bluuebunny/crossref_metadata_2025 huggingface dataset:
Common origins and the ethics of planetary seeding
Authors: Milligan Tony
Published: September 2016

Faced with a choice between attempting to seed another world with terrestrially-sourced microbes (with which we would have a shared origin) and microbes sourced from elsewhere within the solar system (whose origins might therefore differ), would we have any non-instrumental ethical reason to favour the terrestrial microbes? What follows will argue that in relation to the goals of promoting life similar to our own, or even simply microbial life, we might conceivably make such an appeal and do so in a defensible manner. However, in no case would such a consideration operate as a silencer for rival considerations (such as likelihood of success, enhancing diversity or historical justice). The thought experiment serves to highlight the diversity of considerations which are in play in ethical deliberation about matters of astrobiology and the role of practical wisdom rather than trumping considerations.
Protective and Harmful Effects of Physical Activity for Low Back Pain: A Protocol for the AUstralian Twin BACK Pain (AUTBACK) Feasibility Study
Authors: Pinheiro Marina B. , Ferreira Manuela L. , Refshauge Kathryn , Hopper John , Maher Christopher G. , Hartvigsen Jan , Koes Bart , Hübscher Markus , Ferreira Paulo H.
Published: September 2016

Low back pain (LBP) is a major health problem globally, but approaches to prevention are not yet clearly identified because modifiable risk factors are not well established. Although physical activity is one promising modifiable risk factor, it is still not known what types and doses of physical activity are protective or harmful for LBP. The aim of this study is to establish the feasibility of a definitive cohort study that will investigate the effects of different types and doses of physical activity on the risk of developing recurrent LBP while accounting for genetic factors. This will be a pilot longitudinal twin study and twins will be recruited from the Australian Twin Registry, and will be followed over 1 year. Thirty adult complete twin pairs with a history of LBP, but symptom free at recruitment, will be included. Data on physical activity (predictor) will be collected using four questionnaires and an objective measure (accelerometer) at baseline and at 6-month follow-up. Twins will also complete an additional physical activity questionnaire monthly. Data on LBP (outcome) will be collected at baseline and weekly. Data will be collected using short message service (SMS) and email. We will keep records of the recruitment rate, follow-up rate, and completeness of data. Barriers to completing the study will be investigated. The results of this study will inform the design and implementation of a future definitive study, which will help to clarify the effects of different types and doses of physical activity on the risk of developing recurrent LBP.
The Geomagnetic Blitz of September 1941
Authors: Love Jeffrey , Coïsson Pierdavide
Published: September 2016

Seventy-five years ago next week, a massive geomagnetic storm disrupted electrical power, interrupted radio broadcasts, and illuminated the night sky in a World War II battle theater.
Scientists Solve Charon's Red Mystery
Authors: Wendel JoAnna
Published: September 2016

Why are Charon's poles dusted with reddish material?
MATE1 regulates cellular uptake and sensitivity to imatinib in CML patients
Authors: Harrach S , Schmidt-Lauber C , Pap T , Pavenstädt H , Schlatter E , Schmidt E , Berdel W E , Schulze U , Edemir B , Jeromin S , Haferlach T , Ciarimboli G , Bertrand J
Published: September 2016

Although imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), 25–30% patients do not respond or relapse after initial response. Imatinib uptake into targeted cells is crucial for its molecular response and clinical effectiveness. The organic cation transporter 1 (OCT1) has been proposed to be responsible for this process, but its relevance has been discussed controversially in recent times. Here we found that the multidrug and toxin extrusion protein 1 (MATE1) transports imatinib with a manifold higher affinity. MATE1 mainly mediates the cellular uptake of imatinib into targeted cells and thereby controls the intracellular effectiveness of imatinib. Importantly, MATE1 but not OCT1 expression is reduced in total bone marrow cells of imatinib-non-responding CML patients compared with imatinib-responding patients, indicating that MATE1 but not OCT1 determines the therapeutic success of imatinib. We thus propose that imatinib non-responders could be identified early before starting therapy by measuring MATE1 expression levels.
Valence-state reflectometry of complex oxide heterointerfaces
Authors: Hamann-Borrero Jorge E , Macke Sebastian , Choi Woo Seok , Sutarto Ronny , He Feizhou , Radi Abdullah , Elfimov Ilya , Green Robert J , Haverkort Maurits W , Zabolotnyy Volodymyr B , Lee Ho Nyung , Sawatzky George A , Hinkov Vladimir
Published: September 2016

Emergent phenomena in transition-metal-oxide heterostructures such as interface superconductivity and magnetism have been attributed to electronic reconstruction, which, however, is difficult to detect and characterise. Here we overcome the associated difficulties to simultaneously address the electronic degrees of freedom and distinguish interface from bulk effects by implementing a novel approach to resonant X-ray reflectivity (RXR). Our RXR study of the chemical and valance profiles along the polar (001) direction of a LaCoO3 film on NdGaO3 reveals a pronounced valence-state reconstruction from Co3+ in the bulk to Co2+ at the surface, with an areal density close to 0.5 Co2+ ions per unit cell. An identical film capped with polar (001) LaAlO3 maintains the Co3+ valence over its entire thickness. We interpret this as evidence for electronic reconstruction in the uncapped film, involving the transfer of 0.5e− per unit cell to the subsurface CoO2 layer at its LaO-terminated polar surface.
ZikaVR: An Integrated Zika Virus Resource for Genomics, Proteomics, Phylogenetic and Therapeutic Analysis
Authors: Gupta Amit Kumar , Kaur Karambir , Rajput Akanksha , Dhanda Sandeep Kumar , Sehgal Manika , Khan Md. Shoaib , Monga Isha , Dar Showkat Ahmad , Singh Sandeep , Nagpal Gandharva , Usmani Salman Sadullah , Thakur Anamika , Kaur Gazaldeep , Sharma Shivangi , Bhardwaj Aman , Qureshi Abid , Raghava Gajendra Pal Singh , Kumar Manoj
Published: September 2016

Current Zika virus (ZIKV) outbreaks that spread in several areas of Africa, Southeast Asia, and in pacific islands is declared as a global health emergency by World Health Organization (WHO). It causes Zika fever and illness ranging from severe autoimmune to neurological complications in humans. To facilitate research on this virus, we have developed an integrative multi-omics platform; ZikaVR (http://bioinfo.imtech.res.in/manojk/zikavr/), dedicated to the ZIKV genomic, proteomic and therapeutic knowledge. It comprises of whole genome sequences, their respective functional information regarding proteins, genes, and structural content. Additionally, it also delivers sophisticated analysis such as whole-genome alignments, conservation and variation, CpG islands, codon context, usage bias and phylogenetic inferences at whole genome and proteome level with user-friendly visual environment. Further, glycosylation sites and molecular diagnostic primers were also analyzed. Most importantly, we also proposed potential therapeutically imperative constituents namely vaccine epitopes, siRNAs, miRNAs, sgRNAs and repurposing drug candidates.
Extracellular cGMP Modulates Learning Biphasically by Modulating Glycine Receptors, CaMKII and Glutamate-Nitric Oxide-cGMP Pathway
Authors: Cabrera-Pastor Andrea , Malaguarnera Michele , Taoro-Gonzalez Lucas , Llansola Marta , Felipo Vicente
Published: September 2016

It has been proposed that extracellular cGMP modulates the ability to learn a Y maze task, but the underlying mechanisms remained unknown. Here we show that extracellular cGMP, at physiological concentrations, modulates learning in the Y maze in a biphasic way by modulating the glutamate-nitric oxide-cGMP pathway in cerebellum. Extracellular cGMP reduces glycine receptors activation inducing a voltage-dependent calcium-channels-mediated increase of calcium in Purkinje neurons. This calcium increase modulates CaMKII phosphorylation in a biphasic way. When basal calcium concentration is low extracellular cGMP reduces CaMKII phosphorylation, increasing nitric oxide synthase activity, the glutamate-NO-cGMP pathway function and learning ability. When basal calcium is normal extracellular cGMP increases CaMKII phosphorylation, reducing nitric oxide synthase activity, the pathway function and learning. These data unveil new mechanisms modulating learning in the Y maze and likely other learning types which may be therapeutic targets to improve learning in pathological situations associated with altered cGMP levels.
Horizontal gene transfer drives adaptive colonization of apple trees by the fungal pathogen Valsa mali
Authors: Yin Zhiyuan , Zhu Baitao , Feng Hao , Huang Lili
Published: September 2016

Horizontal gene transfer (HGT) often has strong benefits for fungi. In a study of samples from apple canker in Shaanxi Province, China, diverse microbes, along with the necrotrophic pathogen Valsa mali, were found to colonize the apple bark, thus providing ample opportunity for HGT to occur. In the present study, we identified 32 HGT events in V. mali by combining phyletic distribution-based methods with phylogenetic analyses. Most of these HGTs were from bacteria, whereas several others were from eukaryotes. Three HGTs putatively functioned in competition with actinomycetes, some of which showed a significant inhibitory effect on V. mali. Three HGTs that were probably involved in nitrogen uptake were also identified. Ten HGTs were thought to be involved in pathogenicity because they were related to known virulence factors, including cell wall-degrading enzymes and candidate effector proteins. HGT14, together with HGT32, was shown to contribute to bleomycin resistance of V. mali.These results suggest that HGT drives the adaptive evolution of V. mali. The HGTs identified here provide new clues for unveiling the adaptation mechanisms and virulence determinants of V. mali.
Correction: Corrigendum: Environmental chemicals impact dog semen quality in vitro and may be associated with a temporal decline in sperm motility and increased cryptorchidism
Authors: Lea Richard G. , Byers Andrew S. , Sumner Rebecca N. , Rhind Stewart M. , Zhang Zulin , Freeman Sarah L. , Moxon Rachel , Richardson Holly M. , Green Martin , Craigon Jim , England Gary C. W.
Published: September 2016

Scientific Reports 6: Article number: 31281; published online: 09 August 2016; updated: 16 September 2016.
Nitroaromatic explosives detection using electrochemically exfoliated graphene
Authors: Yew Ying Teng , Ambrosi Adriano , Pumera Martin
Published: September 2016

Detection of nitroaromatic explosives is of paramount importance from security point of view. Graphene sheets obtained from the electrochemical anodic exfoliation of graphite foil in different electrolytes (LiClO4 and Na2SO4) were compared and tested as electrode material for the electrochemical detection of 2,4-dinitrotoluene (DNT) and 2,4,6-trinitrotoluene (TNT) in seawater. Voltammetry analysis demonstrated the superior electrochemical performance of graphene produced in LiClO4, resulting in higher sensitivity and linearity for the explosives detection and lower limit of detection (LOD) compared to the graphene obtained in Na2SO4. We attribute this to the presence of oxygen functionalities onto the graphene material obtained in LiClO4 which enable charge electrostatic interactions with the –NO2 groups of the analyte, in addition to π-π stacking interactions with the aromatic moiety. Research findings obtained from this study would assist in the development of portable devices for the on-site detection of nitroaromatic explosives.
Superfluidity enhanced by spin-flip tunnelling in the presence of a magnetic field
Authors: Zheng Jun-Hui , Wang Daw-Wei , Juzeliūnas Gediminas
Published: September 2016

It is well-known that when the magnetic field is stronger than a critical value, the spin imbalance can break the Cooper pairs of electrons and hence hinder the superconductivity in a spin-singlet channel. In a bilayer system of ultra-cold Fermi gases, however, we demonstrate that the critical value of the magnetic field at zero temperature can be significantly increased by including a spin-flip tunnelling, which opens a gap in the spin-triplet channel near the Fermi surface and hence reduces the influence of the effective magnetic field on the superfluidity. The phase transition also changes from first order to second order when the tunnelling exceeds a critical value. Considering a realistic experiment, this mechanism can be implemented by applying an intralayer Raman coupling between the spin states with a phase difference between the two layers.
Identification of Doxorubicin as an Inhibitor of the IRE1α-XBP1 Axis of the Unfolded Protein Response
Authors: Jiang Dadi , Lynch Connor , Medeiros Bruno C. , Liedtke Michaela , Bam Rakesh , Tam Arvin B. , Yang Zhifen , Alagappan Muthuraman , Abidi Parveen , Le Quynh-Thu , Giaccia Amato J. , Denko Nicholas C. , Niwa Maho , Koong Albert C.
Published: September 2016

Activation of the IRE1α-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through anin silicodrug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as anin vitroandin vivoinhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1α-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1α-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138+tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1α–XBP1-dependent tumors such as MM.
Ursolic acid-mediated apoptosis of K562 cells involves Stat5/Akt pathway inhibition through the induction of Gfi-1
Authors: Lin Ze , Jiang Jikai , Liu Xiao-Shan
Published: September 2016

Ursolic acid (UA) is a promising natural compound for cancer prevention and therapy. We previously reported that UA induced apoptosis in CML-derived K562 cells. Here we show that the apoptotic process is accompanied by down-regulation of Bcl-xL and Mcl-1 expression and dephosphorylation of Bad. These events are associated with Stat5 inhibition, which is partially mediated through elevated expression of transcriptional repressor Gfi-1. Gfi-1 knockdown using siRNA abrogates the ability of UA to decrease Stat5b expression and attenuates apoptosis induction by UA. We also demonstrate that UA suppresses the Akt kinase activity by inhibiting Akt1/2 expression, which correlates with Stat5 inhibition. Stat5 activity inhibited by a chemical inhibitor or siRNA, Akt1/2 mRNA expression is suppressed. Moreover, we show that UA exerts growth-inhibition in Imatinib-resistant K562/G01. UA has synergistic effects when used in combination with Imatinib in both K562 and K562/G01. Altogether, the data provide evidence that UA’s pro-apoptotic effect in K562 cells is associated with the Gfi-1/Stat5/Akt pathway. The findings indicate that UA could potentially be a useful agent in the treatment of CML.
Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: A systematic review and meta-analysis
Authors: Wu Shunquan , Wu Fuquan , Ding Yingying , Hou Jun , Bi Jingfeng , Zhang Zheng
Published: September 2016

Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to cardiovascular disease (CVD). The aim of this study is to assess whether and to what extent the excess risk of CVD is conferred by NAFLD in a meta-analysis. We systematically searched PubMed, EmBase, Web of Science, and Cochrane Library for reports published between 1965 and July 3, 2015. Studies that reported data on association between NAFLD and adverse cardiovascular events or mortality were included. Thirty-four studies (164,494 participants, 21 cross-sectional studies, and 13 cohort studies) were included. NAFLD was not associated with overall mortality (HR = 1.14, 95% CI: 0.99–1.32) and CVD mortality (HR = 1.10, 95% CI: 0.86–1.41). However, NAFLD was associated with an increased risk of prevalent (OR = 1.81, 95% CI: 1.23–2.66) and incident (HR = 1.37, 95% CI: 1.10–1.72) CVD. For some specific CVDs, NAFLD was associated with an increased risk of prevalent (OR = 1.87, 95% CI: 1.47–2.37) and incident (HR = 2.31, 95% CI: 1.46–3.65) coronary artery disease (CAD), prevalent (OR = 1.24, 95% CI: 1.14–1.36) and incident (HR = 1.16, 95% CI: 1.06–1.27) hypertension, and prevalent (OR = 1.32, 95% CI: 1.07–1.62) atherosclerosis. In conclusion, the presence of NAFLD is associated with an increased risk of major adverse cardiovascular events, although it is not related to mortality from all causes or CVD.
Potential of in vivo real-time gastric gas profiling: a pilot evaluation of heat-stress and modulating dietary cinnamon effect in an animal model
Authors: Ou Jian Zhen , Cottrell Jeremy J. , Ha Nam , Pillai Naresh , Yao Chu K. , Berean Kyle J. , Ward Stephanie A. , Grando Danilla , Muir Jane G. , Harrison Christopher J. , Wijesiriwardana Udani , Dunshea Frank R. , Gibson Peter R. , Kalantar-zadeh Kourosh
Published: September 2016

Gastroenterologists are still unable to differentiate between some of the most ordinary disorders of the gut and consequently patients are misdiagnosed. We have developed a swallowable gas sensor capsule for addressing this. The gases of the gut are the by-product of the fermentation processes during digestion, affected by the gut state and can consequently provide the needed information regarding the health of the gut. Here we present the first study on gas sensor capsules for revealing the effect of a medical supplement in an animal (pig) model. We characterise the real-time alterations of gastric-gas in response to environmental heat-stress and dietary cinnamon and use the gas profiles for understanding the bio-physiological changes. Under no heat-stress, feeding increases gastric CO2 concentration, while dietary cinnamon reduces it due to decrease in gastric acid and pepsin secretion. Alternatively, heat-stress leads to hyperventilation in pigs, which reduces CO2 concentration and with the cinnamon treatment, CO2 diminishes even more, resulting in health improvement outcomes. Overall, a good repeatability in gas profiles is also observed. The model demonstrates the strong potential of real-time gas profiler in providing new physiological information that will impact understanding of therapeutics, presenting a highly reliable device for monitoring/diagnostics of gastrointestinal disorders.
A comprehensive validation of HBV-related acute-on-chronic liver failure models to assist decision-making in targeted therapeutics
Authors: Shen Yi , Wang Xulin , Zhang Sheng , Qin Gang , Liu Yanmei , Lu Yihua , Liang Feng , Zhuang Xun
Published: September 2016

This research utilized an external longitudinal dataset of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) to compare and validate various predictive models that support the current recommendations to select the most effective predictive risk models to estimate short- and long-term mortality and facilitate decision-making about preferable therapeutics for HBV-ACLF patients. Twelve ACLF prognostic models were developed after a systematic literature search using the longitudinal data of 232 HBV-ACLF patients on the waiting list for liver transplantation (LT). Four statistical measures, the constant (A) and slope (B) of the fitted line, the area under the curve (C) and the net benefit (D), were calculated to assess and compare the calibration, discrimination and clinical usefulness of the 12 predictive models. According to the model calibration and discrimination, the logistic regression models (LRM2) and the United Kingdom model of end-stage liver disease(UKELD) were selected as the best predictive models for both 3-month and 5-year outcomes. The decision curve summarizes the benefits of intervention relative to the costs of unnecessary treatment. After the comprehensive validation and comparison of the currently used models, LRM2 was confirmed as a markedly effective prognostic model for LT-free HBV-ACLF patients for assisting targeted and standardized therapeutic decisions.
Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression
Authors: Dogra Shalini , Kumar Ajeet , Umrao Deepmala , Sahasrabuddhe Amogh A. , Yadav Prem N.
Published: September 2016

Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice.
Ultrasensitive and low-volume point-of-care diagnostics on flexible strips – a study with cardiac troponin biomarkers
Authors: Shanmugam Nandhinee Radha , Muthukumar Sriram , Prasad Shalini
Published: September 2016

We demonstrate a flexible, mechanically stable, and disposable electrochemical sensor platform for monitoring cardiac troponins through the detection and quantification of cardiac Troponin-T (cTnT). We designed and fabricated nanostructured zinc oxide (ZnO) sensing electrodes on flexible porous polyimide substrates. We demonstrate ultrasensitive detection is capable at very low sample volumes due to the confinement phenomenon of target species within the ZnO nanostructures leading to enhancement of biomolecular binding on the sensor electrode surface. The performance of the ZnO nanostructured sensor electrode was evaluated against gold and nanotextured ZnO electrodes. The electrochemical sensor functions on affinity based immunoassay principles whereby monoclonal antibodies for cTnT were immobilized on the sensor electrodes using thiol based chemistry. Detection of cTnT in phosphate buffered saline (PBS) and human serum (HS) buffers was achieved at low sample volumes of 20 μL using non-faradaic electrochemical impedance spectroscopy (EIS). Limit of detection (LOD) of 1E-4 ng/mL (i.e. 1 pg/mL) at 7% CV (coefficient of variation) for cTnT in HS was demonstrated on nanostructured ZnO electrodes. The mechanical integrity of the flexible biosensor platform was demonstrated with cyclic bending tests. The sensor performed within 12% CV after 100 bending cycles demonstrating the robustness of the nanostructured ZnO electrochemical sensor platform.
Correction: Corrigendum: First Experience of Ultrasound-guided Percutaneous Ablation for Recurrent Hepatoblastoma after Liver Resection in Children
Authors: Liu Baoxian , Zhou Luyao , Huang Guangliang , Zhong Zhihai , Jiang Chunlin , Shan Quanyuan , Xu Ming , Kuang Ming , Xie Xiaoyan
Published: September 2016

Scientific Reports 5: Article number: 16805; published online: 18 November 2015; updated: 16 September 2016.
Protein aggregation activates erratic stress response in dietary restricted yeast cells
Authors: Bhadra Ankan Kumar , Das Eshita , Roy Ipsita
Published: September 2016

Chronic stress and prolonged activation of defence pathways have deleterious consequences for the cell. Dietary restriction is believed to be beneficial as it induces the cellular stress response machinery. We report here that although the phenomenon is beneficial in a wild-type cell, dietary restriction leads to an inconsistent response in a cell that is already under proteotoxicity-induced stress. Using a yeast model of Huntington’s disease, we show that contrary to expectation, aggregation of mutant huntingtin is exacerbated and activation of the unfolded protein response pathway is dampened under dietary restriction. Global proteomic analysis shows that when exposed to a single stress, either protein aggregation or dietary restriction, the expression of foldases like peptidyl-prolyl isomerase, is strongly upregulated. However, under combinatorial stress, this lead is lost, which results in enhanced protein aggregation and reduced cell survival. Successful designing of aggregation-targeted therapeutics will need to take additional stressors into account.
A highly efficient sorbitol dehydrogenase from Gluconobacter oxydans G624 and improvement of its stability through immobilization
Authors: Kim Tae-Su , Patel Sanjay K. S. , Selvaraj Chandrabose , Jung Woo-Suk , Pan Cheol-Ho , Kang Yun Chan , Lee Jung-Kul
Published: September 2016

A sorbitol dehydrogenase (GoSLDH) from Gluconobacter oxydans G624 (G. oxydans G624) was expressed in Escherichia coli BL21(DE3)-CodonPlus RIL. The complete 1455-bp codon-optimized gene was amplified, expressed, and thoroughly characterized for the first time. GoSLDH exhibited Km and kcat values of 38.9 mM and 3820 s−1 toward L-sorbitol, respectively. The enzyme exhibited high preference for NADP+ (vs. only 2.5% relative activity with NAD+). GoSLDH sequencing, structure analyses, and biochemical studies, suggested that it belongs to the NADP+-dependent polyol-specific long-chain sorbitol dehydrogenase family. GoSLDH is the first fully characterized SLDH to date, and it is distinguished from other L-sorbose-producing enzymes by its high activity and substrate specificity. Isothermal titration calorimetry showed that the protein binds more strongly to D-sorbitol than other L-sorbose-producing enzymes, and substrate docking analysis confirmed a higher turnover rate. The high oxidation potential of GoSLDH for D-sorbitol was confirmed by cyclovoltametric analysis. Further, stability of GoSLDH significantly improved (up to 13.6-fold) after cross-linking of immobilized enzyme on silica nanoparticles and retained 62.8% residual activity after 10 cycles of reuse. Therefore, immobilized GoSLDH may be useful for L-sorbose production from D-sorbitol.
Dynamics of genome change among Legionella species
Authors: Joseph Sandeep J. , Cox Daniel , Wolff Bernard , Morrison Shatavia S. , Kozak-Muiznieks Natalia A. , Frace Michael , Didelot Xavier , Castillo-Ramirez Santiago , Winchell Jonas , Read Timothy D. , Dean Deborah
Published: September 2016

Legionella species inhabit freshwater and soil ecosystems where they parasitize protozoa. L. pneumonphila (LP) serogroup-1 (Lp1) is the major cause of Legionnaires’ Disease (LD), a life-threatening pulmonary infection that can spread systemically. The increased global frequency of LD caused by Lp and non-Lp species underscores the need to expand our knowledge of evolutionary forces underlying disease pathogenesis. Whole genome analyses of 43 strains, including all known Lp serogroups 1–17 and 17 emergent LD-causing Legionella species (of which 33 were sequenced in this study) in addition to 10 publicly available genomes, resolved the strains into four phylogenetic clades along host virulence demarcations. Clade-specific genes were distinct for genetic exchange and signal-transduction, indicating adaptation to specific cellular and/or environmental niches. CRISPR spacer comparisons hinted at larger pools of accessory DNA sequences in Lp than predicted by the pan-genome analyses. While recombination within Lp was frequent and has been reported previously, population structure analysis identified surprisingly few DNA admixture events between species. In summary, diverse Legionella LD–causing species share a conserved core-genome, are genetically isolated from each other, and selectively acquire genes with potential for enhanced virulence.
FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis
Authors: Verbeke Len , Mannaerts Inge , Schierwagen Robert , Govaere Olivier , Klein Sabine , Vander Elst Ingrid , Windmolders Petra , Farre Ricard , Wenes Mathias , Mazzone Massimiliano , Nevens Frederik , van Grunsven Leo A. , Trebicka Jonel , Laleman Wim
Published: September 2016

Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis.
Molecular basis of a novel renal amyloidosis due to N184K gelsolin variant
Authors: Bonì Francesco , Milani Mario , Porcari Riccardo , Barbiroli Alberto , Ricagno Stefano , de Rosa Matteo
Published: September 2016

Mutations in gelsolin are responsible for a systemic amyloidosis first described in 1969. Until recently, the disease was associated with two substitutions of the same residue, leading to the loss of the calcium binding site. Novel interest arose in 2014 when the N184K variant of the protein was identified as the etiological agent of a novel kidney-localized amyloidosis. Here we provide a first rationale for N184K pathogenicity. We show that the mutation induces a destabilization of gelsolin second domain, without compromising its calcium binding capacity. X-ray data combined with molecular dynamics simulations demonstrates that the primary source of the destabilization is a loss of connectivity in proximity of the metal. Such rearrangement of the H-bond network does not have a major impact on the overall fold of the domain, nevertheless, it increases the flexibility of a stretch of the protein, which is consequently processed by furin protease. Overall our data suggest that the N184K variant is subjected to the same aberrant proteolytic events responsible for the formation of amyloidogenic fragments in the previously characterized mutants. At the same time our data suggest that a broader number of mutations, unrelated to the metal binding site, can lead to a pathogenic phenotype.
Protein malnutrition potentiates the amplifying pathway of insulin secretion in adult obese mice
Authors: Leite Nayara Carvalho , de Paula Flávia , Borck Patrícia Cristine , Vettorazzi Jean Franciesco , Branco Renato Chaves Souto , Lubaczeuski Camila , Boschero Antonio Carlos , Zoppi Claudio Cesar , Carneiro Everardo Magalhães
Published: September 2016

Pancreatic beta cell (β) dysfunction is an outcome of malnutrition. We assessed the role of the amplifying pathway (AMP PATH) in β cells in malnourished obese mice. C57Bl-6 mice were fed a control (C) or a low-protein diet (R). The groups were then fed a high-fat diet (CH and RH). AMP PATH contribution to insulin secretion was assessed upon incubating islets with diazoxide and KCl. CH and RH displayed increased glucose intolerance, insulin resistance and glucose-stimulated insulin secretion. Only RH showed a higher contribution of the AMP PATH. The mitochondrial membrane potential of RH was decreased, and ATP flux was unaltered. In RH islets, glutamate dehydrogenase (GDH) protein content and activity increased, and the AMP PATH contribution was reestablished when GDH was blunted. Thus, protein malnutrition induces mitochondrial dysfunction in β cells, leading to an increased contribution of the AMP PATH to insulin secretion through the enhancement of GDH content and activity.
Lateral photovoltaic effect in flexible free-standing reduced graphene oxide film for self-powered position-sensitive detection
Authors: Moon In Kyu , Ki Bugeun , Yoon Seonno , Choi Jongwan , Oh Jungwoo
Published: September 2016

Lightweight, simple and flexible self-powered photodetectors are urgently required for the development and application of advanced optical systems for the future of wearable electronic technology. Here, using a low-temperature reduction process, we report a chemical approach for producing freestanding monolithic reduced graphene oxide papers with different gradients of the carbon/oxygen concentration ratio. We also demonstrate a novel type of freestanding monolithic reduced graphene oxide self-powered photodetector based on a symmetrical metal–semiconductor–metal structure. Upon illumination by a 633-nm continuous wave laser, the lateral photovoltage is observed to vary linfearly with the laser position between two electrodes on the reduced graphene oxide surface. This result may suggest that the lateral photovoltaic effect in the reduced graphene oxide film originates from the built-in electric field by the combination of both the photothermal electric effect and the gradient of the oxygen-to-carbon composition. These results represent substantial progress toward novel, chemically synthesized graphene-based photosensors and suggest one-step integration of graphene-based optoelectronics in the future.
Eukaryotic pathways targeted by the type III secretion system effector protein, BipC, involved in the intracellular lifecycle of Burkholderia pseudomallei
Authors: Kang Wen-Tyng , Vellasamy Kumutha Malar , Vadivelu Jamuna
Published: September 2016

Burkholderia pseudomallei, the etiological agent for melioidosis, is known to secrete a type III secretion system (TTSS) protein into the host’s internal milieu. One of the TTSS effector protein, BipC, has been shown to play an important role in the B. pseudomallei pathogenesis. To identify the host response profile that was directly or indirectly regulated by this protein, genome-wide transcriptome approach was used to examine the gene expression profiles of infected mice. The transcriptome analysis of the liver and spleen revealed that a total of approximately 1,000 genes were transcriptionally affected by BipC. Genes involved in bacterial invasion, regulation of actin cytoskeleton, and MAPK signalling pathway were over-expressed and may be specifically regulated by BipC in vivo. These results suggest that BipC mainly targets pathways related to the cellular processes which could modulate the cellular trafficking processes. The host transcriptional response exhibited remarkable differences with and without the presence of the BipC protein. Overall, the detailed picture of this study provides new insights that BipC may have evolved to efficiently manipulate host-cell pathways which is crucial in the intracellular lifecycle of B. pseudomallei.
Redox-dependent Regulation of Gluconeogenesis by a Novel Mechanism Mediated by a Peroxidatic Cysteine of Peroxiredoxin
Authors: Irokawa Hayato , Tachibana Tsuyoshi , Watanabe Toshihiko , Matsuyama Yuka , Motohashi Hozumi , Ogasawara Ayako , Iwai Kenta , Naganuma Akira , Kuge Shusuke
Published: September 2016

Peroxiredoxin is an abundant peroxidase, but its non-peroxidase function is also important. In this study, we discovered that Tsa1, a major peroxiredoxin of budding yeast cells, is required for the efficient flux of gluconeogenesis. We found that the suppression of pyruvate kinase (Pyk1) via the interaction with Tsa1 contributes in part to gluconeogenic enhancement. The physical interactions between Pyk1 and Tsa1 were augmented during the shift from glycolysis to gluconeogenesis. Intriguingly, a peroxidatic cysteine in the catalytic center of Tsa1 played an important role in the physical Tsa1-Pyk1 interactions. These interactions are enhanced by exogenous H2O2 and by endogenous reactive oxygen species, which is increased during gluconeogenesis. Only the peroxidatic cysteine, but no other catalytic cysteine of Tsa1, is required for efficient growth during the metabolic shift to obtain maximum yeast growth (biomass). This Tsa1 function is separable from the peroxidase function as an antioxidant. This is the first report to demonstrate that peroxiredoxin has a novel nonperoxidase function as a redox-dependent target modulator and that pyruvate kinase is modulated via an alternative mechanism.
Rare variants in BRCA2 and CHEK2 are associated with the risk of urinary tract cancers
Authors: Ge Yuqiu , Wang Yunyan , Shao Wei , Jin Jing , Du Mulong , Ma Gaoxiang , Chu Haiyan , Wang Meilin , Zhang Zhengdong
Published: September 2016

Previous studies have shown that two rare variants, rs11571833 in BRCA2 and rs17879961 in CHEK2 were associated with lung cancer. However, the associations between these two variants and urinary tract cancers risk remain largely unexplored. We applied imputation of three genome-wide association studies published in the database of Genotypes and Phenotypes (dbGaP). Unconditional logistic regression analysis and meta-analysis were performed to assess the association between these two variants and the risk of urinary tract cancers. Our results showed that rs11571833[T] had an effect on urinary tract cancers predisposition (ORmeta = 1.45, Pmeta = 0.013), especially associated with increased the risk of bladder cancer (ORmeta = 1.60, Pmeta = 0.010). Moreover, rs17879961[C] had a protective effect on the urinary tract cancers (ORmeta = 0.67, Pmeta = 1.0 × 10−3) and was mostly associated with a lower incidence of renal cell carcinoma (ORmeta = 0.51, Pmeta = 2.0 × 10−3). Together, our study indicates that BRCA2 and CHEK2 play an important role in the genetic susceptibility to urinary tract cancers.
Meta-analysis of associations between DLG5 R30Q and P1371Q polymorphisms and susceptibility to inflammatory bowel disease
Authors: Li Yunhai , Chen Ping , Sun Jiazheng , Huang Jing , Tie Hongtao , Li Liangliang , Li Hongzhong , Ren Guosheng
Published: September 2016

Growing evidence from recent studies has demonstrated an association between inflammatory bowel disease (IBD) susceptibility and two polymorphisms of DLG5 R30Q (rs1248696) and P1371Q (rs2289310), but the results remain controversial. We conducted a meta-analysis including a total of 22 studies with 10,878 IBD patients and 7917 healthy controls for R30Q and 5277 IBD cases and 4367 controls for P1371Q in order to systematically assess their association with the disease. The results indicated that R30Q was significantly associated with reduced susceptibility to IBD in Europeans by allelic and dominant comparisons, but not in overall population. No significant association was found between R30Q and Crohn’s disease (CD) or ulcerative colitis (UC). P1371Q was associated with increased risk of IBD in Europeans and Americans. On the contrary, a decreased risk of IBD was observed in Asian population for P1371Q. In disease subgroup analysis, we found that P1371Q was also significantly associated with CD, but this relationship was not present for UC. In conclusion, our results strongly suggest that the both polymorphisms of DLG5 are correlated with IBD susceptibility in an ethnic-specific manner. Additional well-designed studies with large and diverse cohorts are needed to further strengthen our findings.
Reprofiled anthelmintics abate hypervirulent stationary-phase Clostridium difficile
Authors: Gooyit Major , Janda Kim D.
Published: September 2016

Prolonged use of broad-spectrum antibiotics disrupts the indigenous gut microbiota, which consequently enables toxigenic Clostridium difficile species to proliferate and cause infection. The burden of C. difficile infections was exacerbated with the outbreak of hypervirulent strains that produce copious amounts of enterotoxins and spores. In recent past, membrane-active agents have generated a surge of interest due to their bactericidal property with a low propensity for resistance. In this study, we capitalized on the antimicrobial property and low oral bioavailability of salicylanilide anthelmintics (closantel, rafoxanide, niclosamide, oxyclozanide) to target the gut pathogen. By broth microdilution techniques, we determined the MIC values of the anthelmintics against 16 C. difficile isolates of defined PCR-ribotype. The anthelmintics broadly inhibited C. difficile growth in vitro via a membrane depolarization mechanism. Interestingly, the salicylanilides were bactericidal against logarithmic- and stationary-phase cultures of the BI/NAP1/027 strain 4118. The salicylanilides were poorly active against select gut commensals (Bacteroides, Bifidobacterium and Lactobacillus species) and were non-hemolytic and non-toxic to mammalian cell lines HepG2 and HEK 293T/17 within the range of their in vitro MICs and MBCs. The salicylanilide anthelmintics exhibit desirable properties for repositioning as anti-C. difficile agents.
Autophagy-related proteins are functionally active in human spermatozoa and may be involved in the regulation of cell survival and motility
Authors: Aparicio I. M. , Espino J. , Bejarano I. , Gallardo-Soler A. , Campo M. L. , Salido G. M. , Pariente J. A. , Peña F. J. , Tapia J. A.
Published: September 2016

Macroautophagy (hereafter autophagy) is an evolutionarily highly conserved cellular process that participates in the maintenance of intracellular homeostasis through the degradation of most long-lived proteins and entire organelles. Autophagy participates in some reproductive events; however, there are not reports regarding the role of autophagy in the regulation of sperm physiology. Hence, the aim of this study was to investigate whether autophagy-related proteins are present and functionally active in human spermatozoa. Proteins related to autophagy/mitophagy process (LC3, Atg5, Atg16, Beclin 1, p62, m-TOR, AMPKα 1/2 and PINK1) were present in human spermatozoa. LC3 colocalized with p62 in the middle piece of the spermatozoa. Autophagy activation induced a significant increase in motility and a decrease in PINK1, TOM20 expression and caspase 3/7 activation. In contrast, autophagy inhibition resulted in decreased motility, viability, ATP and intracellular calcium concentration whereas PINK1, TOM20 expression, AMPK phosphorylation and caspase 3/7 activation were significantly increased. In conclusion our results show that autophagy related proteins and upstream regulators are present and functional in human spermatozoa. Modification of mitochondrial proteins expression after autophagy activation/inhibition may be indicating that a specialized form of autophagy named mitophagy may be regulating sperm function such as motility and viability and may be cooperating with apoptosis.
High-throughput sialylation measurement using lectins on an Octet platform for clone screening
Authors: Jonnalagadda Kanvasri N. , Markely Lam Raga A. , Guan Bing , Alves Christina , Prajapati Shashi
Published: September 2016

A high-throughput method to quantify sialic acids was developed on a ForteBio Octet QK384 platform to support cell-line development.
Cu- and Pd-catalyzed Ullmann reaction on a hexagonal boron nitride layer
Authors: Zhao Wei , Dong Lei , Huang Chao , Win Zaw Myo , Lin Nian
Published: September 2016

This study demonstrates that Cu and Pd can efficiently activate Ullmann reactions on inert h-BN with two distinctive reaction paths.
Gold(i)-catalyzed C-glycosylation of glycosyl ortho-alkynylbenzoates: the role of the moisture sequestered by molecular sieves
Authors: Chen Xiaoping , Wang Qiaoling , Yu Biao
Published: September 2016

C-Glycosylation of glycosyl ortho-hexynylbenzoates with allyltrimethylsilane or silyl enol ethers could proceed smoothly under the catalysis of Ph3PAuNTf2, wherein the moisture sequestered by the molecular sieves ensured the gold(i)-catalytic cycle.
Osmotic pressures of lysozyme solutions from gas-like to crystal states
Authors: Pasquier Coralie , Beaufils Sylvie , Bouchoux Antoine , Rigault Sophie , Cabane Bernard , Lund Mikael , Lechevalier Valérie , Le Floch-Fouéré Cécile , Pasco Maryvonne , Pabœuf Gilles , Pérez Javier , Pezennec Stéphane
Published: September 2016

Osmotic pressures of lysozyme solutions at concentrations up to 850 g L−1show three regimes and a clear influence of ionic strength.
Charge compensation assisted enhancement of photoluminescence in combustion derived Li+ co-doped cubic ZrO2:Eu3+ nanophosphors
Authors: Prakashbabu D. , Ramalingam H. B. , Hari Krishna R. , Nagabhushana B. M. , Chandramohan R. , Shivakumara C. , Thirumalai J. , Thomas Tiju
Published: September 2016

Doping of a Eu3+ for a tetravalent ion (Zr4+ here) creates charge imbalance in the system that results in vacancies in the ZrO2 lattice. Here, charge compensation is achieved by replacement of one Zr4+ ion by a Eu3+ and a Li+.
Incorporating QM and solvation into docking for applications to GPCR targets
Authors: Kim Minsup , Cho Art E.
Published: September 2016

Solvation QM/MM docking for GPCR targets.
Transition path time distribution and the transition path free energy barrier
Authors: Pollak Eli
Published: September 2016

Free energy profile, showing why the transition path barrier is lower than the free energy of activation.
Maximizing ion current rectification in a bipolar conical nanopore fluidic diode using optimum junction location
Authors: Singh Kunwar Pal
Published: September 2016

The optimum location of junction z0m as a function of base diameter for different surface charge densities with data from a fitted equation.
Half-metallic YN2 monolayer: dual spin filtering, dual spin diode and spin Seebeck effects
Authors: Li Jie , Gao Guoying , Min Yi , Yao Kailun
Published: September 2016

The device based on the YN2 monolayer with dual spin filtering and dual spin diode effects.
Application of classical simulations for the computation of vibrational properties of free molecules
Authors: Tikhonov Denis S. , Sharapa Dmitry I. , Schwabedissen Jan , Rybkin Vladimir V.
Published: September 2016

In this study, we investigate the ability of classical molecular dynamics (MD) and Monte-Carlo (MC) simulations for modeling of the intramolecular vibrational motion.
An efficient and inexpensive water-oxidizing manganese-based oxide electrode
Authors: Najafpour Mohammad Mahdi , Hosseini Seyedeh Maedeh
Published: September 2016

A cheap and very simple method to synthesize an efficient water-oxidizing manganese-based oxide coated fluorine doped tin oxide electrode was reported.