration did not differ between non-psychiatric control and schizophrenia subjects (t = 1.27, p = 0.21). Our findings suggest there is no acceleration of brain aging in schizophrenia. Larger studies using samples from multiple brain regions and homogenous cell populations will be necessary to confirm these findings.
Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma
Authors: Zeng Wenjun , Zhang Chunyun , Cheng Hongwei , Wu Yun-Long , Liu Jie , Chen Zekun , Huang Jian-gang , Ericksen Russell Erick , Chen Liqun , Zhang Haiping , Wong Alice Sze Tsai , Zhang Xiao-kun , Han Weiping , Zeng Jin-Zhang
Published: March 2017

We recently demonstrated that retinoic acid receptor-γ (RARγ) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARγ is mainly attributed to its physiological interaction with p85α regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RARγ as a negative regulator of p53 signaling and thus extend the oncogenic potential of RARγ to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RARγ-dependent AKT-p53 network. It specifically binds to RARγ and inhibitsall-transretinoic acid (atRA) stimulation of RARγ transactivation. However, the anticancer action of acacetin is independent on its modulation of RARγ-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RARγ on AKT and p53. When bound to RARγ, acacetin prevents RARγ from its activation of AKT followed by recovery of the normal p53 signaling. Given the implication of AKT-p53 dysregulation in most HCC, targeting the non-genomic signaling of RARγ that switches AKT-p53 from a pro-survival to a pro-apoptotic program in cancer cells should be a promising strategy for developing novel anti-HCC drugs.
Multimode fiber tip Fabry-Perot cavity for highly sensitive pressure measurement
Authors: Chen W. P. , Wang D. N. , Xu Ben , Zhao C. L. , Chen H. F.
Published: March 2017

We demonstrate an optical Fabry-Perot interferometer fiber tip sensor based on an etched end of multimode fiber filled with ultraviolet adhesive. The fiber device is miniature (with diameter of less than 60 μm), robust and low cost, in a convenient reflection mode of operation, and has a very high gas pressure sensitivity of −40.94 nm/MPa, a large temperature sensitivity of 213 pm/°C within the range from 55 to 85 °C, and a relatively low temperature cross-sensitivity of 5.2 kPa/°C. This device has a high potential in monitoring environment of high pressure.
Model explanation of the seasonal variation of δ18O in cow (Bos taurus) hair under temperate conditions
Authors: Chen Guo , Schnyder Hans , Auerswald Karl
Published: March 2017

Oxygen isotopes (δ18O) in animal and human tissues are expected to be good recorders of geographical origin and migration histories. However, seasonal variation of δ18O may diminish the origin information in the tissues. Here the seasonality of δ18O in tail hair was investigated in a domestic suckler cow (Bos taurus) that underwent different ambient conditions, physiological states, keeping and feeding during five years. A detailed mechanistic model was built to explain this variation. The measured δ18O in hair significantly related (p < 0.05) to the δ18O in meteoric water in a regression analysis. Modelling suggested that this relation was only partly derived from the direct influence of feed moisture. Ambient conditions (temperature, moisture) also affected the animal itself (drinking water demand, transcutaneous vapor etc.). The clear temporal variation thus resulted from complex interactions with multiple influences. The twofold influence of ambient conditions via the feed and via the animal itself is advantageous for tracing the geographic origin because δ18O is then less influenced by variations in moisture uptake; however, it is unfavorable for indicating the production system, e.g. to distinguish between milk produced from fresh grass or from silage. The model is versatile but needs testing under a wider range of conditions.
Apigenin-induced lysosomal degradation of β-catenin in Wnt/β-catenin signaling
Authors: Lin Chung-Ming , Chen Hsin-Han , Lin Chun-An , Wu Hui-Chung , Sheu Jim Jinn-Chyuan , Chen Hui-Jye
Published: March 2017

The bioflavonoid apigenin has been shown to possess cancer-preventive and anti-cancer activities. In a drug screening, we found that apigenin can inhibit Wnt/β-catenin signaling, a pathway that participates in pivotal biological functions, which dis-regulation results in various human diseases including cancers. However, the underlying mechanism of apigenin in this pathway and its link to anti-cancer activities remain largely unknown. Here we showed that apigenin reduced the amount of total, cytoplasmic, and nuclear β-catenin, leading to the suppression in the β-catenin/TCF-mediated transcriptional activity, the expression of Wnt target genes, and cell proliferation of Wnt-stimulated P19 cells and Wnt-driven colorectal cancer cells. Western blotting and immunofluorescent staining analyses further revealed that apigenin could induce autophagy-mediated down-regulation of β-catenin in treated cells. Treatment with autophagy inhibitors wortmannin and chloroquine compromised this effect, substantiating the involvement of autophagy-lysosomal system on the degradation of β-catenin during Wnt signaling through inhibition of the AKT/mTOR signaling pathway. Our data not only pointed out a route for the inhibition of canonical Wnt signaling through the induction of autophagy-lysosomal degradation of key player β-catenin, but also suggested that apigenin or other treatments which can initiate this degradation event are potentially used for the therapy of Wnt-related diseases including cancers.
Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders
Authors: Bezzerides Vassilios J. , Zhang Aifeng , Xiao Ling , Simonson Bridget , Khedkar Santosh A. , Baba Shiro , Ottaviano Filomena , Lynch Stacey , Hessler Katherine , Rigby Alan C. , Milan David , Das Saumya , Rosenzweig Anthony
Published: March 2017

Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia. Here we show that SGK1 directly regulates NaV1.5 channel function, and genetic inhibition of SGK1 in a zebrafish model of inherited long QT syndrome rescues the long QT phenotype. Using computer-aided drug discovery coupled with in vitro kinase assays, we identified a novel class of SGK1 inhibitors. Our lead SGK1 inhibitor (5377051) selectively inhibits SGK1 in cultured cardiomyocytes, and inhibits phosphorylation of an SGK1-specific target as well as proliferation in the prostate cancer cell line, LNCaP. Finally, 5377051 can reverse SGK1’s effects on NaV1.5 and shorten the action potential duration in induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a patient with a gain-of-function mutation in Nav 1.5 (Long QT3 syndrome). Our data suggests that SGK1 inhibitors warrant further investigation in the treatment of cardiac arrhythmias.
Different antiviral effects of IFNα subtypes in a mouse model of HBV infection
Authors: Song Jingjiao , Li Sheng , Zhou Yun , Liu Jia , Francois Sandra , Lu Mengji , Yang Dongliang , Dittmer Ulf , Sutter Kathrin
Published: March 2017

Interferon alpha (IFNα) is commonly used for the treatment of chronic hepatitis B (CHB) patients. There are 13 different IFNα subtypes in humans, but only the subtype IFNα2 is used for clinical treatment. The antiviral activities of all other IFNα subtypes against HBV have not been studied. To obtain basic knowledge about the direct antiviral as well as the immunomodulatory effects of IFNα subtypes, we used the HBV hydrodynamic injection (HI) mouse model. Application of most IFNα subtype proteins inhibited HBV replication in vivo, with IFNα4 and IFNα5 being the most effective subtypes. Decreased viral loads after therapeutic application of IFNα4 and IFNα5 correlated with expanded effector cell populations of NK cells and T cells in both liver and spleen. Hydrodynamic injection of plasmids encoding for the effective IFNα subtypes (pIFNα) was even more potent against HBV than injecting IFNα proteins. The combination of pIFNα4 and pIFNα5 showed a synergistic antiviral effect on HBV replication, with a strong increase in NK cell and T cell activity. The results demonstrate distinct anti-HBV effects of different IFNα subtypes against HBV in the mouse model, which may be relevant for new therapeutic approaches.
Radiological and Clinical Features associated with Epidermal Growth Factor Receptor Mutation Status of Exon 19 and 21 in Lung Adenocarcinoma
Authors: Shi Zhang , Zheng Xuan , Shi Ruifeng , Song Changen , Yang Runhong , Zhang Qianwen , Wang Xinrui , Lu Jianping , Yu Yongwei , Liu Qi , Jiang Tao
Published: March 2017

The exon 19 and 21 in Epidermal Growth Factor Receptor (EGFR) mutation are the most common subtype of lung adenocarcinoma, and the strongest predictive biomarker for progression-free survival and tumor response. Although some studies have shown differences in radiological features between cases with and without EFGR mutations, they lacked necessary stratification. This article is to evaluate the association of CT features between the wild type and the subtype (exon 19 and 21) of EGFR mutations in patients with lung adenocarcinoma. Of the 721 finally included patients, 132 were positive for EGFR mutation in exon 19, 140 were positive for EGFR mutation in exon 21, and 449 were EGFR wild type. EGFR mutation in exon 19 was associated with a small-maximum diameter (28.51 ± 14.07) (p < 0.0001); sex (p < 0.0001); pleural retraction (p = 0.0034); and the absence of fibrosis (p < 0.0001), while spiculated margins (p = 0.0095), subsolid density (p < 0.0001) and no smoking (p < 0.0001) were associated with EGFR mutation in exon 21. Receiver Operating Characteristic (ROC) curves suggested that the maximum Area Under the Curve (AUC) was related to the female gender (AUC = 0.636) and the absence of smoking (AUC = 0.681). This study demonstrated the radiological and clinical features could be used to prognosticate EGFR mutation subtypes in exon 19 and 21.
Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication
Authors: Tian Jide , Dang Hoa , Middleton Blake , Kaufman Daniel L.
Published: March 2017

A key goal of diabetes research is to develop treatments to safely promote human ß-cell replication. It has recently become appreciated that activation of γ-aminobutyric acid receptors (GABA-Rs) on ß-cells can promote their survival and replication. A number of positive allosteric modulators (PAMs) that enhance GABA’s actions on neuronal GABAA-Rs are in clinical use. Repurposing these GABAA-R PAMs to help treat diabetes is theoretically appealing because of their safety and potential to enhance the ability of GABA, secreted from ß-cells, or exogenously administered, to promote ß-cell replication and survival. Here, we show that clinically applicable GABAA-R PAMs can increase significantly INS-1 ß-cell replication, which is enhanced by exogenous GABA application. Furthermore, a GABAA-R PAM promoted human islet cell replication in vitro. This effect was abrogated by a GABAA-R antagonist. The combination of a PAM and low levels of exogenous GABA further increased human islet cell replication. These findings suggest that PAMs may potentiate the actions of GABA secreted by islet ß-cells on GABAA-Rs and provide a new class of drugs for diabetes treatment. Finally, our findings may explain a past clinical observation of a GABAA-R PAM reducing HbA1c levels in diabetic patients.
Rheumatoid Arthritis Fibroblast-like Synoviocyte Suppression Mediated by PTEN Involves Survivin Gene Silencing
Authors: Chen Danna , Liu Dongdong , Liu Dan , He Min , Peng Anping , Xu Jiarui , Lin Li , Luo Fudong , Chen Lin , Huang Xianzhang , Zhuang Junhua , Xu Jianhua
Published: March 2017

Survivin is a proto-oncogene biomarker known for its anti-apoptotic and cell cycle regulating properties induced by the activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. In the context of non-cancer pathology, such as rheumatoid arthritis (RA), survivin has emerged as a feature associated with severe joint damage and poor treatment response. Phosphatase and tensin homolog (PTEN) is a phosphatase antagonizing all classes of PI3K. The interplay between survivin oncogenic mechanisms and proliferation suppression networks in RA has remained largely elusive. This study investigated the effect of PTEN on survivin gene expression in rheumatiod arthritis fibroblast-like synoviocyte (RA-FLS). We showed for the first time that the suppression of RA-FLS was mediated by PTEN involving survivin silencing. Considering that survivin suppressants are currently available in clinical trials and clinical use, their effects in RA-FLS support a probably RA therapy to clinical practice.
Voltage-induced Interface Reconstruction and Electrical Instability of the Ferromagnet-Semiconductor Device
Authors: Chang Shu-Jui , Chang Po-Chun , Lin Wen-Chin , Lo Shao-Hua , Chang Liang-Chun , Lee Shang-Fan , Tseng Yuan-Chieh
Published: March 2017

Using x-ray magnetic spectroscopy with in-situ electrical characterizations, we investigated the effects of external voltage on the spin-electronic and transport properties at the interface of a Fe/ZnO device. Layer-, element-, and spin-resolved information of the device was obtained by cross-tuning of the x-ray mode and photon energy, when voltage was applied. At the early stage of the operation, the device exhibited a low-resistance state featuring robust Fe-O bonds. However, the Fe-O bonds were broken with increasing voltage. Breaking of the Fe-O bonds caused the formation of oxygen vacancies and resulted in a high-resistance state. Such interface reconstruction was coupled to a charge-transfer effect via Fe-O hybridization, which suppressed/enhanced the magnetization/coercivity of Fe electronically. Nevertheless, the interface became stabilized with the metallic phase if the device was continuously polarized. During this stage, the spin-polarization of Fe was enhanced whereas the coercivity was lowered by voltage, but changes of both characteristics were reversible. This stage is desirable for spintronic device applications, owing to a different voltage-induced electronic transition compared to the first stage. The study enabled a straightforward detection of the spin-electronic state at the ferromagnet-semiconductor interface in relation to the transport and reversal properties during operation process of the device.
Analyses of publicly available genomics resources define FGF-2-expressing bladder carcinomas as EMT-prone, proliferative tumors with low mutation rates and high expression of CTLA-4, PD-1 and PD-L1
Authors: McNiel Elizabeth A , Tsichlis Philip N
Published: March 2017

Fibroblast growth factor 2 (FGF-2) is overexpressed in a subset of invasive bladder carcinomas and its overexpression correlates with poor prognosis. Analyses of publicly available databases addressing the molecular mechanisms that may be responsible for the poor prognosis of these tumors, revealed that FGF-2 expression correlates positively with the expression of epithelial to mesenchymal transition (EMT)-promoting transcription factors and with changes in gene expression that are characteristic of EMT. The same analyses also revealed that FGF-2 correlates negatively with the expression, mutation and copy number variations of FGFR-3, all of which are associated with noninvasive bladder carcinomas. Finally, they showed that FGF-2 expression correlates with the expression of FGFR-1, the expression of the IIIc variant of FGFR-2 and with the expression of Akt3. The latter observation is significant because our earlier studies had shown that Akt3 regulates FGFR-2 alternative splicing, shifting the balance toward the IIIc relative to the IIIb FGFR-2 splice variant. As the IIIc variant is recognized by FGF-2, while the IIIb variant is not, we conclude that Akt3 may facilitate the FGF-2 response. FGF-2 is known to promote the expression of KDM2B, which functions in concert with EZH2 to repress the EZH2-targeting microRNA miR-101, activating a switch, which stably upregulates EZH2. The cancer genome atlas (TCGA) data showing a correlation between KDM2B and EZH2 expression and Oncomine data, showing a correlation between KDM2B and tumor progression, strongly support the role of the FGF-2/KDM2B/miR-101/EZH2 pathway in bladder cancer. These observations combined, suggest a model according to which FGF-2 induces EMT, cell proliferation and cancer stem cell self-renewal by coupling the Akt3 and KDM2B-controlled pathways outlined above, in bladder carcinomas. Further analyses of publicly available databases, revealed that FGF-2-expressing bladder carcinomas carry fewer genetic alterations and they tend to express high levels of CTLA-4, PD-1 and PD-L1, which suggests immune blockade by checkpoint activation. EMT, enhanced proliferation and immune checkpoint activation combined, may be responsible for the poor prognosis of FGF-2-expressing bladder carcinomas.
Locus-specific Retention Predictor (LsRP): A Peptide Retention Time Predictor Developed for Precision Proteomics
Authors: Lu Wenyuan , Liu Xiaohui , Liu Shanshan , Cao Weiqian , Zhang Yang , Yang Pengyuan
Published: March 2017

The precision prediction of peptide retention time (RT) plays an increasingly important role in liquid chromatography–tandem mass spectrometry (LC–MS/MS) based proteomics. Owing to the high reproducibility of liquid chromatography, RT prediction provides promising information for both identification and quantification experiment design. In this work, we present a Locus-specific Retention Predictor (LsRP) for precise prediction of peptide RT, which is based on amino acid locus information and Support Vector Regression (SVR) algorithm. Corresponding to amino acid locus, each peptide sequence was converted to a featured locus vector consisting of zeros and ones. With locus vector information from LC-MS/MS data sets, an SVR computational process was trained and evaluated. LsRP finally provided a prediction correlation coefficient of 0.95~0.99. We compared our method with two common predictors. Results showed that LsRP outperforms these methods and tracked up to 30% extra peptides in an extraction RT window of 2 min. A new strategy by combining LsRP and calibration peptide approach was then proposed, which open up new opportunities for precision proteomics.
Changes in miRNA in the lung and whole blood after whole thorax irradiation in rats
Authors: Gao Feng , Liu Pengyuan , Narayanan Jayashree , Yang Meiying , Fish Brian L. , Liu Yong , Liang Mingyu , Jacobs Elizabeth R. , Medhora Meetha
Published: March 2017

We used a rat model of whole thorax x-ray irradiation to profile the microRNA (miRNA) in lung and blood up to 4 weeks after radiation. MiRNA from normal and irradiated Wistar rat lungs and whole blood were analyzed by next-generation sequencing and the changes by radiation were identified by differential deRNA-seq 1, 2, 3 and 4 weeks after irradiation. The average total reads/library was 2,703,137 with a mean of 88% mapping to the rat genome. Detailed profiles of 100 of the most abundant miRNA in rat blood and lung are described. We identified upregulation of 4 miRNA, miR-144-5p, miR-144-3p, miR-142-5p and miR-19a-3p in rat blood 2 weeks after radiation that have not previously been shown to be altered after radiation to the lung. Ingenuity Pathway Analysis identified signaling of inflammatory response pathways. These findings will support development of early detection methods, as well as mechanism(s) of injury and mitigation in patients after radiotherapy or radiological accidents.
Exploring the under-investigated “microbial dark matter” of drinking water treatment plants
Authors: Bruno Antonia , Sandionigi Anna , Rizzi Ermanno , Bernasconi Marzia , Vicario Saverio , Galimberti Andrea , Cocuzza Clementina , Labra Massimo , Casiraghi Maurizio
Published: March 2017

Scientists recently reported the unexpected detection of unknown or poorly studied bacterial diversity in groundwater. The ability to uncover this neglected biodiversity mainly derives from technical improvements, and the term “microbial dark matter” was used to group taxa poorly investigated and not necessarily monophyletic. We focused on such under-investigated microbial dark matter of drinking water treatment plant from groundwater, across carbon filters, to post-chlorination. We tackled this topic using an integrated approach where the efficacy of stringent water filtration (10000 MWCO) in recovering even the smallest environmental microorganisms was coupled with high-throughput DNA sequencing to depict an informative spectrum of the neglected microbial diversity. Our results revealed that the composition of bacterial communities varies across the plant system: Parcubacteria (OD1) superphylum is found mainly in treated water, while groundwater has the highest heterogeneity, encompassing non-OD1 candidate phyla (Microgenomates, Saccharibacteria, Dependentiae, OP3, OP1, BRC1, WS3). Carbon filters probably act as substrate for microorganism growth and contribute to seeding water downstream, since chlorination does not modify the incoming bacterial community. New questions arise about the role of microbial dark matter in drinking water. Indeed, our results suggest that these bacteria might play a central role in the microbial dynamics of drinking water.
Vitamin D inhibits lymphangiogenesis through VDR-dependent mechanisms
Authors: Yazdani Saleh , Poosti Fariba , Toro Luis , Wedel Johannes , Mencke Rik , Mirković Katarina , de Borst Martin H. , Alexander J. Steven , Navis Gerjan , van Goor Harry , van den Born Jacob , Hillebrands Jan-Luuk
Published: March 2017

Excessive lymphangiogenesis is associated with cancer progression and renal disease. Attenuation of lymphangiogenesis might represent a novel strategy to target disease progression although clinically approved anti-lymphangiogenic drugs are not available yet. VitaminD(VitD)-deficiency is associated with increased cancer risk and chronic kidney disease. Presently, effects of VitD on lymphangiogenesis are unknown. Given the apparently protective effects of VitD and the deleterious associations of lymphangiogenesis with renal disease, we here tested the hypothesis that VitD has direct anti-lymphangiogenic effects in vitro and is able to attenuate lymphangiogenesis in vivo. In vitro cultured mouse lymphatic endothelial cells (LECs) expressed VitD Receptor (VDR), both on mRNA and protein levels. Active VitD (calcitriol) blocked LEC tube formation, reduced LEC proliferation, and induced LEC apoptosis. siRNA-mediated VDR knock-down reversed the inhibitory effect of calcitriol on LEC tube formation, demonstrating how such inhibition is VDR-dependent. In vivo, proteinuric rats were treated with vehicle or paricalcitol for 6 consecutive weeks. Compared with vehicle-treated proteinuric rats, paricalcitol showed markedly reduced renal lymphangiogenesis. In conclusion, our data show that VitD is anti-lymphangiogenic through VDR-dependent anti-proliferative and pro-apoptotic mechanisms. Our findings highlight an important novel function of VitD demonstrating how it may have therapeutic value in diseases accompanied by pathological lymphangiogenesis.
Synergistic efficacy of Bisbenzimidazole and Carbonyl Cyanide 3-Chlorophenylhydrazone combination against MDR bacterial strains
Authors: Sinha Devapriya , Pandey Stuti , Singh Raja , Tiwari Vinod , Sad Kirti , Tandon Vibha
Published: March 2017

Activation of efflux systems and the formation of biofilm are majorly adapted by microbes to resist antimicrobial agents. PPEF (bisbenzimidazole) targeting topoisomerase IA is observed to be an effective bactericidal agent against both Gram-positive and Gram-negative bacterial strains and thus can be developed as potent broad-spectrum antibiotic against MDR strains. PPEF treatment did not cause target specific mutation instead it leads to up-regulation of efflux gene in E. coli K12 as a mechanism of resistance. Microscopy, fluorescence spectroscopy and flow cytometry result demonstrate higher accumulation of PPEF in efflux gene deleted E. coli K12 mutants, and also suggest that Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP), resist the efflux of PPEF, and thus increases efficacy of PPEF. Herein, we report, PPEF and CCCP synergistically killed the persistent bacterial cells, which are not killed by PPEF alone. The above two compounds together inhibited biofilm formation, eradicate preformed biofilms and kills the biofilm cells of P. aeruginosa. PPEF and CCCP together reduced bacterial load of E. coli ATCC25922 by 6 log10 in neutropenic thigh infection model of balb/c mice. Present study suggests that combination therapy could be a promising antimicrobial strategy to handle MDR pathogenic strains.
Strain differences in arsenic-induced oxidative lesion via arsenic biomethylation between C57BL/6J and 129X1/SvJ mice
Authors: Wu Ruirui , Wu Xiafang , Wang Huihui , Fang Xin , Li Yongfang , Gao Lanyue , Sun Guifan , Pi Jingbo , Xu Yuanyuan
Published: March 2017

Arsenic is a common environmental and occupational toxicant with dramatic species differences in its susceptibility and metabolism. Mouse strain variability may provide a better understanding of the arsenic pathological profile but is largely unknown. Here we investigated oxidative lesion induced by acute arsenic exposure in the two frequently used mouse strains C57BL/6J and 129X1/SvJ in classical gene targeting technique. A dose of 5 mg/kg body weight arsenic led to a significant alteration of blood glutathione towards oxidized redox potential and increased hepatic malondialdehyde content in C57BL/6J mice, but not in 129X1/SvJ mice. Hepatic antioxidant enzymes were induced by arsenic in transcription in both strains and many were higher in C57BL/6J than 129X1/SvJ mice. Arsenic profiles in the liver, blood and urine and transcription of genes encoding enzymes involved in arsenic biomethylation all indicate a higher arsenic methylation capacity, which contributes to a faster hepatic arsenic excretion, in 129X1/SvJ mice than C57BL/6J mice. Taken together, C57BL/6J mice are more susceptible to oxidative hepatic injury compared with 129X1/SvJ mice after acute arsenic exposure, which is closely associated with arsenic methylation pattern of the two strains.
Reduced Regional Grey Matter Volumes in Pediatric Obstructive Sleep Apnea
Authors: Philby Mona F. , Macey Paul M. , Ma Richard A. , Kumar Rajesh , Gozal David , Kheirandish-Gozal Leila
Published: March 2017

Pediatric OSA is associated with cognitive risk. Since adult OSA manifests MRI evidence of brain injury, and animal models lead to regional neuronal losses, pediatric OSA patients may also be affected. We assessed the presence of neuronal injury, measured as regional grey matter volume, in 16 OSA children (8 male, 8.1 ± 2.2 years, AHI:11.1 ± 5.9 events/hr), and 200 control subjects (84 male, 8.2 ± 2.0 years), 191 of whom were from the NIH-Pediatric MRI database. High resolution T1-weighted whole-brain images were assessed between groups with voxel-based morphometry, using ANCOVA (covariates, age and gender; family-wise error correction, P < 0.01). Significant grey matter volume reductions appeared in OSA throughout areas of the superior frontal and prefrontal, and superior and lateral parietal cortices. Other affected sites included the brainstem, ventral medial prefrontal cortex, and superior temporal lobe, mostly on the left side. Thus, pediatric OSA subjects show extensive regionally-demarcated grey matter volume reductions in areas that control cognition and mood functions, even if such losses are apparently independent of cognitive deficits. Since OSA disease duration in our subjects is unknown, these findings may result from either delayed neuronal development, neuronal damaging processes, or a combination thereof, and could either reflect neuronal atrophy or reductions in cellular volume (neurons and glia).
The Golgi protein ACBD3 facilitates Enterovirus 71 replication by interacting with 3A
Authors: Lei Xiaobo , Xiao Xia , Zhang Zhenzhen , Ma Yijie , Qi Jianli , Wu Chao , Xiao Yan , Zhou Zhuo , He Bin , Wang Jianwei
Published: March 2017

Enterovirus 71 (EV71) is a human pathogen that causes hand, foot, mouth disease and neurological complications. Although EV71, as well as other enteroviruses, initiates a remodeling of intracellular membrane for genomic replication, the regulatory mechanism remains elusive. By screening human cDNA library, we uncover that the Golgi resident protein acyl-coenzyme A binding domain-containing 3 (ACBD3) serves as a target of the 3A protein of EV71. This interaction occurs in cells expressing 3A or infected with EV71. Genetic inhibition or deletion of ACBD3 drastically impairs viral RNA replication and plaque formation. Such defects are corrected upon restoration of ACBD3. In infected cells, EV71 3A redirects ACBD3, to the replication sites. I44A or H54Y substitution in 3A interrupts the binding to ACBD3. As such, viral replication is impeded. These results reveal a mechanism of EV71 replication that involves host ACBD3 for viral replication.
The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling
Authors: Merhi Ahmad , Delrée Paul , Marini Anna Maria
Published: March 2017

Two structurally and functionally distinct mammalian TOR complexes control cell growth and metabolism in physiological and pathological contexts including cancer. Upregulated glutaminolysis is part of the metabolic reprogramming occurring in cancer, providing fuels for growth but also liberating ammonium, a potent neurotoxic waste product. Here, we identify ammonium as a novel dose-dependent signal mediating rapid mTORC2 activation and further regulating mTORC1. We show that ammonium induces rapid RICTOR-dependent phosphorylation of AKT-S473, a process requiring the PI3K pathway and further involving the Src-family kinase YES1, the FAK kinase and the ITGβ1 integrin. Release of calcium from the endoplasmic reticulum store triggers rapid mTORC2 activation, similar to ammonium-induced activation, the latter being conversely prevented by calcium chelation.Moreover, in analogy to growth factors, ammonium triggers the AKT-dependent phosphoinhibition of the TSC complex and of PRAS40, two negative regulators of mTORC1. Consistent with mTORC1 stimulation, ammonium induces the inhibitory phosphorylation of 4EBP1, a negative regulator of protein biogenesis. Ammonium however dually impacts on the phosphorylation of p70S6K1 triggering a transient AKT-independent decrease in the phosphorylation of this second mTORC1 readout. Finally, we reveal ammonium as a dose-dependent stimulator of proliferation. This study underscores an mTORC2 and mTORC1 response to the so-called ammonium waste.
Anticipatory action planning in blind and sighted individuals
Authors: Cavallo Andrea , Ansuini Caterina , Gori Monica , Tinti Carla , Tonelli Alessia , Becchio Cristina
Published: March 2017

Several studies on visually guided reach-to-grasp movements have documented that how objects are grasped differs depending on the actions one intends to perform subsequently. However, no previous study has examined whether this differential grasping may also occur without visual input. In this study, we used motion capture technology to investigate the influence of visual feedback and prior visual experience on the modulation of kinematics by intention in sighted (in both full-vision and no-vision conditions), early-blind and late-blind participants. Results provide evidence of modulation of kinematics by intention to a similar degree under both full-vision and no-vision conditions. Moreover, they demonstrate that prior visual experience has little impact on the tailoring of grasping movements to intention. This suggests that sequential action planning does not depend on visual input, and may instead be ascribed to the function of multisensory-motor cortical network that operates and develops not only in light, but also in darkness.
Generating highly accurate prediction hypotheses through collaborative ensemble learning
Authors: Arsov Nino , Pavlovski Martin , Basnarkov Lasko , Kocarev Ljupco
Published: March 2017

Ensemble generation is a natural and convenient way of achieving better generalization performance of learning algorithms by gathering their predictive capabilities. Here, we nurture the idea of ensemble-based learning by combining bagging and boosting for the purpose of binary classification. Since the former improves stability through variance reduction, while the latter ameliorates overfitting, the outcome of a multi-model that combines both strives toward a comprehensive net-balancing of the bias-variance trade-off. To further improve this, we alter the bagged-boosting scheme by introducing collaboration between the multi-model’s constituent learners at various levels. This novel stability-guided classification scheme is delivered in two flavours: during or after the boosting process. Applied among a crowd of Gentle Boost ensembles, the ability of the two suggested algorithms to generalize is inspected by comparing them against Subbagging and Gentle Boost on various real-world datasets. In both cases, our models obtained a 40% generalization error decrease. But their true ability to capture details in data was revealed through their application for protein detection in texture analysis of gel electrophoresis images. They achieve improved performance of approximately 0.9773 AUROC when compared to the AUROC of 0.9574 obtained by an SVM based on recursive feature elimination.
Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma
Authors: Dinh Timothy A. , Vitucci Eva C. M. , Wauthier Eliane , Graham Rondell P. , Pitman Wendy A. , Oikawa Tsunekazu , Chen Mengjie , Silva Grace O. , Greene Kevin G. , Torbenson Michael S. , Reid Lola M. , Sethupathy Praveen
Published: March 2017

Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation.
Chemical profiling analysis of Maca using UHPLC-ESI-Orbitrap MS coupled with UHPLC-ESI-QqQ MS and the neuroprotective study on its active ingredients
Authors: Zhou Yanyan , Li Peng , Brantner Adelheid , Wang Hongjie , Shu Xinbin , Yang Jian , Si Nan , Han Lingyu , Zhao Haiyu , Bian Baolin
Published: March 2017

Lepidium meyenii (Maca), originated from Peru, has been cultivated widely in China as a popular health care food. However, the chemical and effective studies of Maca were less in-depth, which restricted its application seriously. To ensure the quality of Maca, a feasible and accurate strategy was established. One hundred and sixty compounds including 30 reference standards were identified in 6 fractions of methanol extract of Maca by UHPLC-ESI-Orbitrap MS. Among them, 15 representative active compounds were simultaneously determined in 17 samples by UHPLC-ESI-QqQ MS. The results suggested that Maca from Yunnan province was the potential substitute for the one from Peru. Meanwhile, the neuroprotective effects of Maca were investigated. Three fractions and two pure compounds showed strong activities in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced zebrafish model. Among them, 80% methanol elution fraction (Fr5) showed significant neuroprotective activity, followed by 100% part (Fr6). The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was a possible mechanism of its neuroprotective effect.
HCMV-encoded miR-UL112-3p promotes glioblastoma progression via tumour suppressor candidate 3
Authors: Liang Qing , Wang Kejia , Wang Bin , Cai Qiliang
Published: March 2017

Glioblastoma (GBM) is the most prevalent and lethal type of primary malignant brain tumour. Recent studies suggest that the discovery of human cytomegalovirus (HCMV)-encoded microRNAs (miRNAs) might play a role in the pathogenesis of diseases, including GBM. In this study, we aimed to analyse the expression and function of HCMV-encoded miRNAs in GBM. We found that miR-UL112-3p expression was significantly elevated in GBM, and its expression levels were highly associated with glioma size, differentiation, WHO stage and the overall and disease-free survival of patients. The overexpression of miR-UL112-3p in the GBM cells promoted cell proliferation, clone formation, migration and invasion. In contrast, the down-regulation of miR-UL112-3p exerted an inverse effects. Tumour suppressor candidate 3 (TUSC3), a potential target gene of miR-UL112-3p, was inversely correlated with miR-UL112-3p expression in GBM tissues and cell lines. Furthermore, we demonstrated that TUSC3 was directly regulated by miR-UL112-3p, and the ectopic expression of TUSC3 reversed the effects of miR-UL112-3p on GBM progression via the AKT signalling pathway. Taken together, these findings collectively demonstrate that miR-UL112-3p exerts its oncogene function by directly targeting TUSC3 in GBM, indicating a potential novel therapeutic target for GBM.