bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilization of longitudinal ultrasound to quantify joint soft-tissue changes in a mouse model of posttraumatic osteoarthritis
Authors: Xu Hao , Bouta Echoe M , Wood Ronald W , Schwarz Edward M , Wang Yongjun , Xing Lianping
Published: June 2017

To assess the utility of longitudinal ultrasound (US) to quantify volumetric changes in joint soft tissues during the progression of posttraumatic osteoarthritis (PTOA) in mice, and validate the US results with histological findings. A longitudinal cohort of 3-month-old wild-type C57BL/6 male mice received the Hulth-Telhag surgical procedure on right knee to induce PTOA, and sham surgery on their left knee as control. US scans were performed on both knees before, 2, 4, 6, and 8 weeks post-surgery. Joint space volume and Power-Doppler (PD) volume were obtained from US images via Amira software. A parallel cross-sectional cohort of mice was killed at each US time point, and knee joints were subjected to histological analysis to obtain synovial soft-tissue area and OARSI scores. The correlation between US joint space volume and histological synovial soft-tissue area or OARSI score was assessed via linear regression analysis. US images indicated increased joint space volume in PTOA joints over time, which was associated with synovial inflammation and cartilage damage by histology. These changes started from 2 weeks post-surgery and gradually became more severe. No change was detected in sham joints. Increased joint space volume was significantly correlated with increased synovial soft-tissue area and the OARSI score (P<0.001). PD signal was detected in the joint space of PTOA joints at 6 weeks post-surgery, which was consistent with the location of blood vessels that stained positively for CD31 and alpha-smooth muscle actin in the synovium. This study indicates that US is a cost-effective longitudinal outcome measure of volumetric and vascular changes in joint soft tissues during PTOA progression in mice, which positively correlates with synovial inflammation and cartilage damage.
Cellular senescence drives age-dependent hepatic steatosis
Authors: Ogrodnik Mikolaj , Miwa Satomi , Tchkonia Tamar , Tiniakos Dina , Wilson Caroline L. , Lahat Albert , Day Christoper P. , Burt Alastair , Palmer Allyson , Anstee Quentin M. , Grellscheid Sushma Nagaraja , Hoeijmakers Jan H J. , Barnhoorn Sander , Mann Derek A. , Bird Thomas G. , Vermeij Wilbert P. , Kirkland James L. , Passos João F. , von Zglinicki Thomas , Jurk Diana
Published: June 2017

The incidence of non-alcoholic fatty liver disease (NAFLD) increases with age. Cellular senescence refers to a state of irreversible cell-cycle arrest combined with the secretion of proinflammatory cytokines and mitochondrial dysfunction. Senescent cells contribute to age-related tissue degeneration. Here we show that the accumulation of senescent cells promotes hepatic fat accumulation and steatosis. We report a close correlation between hepatic fat accumulation and markers of hepatocyte senescence. The elimination of senescent cells by suicide gene-meditated ablation of p16Ink4a-expressing senescent cells in INK-ATTAC mice or by treatment with a combination of the senolytic drugs dasatinib and quercetin (D+Q) reduces overall hepatic steatosis. Conversely, inducing hepatocyte senescence promotes fat accumulation in vitro and in vivo. Mechanistically, we show that mitochondria in senescent cells lose the ability to metabolize fatty acids efficiently. Our study demonstrates that cellular senescence drives hepatic steatosis and elimination of senescent cells may be a novel therapeutic strategy to reduce steatosis.
An ubiquitin-dependent balance between mitofusin turnover and fatty acids desaturation regulates mitochondrial fusion
Authors: Cavellini Laetitia , Meurisse Julie , Findinier Justin , Erpapazoglou Zoi , Belgareh-Touzé Naïma , Weissman Allan M. , Cohen Mickael M.
Published: June 2017

Mitochondrial integrity relies on homotypic fusion between adjacent outer membranes, which is mediated by large GTPases called mitofusins. The regulation of this process remains nonetheless elusive. Here, we report a crosstalk between the ubiquitin protease Ubp2 and the ubiquitin ligases Mdm30 and Rsp5 that modulates mitochondrial fusion. Ubp2 is an antagonist of Rsp5, which promotes synthesis of the fatty acids desaturase Ole1. We show that Ubp2 also counteracts Mdm30-mediated turnover of the yeast mitofusin Fzo1 and that Mdm30 targets Ubp2 for degradation thereby inducing Rsp5-mediated desaturation of fatty acids. Exogenous desaturated fatty acids inhibit Ubp2 degradation resulting in higher levels of Fzo1 and maintenance of efficient mitochondrial fusion. Our results demonstrate that the Mdm30-Ubp2-Rsp5 crosstalk regulates mitochondrial fusion by coordinating an intricate balance between Fzo1 turnover and the status of fatty acids saturation. This pathway may link outer membrane fusion to lipids homeostasis.
Reproductive fitness and genetic risk of psychiatric disorders in the general population
Authors: Mullins Niamh , Ingason Andrés , Porter Heather , Euesden Jack , Gillett Alexandra , Ólafsson Sigurgeir , Gudbjartsson Daniel F. , Lewis Cathryn M. , Sigurdsson Engilbert , Saemundsen Evald , Gudmundsson Ólafur Ó , Frigge Michael L. , Kong Augustine , Helgason Agnar , Walters G. Bragi , Gustafsson Omar , Stefansson Hreinn , Stefansson Kari
Published: June 2017

The persistence of common, heritable psychiatric disorders that reduce reproductive fitness is an evolutionary paradox. Here, we investigate the selection pressures on sequence variants that predispose to schizophrenia, autism, bipolar disorder, major depression and attention deficit hyperactivity disorder (ADHD) using genomic data from 150,656 Icelanders, excluding those diagnosed with these psychiatric diseases. Polygenic risk of autism and ADHD is associated with number of children. Higher polygenic risk of autism is associated with fewer children and older age at first child whereas higher polygenic risk of ADHD is associated with having more children. We find no evidence for a selective advantage of a high polygenic risk of schizophrenia or bipolar disorder. Rare copy-number variants conferring moderate to high risk of psychiatric illness are associated with having fewer children and are under stronger negative selection pressure than common sequence variants.
Bayesian inference of physiologically meaningful parameters from body sway measurements
Authors: Tietäväinen A. , Gutmann M. U. , Keski-Vakkuri E. , Corander J. , Hæggström E.
Published: June 2017

The control of the human body sway by the central nervous system, muscles, and conscious brain is of interest since body sway carries information about the physiological status of a person. Several models have been proposed to describe body sway in an upright standing position, however, due to the statistical intractability of the more realistic models, no formal parameter inference has previously been conducted and the expressive power of such models for real human subjects remains unknown. Using the latest advances in Bayesian statistical inference for intractable models, we fitted a nonlinear control model to posturographic measurements, and we showed that it can accurately predict the sway characteristics of both simulated and real subjects. Our method provides a full statistical characterization of the uncertainty related to all model parameters as quantified by posterior probability density functions, which is useful for comparisons across subjects and test settings. The ability to infer intractable control models from sensor data opens new possibilities for monitoring and predicting body status in health applications.
Circadian and circatidal clocks control the mechanism of semilunar foraging behaviour
Authors: Cheeseman James F. , Fewster Rachel M. , Walker Michael M.
Published: June 2017

How animals precisely time behaviour over the lunar cycle is a decades-old mystery. Experiments on diverse species show this behaviour to be endogenous and under clock control but the mechanism has remained elusive. We present new experimental and analytical techniques to test the hypotheses for the semilunar clock and show that the rhythm of foraging behaviour in the intertidal isopod, Scyphax ornatus, can be precisely shifted by manipulating the lengths of the light/dark and tidal cycles. Using light T-cycles (Tcd) the resultant semilunar beat period undergoes shifts from 14.79 days to 6.47 days under T = 23 hours (h), or to 23.29 days under T = 24.3 h. In tidal T-cycles (Tt) of natural length Tt = 12.42 h, the semilunar rhythm is shifted to 24.5 days under Tt = 12.25 h and to 9.7 days under Tt = 12.65 h. The implications of this finding go beyond our model species and illustrate that longer period rhythms can be generated by shorter period clocks. Our novel analysis, in which periodic spline models are embedded within randomization tests, creates a new methodology for assessing long-period rhythms in chronobiology. Applications are far-reaching and extend to other species and rhythms, potentially including the human-ovarian cycle.
Attention, cognitive control and motivation in ADHD: Linking event-related brain potentials and DNA methylation patterns in boys at early school age
Authors: Heinrich Hartmut , Grunitz Juliane , Stonawski Valeska , Frey Stefan , Wahl Simone , Albrecht Björn , Goecke Tamme W. , Beckmann Matthias W. , Kornhuber Johannes , Fasching Peter A. , Moll Gunther H. , Eichler Anna
Published: June 2017

In order to better understand the underpinnings of attention-deficit/hyperactivity disorder (ADHD), we targeted the relationship of attentional, cognitive control and motivational processes with DNA methylation patterns of 60 candidate genes in boys at early school age. Participants (6 to 8 years; N = 82) were selected from a German longitudinal cohort (FRANCES). ADHD-related behaviour was assessed via maternal ratings. Performance and event-related potential measures (inter alia Cue-P3 and Nogo-P3), which were recorded in a motivational go/nogo task, indicated diminished attentional orienting, reduced inhibitory response control and a larger motivational effect on performance in ADHD already at this relatively young age. Methylation patterns were analysed in buccal cell DNA with the Illumina HumanMethylation 450K array. For CpG sites at genes of the dopaminergic (COMT, ANKK1) and the neurotrophic (BDNF, NGFR) system, associations with the Nogo-P3 as well as ADHD symptom severity were found suggesting that these systems are involved in response control deficits in ADHD. Methylation effects related to both functional aspects and ADHD behaviour were also observed for DPP10 and TPH2. Epigenetic mechanisms may play a role in ADHD-associated deficits but findings need to be replicated in larger samples and are limited by the fact that only peripheral methylation could be considered.
SMYD3 Promotes Homologous Recombination via Regulation of H3K4-mediated Gene Expression
Authors: Chen Yun-Ju , Tsai Cheng-Hui , Wang Pin-Yu , Teng Shu-Chun
Published: June 2017

SMYD3 is a methyltransferase highly expressed in many types of cancer. It usually functions as an oncogenic protein to promote cell cycle, cell proliferation, and metastasis. Here, we show that SMYD3 modulates another hallmark of cancer, DNA repair, by stimulating transcription of genes involved in multiple steps of homologous recombination. Deficiency of SMYD3 induces DNA-damage hypersensitivity, decreases levels of repair foci, and leads to impairment of homologous recombination. Moreover, the regulation of homologous recombination-related genes is via the methylation of H3K4 at the target gene promoters. These data imply that, besides its reported oncogenic abilities, SMYD3 may maintain genome integrity by ensuring expression levels of HR proteins to cope with the high demand of restart of stalled replication forks in cancers.
Functional Evaluation of a Bioartificial Liver Support System Using Immobilized Hepatocyte Spheroids in a Porcine Model of Acute Liver Failure
Authors: Lee Ji-Hyun , Lee Doo-Hoon , Lee Sanghoon , Kwon Choon Hyuck David , Ryu Jae-Nam , Noh Jeong-Kwon , Jang In Keun , Park Hey-Jung , Yoon Hee-Hoon , Park Jung-Keug , Kim Young-Jin , Kim Sung-Koo , Lee Suk-Koo
Published: June 2017

Bioartificial livers (BAL) may offer acute liver failure (ALF) patients an opportunity for cure without liver transplantation. We evaluated the efficacy of a spheroid-based BAL system, containing aggregates of porcine hepatocytes, in a porcine model of ALF. ALF pigs were divided into three groups. The control group consisted of treatment naïve pigs (n = 5), blank group consisted of pigs that were attached to the BAL system not containing hepatocytes for 12 hours (n = 5) and BAL group consisted of pigs that were attached to the BAL containing hepatocytes for 12 hours (n = 5). Increase in serum ammonia levels were significantly greater in the blank group (P < 0.01) and control group (P < 0.01), compared to the BAL group during the treatment period. Increase in ICP was significantly greater in the control group compared to the BAL group (P = 0.01). Survival was significantly prolonged in the BAL group compared to the blank group (P = 0.03). A BAL system with a bioreactor containing hepatocyte spheroids showed effective clearance of serum ammonia, preservation of renal function and delayed ICP increase in a porcine model of ALF.
A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis
Authors: Ramirez-Busby S. M. , Rodwell T. C. , Fink L. , Catanzaro D. , Jackson R. L. , Pettigrove M. , Catanzaro A. , Valafar F.
Published: June 2017

Pyrazinamide (PZA) is an important first-line drug in all existing and new tuberculosis (TB) treatment regimens. PZA-resistance in M. tuberculosis is increasing, especially among M/XDR cases. Noted issues with PZA Drug Susceptibility Testing (DST) have driven the search for alternative tests. This study provides a comprehensive assessment of PZA molecular diagnostics in M/XDR TB cases. A set of 296, mostly XDR, clinical M. tuberculosis isolates from four countries were subjected to DST for eight drugs, confirmatory Wayne’s assay, and whole-genome sequencing. Three genes implicated in PZA resistance, pncA, rpsA, and panD were investigated. Assuming all non-synonymous mutations cause resistance, we report 90% sensitivity and 65% specificity for a pncA-based molecular test. The addition of rpsA and panD potentially provides 2% increase in sensitivity. Molecular heterogeneity in pncA was associated with resistance and should be evaluated as a diagnostic tool. Mutations near the N-terminus and C-terminus of PZase were associated with East-Asian and Euro-American lineages, respectively. Finally, Euro-American isolates are most likely to have a wild-type PZase and escape molecular detection. Overall, the 8–10% resistance without markers may point to alternative mechanisms of resistance. Confirmatory mutagenesis may improve the disconcertingly low specificity but reduce sensitivity since not all mutations may cause resistance.
The challenges of predicting pesticide exposure of honey bees at landscape level
Authors: Simon-Delso Noa , San Martin Gilles , Bruneau Etienne , Delcourt Christine , Hautier Louis
Published: June 2017

To evaluate the risks of pesticides for pollinators, we must not only evaluate their toxicity but also understand how pollinators are exposed to these xenobiotics in the field. We focused on this last point and modeled honey bee exposure to pesticides at the landscape level. Pollen pellet samples (n = 60) from 40 Belgian apiaries were collected from late July to October 2011 and underwent palynological and pesticide residue analyses. Areas of various crops around each apiary were measured at 4 spatial scales. The most frequently detected pesticides were the fungicides boscalid (n = 19, 31.7%) and pyrimethanil (n = 10, 16.7%) and the insecticide dimethoate (n = 10, 16.7%). We were able to predict exposure probability for boscalid and dimethoate by using broad indicators of cropping intensity, but it remained difficult to identify the precise source of contamination (e.g. specific crops in which the use of the pesticide is authorized). For pyrimethanil, we were not able to build any convincing landscape model that could explain the contamination. Our results, combined with the late sampling period, strongly suggest that pesticides applied to crops unattractive to pollinators, and therefore considered of no risk for them, may be sources of exposure through weeds, drift to neighboring plants, or succeeding crops.
Gut microbiota of liver transplantation recipients
Authors: Sun Li-Ying , Yang Yun-Sheng , Qu Wei , Zhu Zhi-Jun , Wei Lin , Ye Zhi-Sheng , Zhang Jian-Rui , Sun Xiao-Ye , Zeng Zhi-Gui
Published: June 2017

The characteristics of intestinal microbial communities may be affected by changes in the pathophysiology of patients with end-stage liver disease. Here, we focused on the characteristics of intestinal fecal microbial communities in post-liver transplantation (LT) patients in comparison with those in the same individuals pre-LT and in healthy individuals. The fecal microbial communities were analyzed via MiSeq-PE250 sequencing of the V4 region of 16S ribosomal RNA and were then compared between groups. We found that the gut microbiota of patients with severe liver disease who were awaiting LT was significantly different from that of healthy controls, as represented by the first principal component (p = 0.0066). Additionally, the second principal component represented a significant difference in the gut microbiota of patients between pre-LT and post-LT surgery (p = 0.03125). After LT, there was a significant decrease in the abundance of certain microbial species, such as Actinobacillus, Escherichia, and Shigella, and a significant increase in the abundance of other microbial species, such as Micromonosporaceae, Desulfobacterales, the Sarcina genus of Eubacteriaceae, and Akkermansia. Based on KEGG profiles, 15 functional modules were enriched and 21 functional modules were less represented in the post-LT samples compared with the pre-LT samples. Our study demonstrates that fecal microbial communities were significantly altered by LT.
C2238 ANP gene variant promotes increased platelet aggregation through the activation of Nox2 and the reduction of cAMP
Authors: Carnevale Roberto , Pignatelli Pasquale , Frati Giacomo , Nocella Cristina , Stanzione Rosita , Pastori Daniele , Marchitti Simona , Valenti Valentina , Santulli Maria , Barbato Emanuele , Strisciuglio Teresa , Schirone Leonardo , Vecchione Carmine , Violi Francesco , Volpe Massimo , Rubattu Speranza , Sciarretta Sebastiano
Published: June 2017

Subjects carrying the C2238 variant of the atrial natriuretic peptide (ANP) gene have a higher occurrence of stroke and acute coronary syndrome, suggesting an increased predisposition to acute thrombotic events in these subjects. We evaluated for the first time the direct effects of mutant ANP (C2238/αANP) on platelet activation in vitro and in human subjects. In vitro, platelets were incubated with no peptide, with T2238/αANP (WT) or with C2238/αANP at different concentrations. C2238/αANP (10−10 M) induced higher collagen-induced platelet aggregation with respect to both control without ANP and T2238/αANP. This effect was even stronger at a higher concentration (10−6 M). Mechanistically, C2238/αANP significantly lowered platelet cAMP levels, increased ROS production and activated Nox2, with respect to both control and T2238/αANP. Forskolin, a cAMP activator, and sNOX2-tat, a Nox2 inhibitor, significantly reduced the pro-aggregant effects of C2238/αANP. In vivo, we found that platelet aggregation resulted to be higher in patients with atrial fibrillation carrying the C2238 ANP gene variant with respect to non-carriers. In conclusions, C2238/αANP promotes platelet aggregation through the activation of Nox2 and the reduction of cAMP.
Marine diatoms change their gene expression profile when exposed to microscale turbulence under nutrient replete conditions
Authors: Amato Alberto , Dell’Aquila Gianluca , Musacchia Francesco , Annunziata Rossella , Ugarte Ari , Maillet Nicolas , Carbone Alessandra , Ribera d’Alcalà Maurizio , Sanges Remo , Iudicone Daniele , Ferrante Maria I.
Published: June 2017

Diatoms are a fundamental microalgal phylum that thrives in turbulent environments. Despite several experimental and numerical studies, if and how diatoms may profit from turbulence is still an open question. One of the leading arguments is that turbulence favours nutrient uptake. Morphological features, such as the absence of flagella, the presence of a rigid exoskeleton and the micrometre size would support the possible passive but beneficial role of turbulence on diatoms. We demonstrate that in fact diatoms actively respond to turbulence in non-limiting nutrient conditions. TURBOGEN, a prototypic instrument to generate natural levels of microscale turbulence, was used to expose diatoms to the mechanical stimulus. Differential expression analyses, coupled with microscopy inspections, enabled us to study the morphological and transcriptional response of Chaetoceros decipiens to turbulence. Our target species responds to turbulence by activating energy storage pathways like fatty acid biosynthesis and by modifying its cell chain spectrum. Two other ecologically important species were examined and the occurrence of a morphological response was confirmed. These results challenge the view of phytoplankton as unsophisticated passive organisms.
Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling
Authors: Kim Jieun , Hyun Jeongeun , Wang Sihyung , Lee Chanbin , Lee Jae-Wook , Moon Eun-Yi , Cha Heejae , Diehl Anna Mae , Jung Youngmi
Published: June 2017

The molecular mechanisms of thymosin beta-4 (TB4) involved in regulating hepatic stellate cell (HSC) functions remain unclear. Therefore, we hypothesize that TB4 influences HSC activation through hedgehog (Hh) pathway. HSC functions declined in a TB4 siRNA-treated LX-2. TB4 suppression down-regulated both integrin linked kinase (ILK), an activator of smoothened, and phosphorylated glycogen synthase kinase 3 beta (pGSK-3B), an inactive form of GSK-3B degrading glioblastoma 2 (GLI2), followed by the decreased expression of both smoothened and GLI2. A TB4 CRISPR also blocked the activation of primary HSCs, with decreased expression of smoothened, GLI2 and ILK compared with cells transfected with nontargeting control CRISPR. Double immunostaining and an immunoprecipitation assay revealed that TB4 interacted with either smoothened at the cytoplasm or GLI2 at the nucleus in LX-2. Smoothened suppression in primary HSCs using a Hh antagonist or adenovirus transduction decreased TB4 expression with the reduced activation of HSCs. Tb4-overexpressing transgenic mice treated with CCl4 were susceptible to the development hepatic fibrosis with higher levels of ILK, pGSK3b, and Hh activity, as compared with wild-type mice. These findings demonstrate that TB4 regulates HSC activation by influencing the activity of Smoothened and GLI2, suggesting TB4 as a novel therapeutic target in liver disease.
Ultrarapid Measurement of Diagnostic Antibodies by Magnetic Capture of Immune Complexes
Authors: Burbelo Peter D. , Gunti Sreenivasulu , Keller Jason M. , Morse Caryn G. , Deeks Steven G. , Lionakis Michail S. , Kapoor Amit , Li Qingxue , Cohen Jeffrey I. , Notkins Abner L. , Alevizos Ilias
Published: June 2017

Rapid point-of-care, antibody-based testing is not currently available for the diagnosis of most autoimmune and infectious diseases. Here we report a simple, robust and ultrafast fluid-phase immunocapture method for clinical measurements of antibody levels. This method employs neodymium magnetic sticks that capture protein A/G-coated paramagnetic beads bound to antibody-luciferase-labeled antigen complexes. We demonstrate the ability to effectively measure specific antibody levels in serum samples from patients with varied infectious or autoimmune disorders, and in the case of Sjögren’s syndrome directly in saliva, requiring about a minute per assay. We also show the feasibility of coupling this method with a hand-held luminometer for portable testing. Our method offers the potential to quickly diagnose a multitude of autoimmune and infectious diseases in point-of-care settings.
Nanoassembly routes stimulate conflicting antibody quantity and quality for transmission-blocking malaria vaccines
Authors: Leneghan Darren B. , Miura Kazutoyo , Taylor Iona J. , Li Yuanyuan , Jin Jing , Brune Karl D. , Bachmann Martin F. , Howarth Mark , Long Carole A. , Biswas Sumi
Published: June 2017

Vaccine development efforts have recently focused on enabling strong immune responses to poorly immunogenic antigens, via display on multimerisation scaffolds or virus like particles (VLPs). Typically such studies demonstrate improved antibody titer comparing monomeric and nano-arrayed antigen. There are many such studies and scaffold technologies, but minimal side-by-side evaluation of platforms for both the amount and efficacy of antibodies induced. Here we present direct comparison of three leading platforms displaying the promising malaria transmission-blocking vaccine (TBV) target Pfs25. These platforms encompass the three important routes to antigen-scaffold linkage: genetic fusion, chemical cross-linking and plug-and-display SpyTag/SpyCatcher conjugation. We demonstrate that chemically-conjugated Qβ VLPs elicited the highest quantity of antibodies, while SpyCatcher-AP205-VLPs elicited the highest quality anti-Pfs25 antibodies for transmission blocking upon mosquito feeding. These quantative and qualitative features will guide future nanoassembly optimisation, as well as the development of the new generation of malaria vaccines targeting transmission.
Identification and molecular characterization of non-polio enteroviruses from children with acute flaccid paralysis in West Africa, 2013–2014
Authors: Fernandez-Garcia Maria D. , Kebe Ousmane , Fall Aichatou D. , Ndiaye Kader
Published: June 2017

Besides polioviruses, non-polio enteroviruses (NPEVs) may also be associated with acute flaccid paralysis (AFP). Because poliomyelitis is on the verge of eradication, more attention should be paid to study NPEVs from non-polio AFP cases and their epidemic patterns. In West African countries the epidemiology of NPEVs remains largely unexplored. We investigated the genetic diversity, frequency, circulation patterns, and molecular epidemiology of NPEVs in seven West African countries by analyzing retrospectively a panel of 3195 stool samples from children with AFP collected through routine poliomyelitis surveillance activities between 2013 and 2014. VP1 sequencing and typing on 201 isolates revealed 39 NPEV types corresponding to EV-A (6.9%), EV-B (90.5%), EV-C (2%) and EV-D (0.5%) species. Echoviruses were isolated most frequently with 138 cases (68.6%), followed by coxsackievirus group B with 35 cases (17.4%). No single NPEV type was remarkably dominant. Interestingly, several rarely described types with limited detection worldwide were identified (EVA76, EVA119, EVB75, EVB77, EVB97, EVC99, CVA20, CVA21 and EVD94). This study demonstrates the extensive diversity and diverse circulation patterns of NPEVs from AFP surveillance and highlights the need to formulate effective long-term strategies to monitor NPEV circulations in West Africa.
Near-surface coherent structures explored by large eddy simulation of entire tropical cyclones
Authors: Ito Junshi , Oizumi Tsutao , Niino Hiroshi
Published: June 2017

Taking advantage of the huge computational power of a massive parallel supercomputer (K-supercomputer), this study conducts large eddy simulations of entire tropical cyclones by employing a numerical weather prediction model, and explores near-surface coherent structures. The maximum of the near-surface wind changes little from that simulated based on coarse-resolution runs. Three kinds of coherent structures appeared inside the boundary layer. The first is a Type-A roll, which is caused by an inflection-point instability of the radial flow and prevails outside the radius of maximum wind. The second is a Type-B roll that also appears to be caused by an inflection-point instability but of both radial and tangential winds. Its roll axis is almost orthogonal to the Type-A roll. The third is a Type-C roll, which occurs inside the radius of maximum wind and only near the surface. It transports horizontal momentum in an up-gradient sense and causes the largest gusts.
First Principles Theory of the hcp-fcc Phase Transition in Cobalt
Authors: Lizárraga Raquel , Pan Fan , Bergqvist Lars , Holmström Erik , Gercsi Zsolt , Vitos Levente
Published: June 2017

Identifying the forces that drive a phase transition is always challenging. The hcp-fcc phase transition that occurs in cobalt at ~700 K has not yet been fully understood, although early theoretical studies have suggested that magnetism plays a main role in the stabilization of the fcc phase at high temperatures. Here, we perform a first principles study of the free energies of these two phases, which we break into contributions arising from the vibration of the lattice, electronic and magnetic systems and volume expansion. Our analysis of the energy of the phases shows that magnetic effects alone cannot drive the fcc-hcp transition in Co and that the largest contribution to the stabilization of the fcc phase comes from the vibration of the ionic lattice. By including all the contributions to the free energy considered here we obtain a theoretical transition temperature of 825 K.
Spatio-temporal analysis of coding and long noncoding transcripts during maize endosperm development
Authors: Kim Eun-Deok , Xiong Yuqing , Pyo Youngjae , Kim Dong-Hwan , Kang Byung-Ho , Sung Sibum
Published: June 2017

The maize endosperm consists of three major compartmentalized cell types: the starchy endosperm (SE), the basal endosperm transfer cell layer (BETL), and the aleurone cell layer (AL). Differential genetic programs are activated in each cell type to construct functionally and structurally distinct cells. To compare gene expression patterns involved in maize endosperm cell differentiation, we isolated transcripts from cryo-dissected endosperm specimens enriched with BETL, AL, or SE at 8, 12, and 16 days after pollination (DAP). We performed transcriptome profiling of coding and long noncoding transcripts in the three cell types during differentiation and identified clusters of the transcripts exhibiting spatio-temporal specificities. Our analysis uncovered that the BETL at 12 DAP undergoes the most dynamic transcriptional regulation for both coding and long noncoding transcripts. In addition, our transcriptome analysis revealed spatio-temporal regulatory networks of transcription factors, imprinted genes, and loci marked with histone H3 trimethylated at lysine 27. Our study suggests that various regulatory mechanisms contribute to the genetic networks specific to the functions and structures of the cell types of the endosperm.
Phylogenetic analysis of F-bZIP transcription factors indicates conservation of the zinc deficiency response across land plants
Authors: Castro Pedro Humberto , Lilay Grmay H. , Muñoz-Mérida Antonio , Schjoerring Jan K. , Azevedo Herlânder , Assunção Ana G. L.
Published: June 2017

Basic leucine zipper (bZIP) transcription factors control important developmental and physiological processes in plants. InArabidopsis thaliana, the three gene F-bZIP subfamily has been associated with zinc deficiency and salt stress response. Benefiting from the present abundance of plant genomic data, we performed an evolutionary and structural characterization of plant F-bZIPs. We observed divergence during seed plant evolution, into two groups and inferred different selective pressures for each. Group 1 contains AtbZIP19 and AtbZIP23 and appears more conserved, whereas Group 2, containing AtbZIP24, is more prone to gene loss and expansion events. Transcriptomic and experimental data reinforced AtbZIP19/23 as pivotal regulators of the zinc deficiency response, mostly via the activation of genes from the ZIP metal transporter family, and revealed that they are the main regulatory switch ofAtZIP4. A survey ofAtZIP4orthologs promoters across different plant taxa revealed an enrichment of theZinc Deficiency Response Element(ZDRE) to which both AtbZIP19/23 bind. Overall, our results indicate that while the AtbZIP24 function in the regulation of the salt stress response may be the result of neo-functionalization, the AtbZIP19/23 function in the regulation of the zinc deficiency response may be conserved in land plants (Embryophytes).
Computational method allowing Hydrogen-Deuterium Exchange Mass Spectrometry at single amide Resolution
Authors: Gessner Chris , Steinchen Wieland , Bédard Sabrina , J. Skinner John , Woods Virgil L. , Walsh Thomas J. , Bange Gert , Pantazatos Dionysios P.
Published: June 2017

Hydrogen-deuterium exchange (HDX) coupled with mass spectrometry (HDXMS) is a rapid and effective method for localizing and determining protein stability and dynamics. Localization is routinely limited to a peptide resolution of 5 to 20 amino acid residues. HDXMS data can contain information beyond that needed for defining protein stability at single amide resolution. Here we present a method for extracting this information from an HDX dataset to generate a HDXMS protein stability fingerprint. High resolution (HR)-HDXMS was applied to the analysis of a model protein of a spectrin tandem repeat that exemplified an intuitive stability profile based on the linkage of two triple helical repeats connected by a helical linker. The fingerprint recapitulated expected stability maximums and minimums with interesting structural features that corroborate proposed mechanisms of spectrin flexibility and elasticity. HR-HDXMS provides the unprecedented ability to accurately assess protein stability at the resolution of a single amino acid. The determination of HDX stability fingerprints may be broadly applicable in many applications for understanding protein structure and function as well as protein ligand interactions.
RETRACTED ARTICLE: New molecular tools in Neospora caninum for studying apicomplexan parasite proteins
Authors: Mota Caroline M. , Chen Allan L. , Wang Kevin , Nadipuram Santhosh , Vashisht Ajay A. , Wohlschlegel James A. , Mineo Tiago W. P. , Bradley Peter J.
Published: June 2017

The development of molecular genetics has greatly enhanced the study of the biology and pathology associated with parasites of the phylum Apicomplexa. We have established a system specifically designed for Neospora caninum, and used this system as a heterologous platform for the expression of foreign genes. Plasmid constructs containing fluorescent proteins or targeted genes of Toxoplasma gondii, driven by N. caninum promoters, have yielded robust expression and correct trafficking of target gene products as assessed by immunofluorescence assays and Western blot analyses. Using this approach, we here demonstrated that N. caninum expressing T. gondii’s GRA15 and ROP16 kinase are biologically active and induced immunological phenotypes consistent with T. gondii strains. N. caninum expressing TgGRA15 differentially disturbed the NF-κB pathway, inducing an increased IL-12 production. On the other hand, N. caninum expressing TgROP16 induced host STAT3 phosphorylation and consequent reduction of IL-12 synthesis. These results indicate that heterologous gene expression in N. caninum is a useful tool for the study of specific gene functions and may allow the identification of antigenic targets responsible for the phenotypic differences observed between these two closely related apicomplexan parasites. Additionally, these observations may prove to be useful for the development of vaccine protocols to control toxoplasmosis and/or neosporosis.
Role of methionine adenosyltransferase 2A in bovine preimplantation development and its associated genomic regions
Authors: Ikeda Shuntaro , Kawahara-Miki Ryouka , Iwata Hisataka , Sugimoto Miki , Kume Shinichi
Published: June 2017

Methionine adenosyltransferase (MAT) is involved in folate-mediated one-carbon metabolism, which is essential for preimplantation embryos in terms of both short-term periconceptional development and long-term phenotypic programming beyond the periconceptional period. Here, our immunofluorescence analysis of bovine oocytes and preimplantation embryos revealed the consistent expression of MAT2A (the catalytic subunit of the ubiquitously expressed-type of MAT isozyme) during this period. Addition of the MAT2A inhibitor FIDAS to the culture media of bovine preimplantation embryos reduced their blastocyst development, revealing the particular importance of MAT2A in successful blastocyst development. Exploration of MAT2A-associated genomic regions in bovine blastocysts using chromatin immunoprecipitation and sequencing (ChIP-seq) identified candidate MAT2A-associated genes implicated not only in short-term periconceptional embryo development, but also in long-term phenotypic programming during this period in terms of growth, metabolism, and immune functions. These results suggest the critical involvement of MAT2A in the periconceptional period in life-long programming of health and disease as well as successful preimplantation development.
Nuclear accumulation of symplekin promotes cellular proliferation and dedifferentiation in an ERK1/2-dependent manner
Authors: Zhang Chen , Mao Hai-Lei , Cao Yi
Published: June 2017

Symplekin is a multifunctional protein that localizes to both tight junctions and the nucleus in polarized epithelial cells, with confirmed roles in mRNA maturation, transcriptional modulation and tight-junction assembly. However, the mechanisms governing its subcellular distribution and related functions remain unclear. In this study, we found that symplekin primarily localizes to the nuclei of cultured dedifferentiated colorectal cancer cells, and nuclear symplekin showed higher phosphorylation and binding affinity with YBX3 than its membrane fraction. Moreover, the accumulation of nuclear symplekin promoted cell proliferation and dedifferentiation as well as β-catenin transactivation in vitro. Nuclear symplekin acts as a transcriptional co-activator for the expression of many cell cycle-related genes. Furthermore, extracellular signal-regulated kinase (ERK) phosphorylated symplekin at T1257 to facilitate its nuclear accumulation upon epidermal growth factor (EGF) stimulation. Meanwhile, reduction of total symplekin also induced certain epithelial-mesenchymal transition features in HT-29 cells. Taken together, our results confirm the coordinated roles of symplekin in cell junctions and gene transcription, which are related to its subcellular localization. The significance of nuclear symplekin in tumorigenesis is also highlighted, and ERK-dependent phosphorylation represents a mechanism for its subcellular sorting.
Integrated optical modulator manipulating the polarization and rotation handedness of Orbital Angular Momentum states
Authors: Mousavi S. Faezeh , Nouroozi Rahman , Vallone Giuseppe , Villoresi Paolo
Published: June 2017

Recent studies demonstrated that the optical channels encoded by Orbital Angular Momentum (OAM) are capable candidates for improving the next generation of communication systems. OAM states can enhance the capacity and security of high-dimensional communication channels in both classical and quantum regimes based on optical fibre and free space. Hence, fast and precise control of the beams encoded by OAM can provide their commercial applications in the compatible communication networks. Integrated optical devices are good miniaturized options to perform this issue. This paper proposes a numerically verified integrated high-frequency electro-optical modulator for manipulation of the guided modes encoded in both OAM and polarization states. The proposed modulator is designed as an electro-optically active Lithium Niobate (LN) core photonic wire with silica as its cladding in a LN on Insulator (LNOI) configuration. It consists of two successive parts; a phase shifter to reverse the rotation handedness of the input OAM state and a polarization converter to change the horizontally polarized OAM state to the vertically polarized one. It is shown that all four possible output polarization-OAM encoded states can be achieved with only 6 V and 7 V applied voltages to the electrodes in the two parts of the modulator.
Pyroptosis, superinfection, and the maintenance of the latent reservoir in HIV-1 infection
Authors: Wodarz Dominik , Levy David N.
Published: June 2017

A long-lived reservoir of latently infected T cells prevents antiretroviral therapy from eliminating HIV-1 infection. Furthering our understanding of the dynamics of latency generation and maintenance is therefore vital to improve treatment outcome. Using mathematical models and experiments, we suggest that the death of latently infected cells brought about by pyroptosis, or to a lesser extent by superinfection, might be key mechanisms to account for the size and composition of the latent reservoir. Pyroptosis is a form of cell death that occurs in a resting (and thus latently infected) T cell when a productively infected cell attempts cell-to-cell transmission of virus. Superinfection of latently infected cells by productive virus could similarly remove those cells through active virus replication and resulting cytopathicity. The mathematical models presented can explain a number of previously published clinical observations including latent reservoir size and the relationships to viral load in acute HIV infection, measurements of the latent reservoir in chronic infection, and the replacement of wild-type virus by CTL escape mutants within the latent reservoir. Basic virus dynamics models of latency that do not take into account pyroptosis, superinfection, or other potential complexities cannot account for the data.
Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors
Authors: Hao Yongjia , Lyu Jiankun , Qu Rong , Sun Deheng , Zhao Zhenjiang , Chen Zhuo , Ding Jian , Xie Hua , Xu Yufang , Li Honglin
Published: June 2017

Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFRL858R/T790M (H1975 cell lines) over EGFRWT (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFRL858R/T790M. These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer.
IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection
Authors: Sung Pil Soo , Hong Seon-Hui , Chung Jae-Hee , Kim Sojeong , Park Su-Hyung , Kim Ho Min , Yoon Seung Kew , Shin Eui-Cheol
Published: June 2017

Genetic polymorphisms in IFNL4 have been shown to predict responses to IFN-α-based therapy in hepatitis C virus (HCV)-infected patients. The IFNL4-ΔG genotype, which encodes functional IFN-λ4 protein, is associated with a poor treatment response. In the present study, we investigated the induction and biological effects of IFN-λ4 in HCV-infected hepatocytes and their association with responsiveness to IFN-α. We also studied the effects of direct-acting antiviral (DAA) treatment on IFN-λ4 expression and IFN-α responsiveness. HCV infection induced IFN-λ4 expression at mRNA and protein levels in primary human hepatocytes (PHHs). In hepatoma cells, IFNL4 gene transfection or recombinant IFN-λ4 protein treatment robustly increased the protein levels of ISG15 and USP18 in an IFNLR1-dependent manner and potently blocked IFN-α signalling. The ISG15/USP18-mediated IFN-α unresponsiveness was demonstrated by transfection of siRNAs targeting ISG15 and/or USP18. This potent IFN-λ4 effect was related to prolonged ISG expression after IFNL4 gene transfection. DAA treatment of HCV-infected PHHs reduced the expression of IFN-λs, including IFN-λ4, and restored IFN-α responsiveness. These results demonstrate that virus-induced IFN-λ4 potently blocks IFN-α signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-α responsiveness in HCV-infected cells.
Down-regulation of KCa2.3 channels causes erectile dysfunction in mice
Authors: Comerma-Steffensen Simon , Kun Attila , Hedegaard Elise R. , Mogensen Susie , Aalkjaer Christian , Köhler Ralf , Mønster Christensen Birgitte , Simonsen Ulf
Published: June 2017

Modulation of endothelial calcium-activated K+ channels has been proposed as an approach to restore arterial endothelial cell function in disease. We hypothesized that small-conductance calcium-activated K+ channels (KCa2.3 or SK3) contributes to erectile function. The research was performed in transgenic mice with overexpression (KCa2.3
T/T(−Dox)) or down-regulation (KCa2.3
T/T(+Dox)) of the KCa2.3 channels and wild-type C57BL/6-mice (WT). QPCR revealed that KCa2.3 and KCa1.1 channels were the most abundant in mouse corpus cavernosum. KCa2.3 channels were found by immunoreactivity and electron microscopy in the apical-lateral membrane of endothelial cells in the corpus cavernosum. Norepinephrine contraction was enhanced in the corpus cavernosum of KCa2.3
T/T(+Dox)versus KCa2.3
T/T(−Dox) mice, while acetylcholine relaxation was only reduced at 0.3 µM and relaxations in response to the nitric oxide donor sodium nitroprusside were unaltered. An opener of KCa2 channels, NS309 induced concentration-dependent relaxations of corpus cavernosum. Mean arterial pressure was lower in KCa2.3
T/T(−Dox) mice compared with WT and KCa2.3
T/T(+Dox) mice. In anesthetized mice, cavernous nerve stimulation augmented in frequency/voltage dependent manner erectile function being lower in KCa2.3
T/T(+Dox) mice at low frequencies. Our findings suggest that down-regulation of KCa2.3 channels contributes to erectile dysfunction, and that pharmacological activation of KCa2.3 channels may have the potential to restore erectile function.
Concurrent talking in immersive virtual reality: on the dominance of visual speech cues
Authors: Gonzalez-Franco Mar , Maselli Antonella , Florencio Dinei , Smolyanskiy Nikolai , Zhang Zhengyou
Published: June 2017

Humans are good at selectively listening to specific target conversations, even in the presence of multiple concurrent speakers. In our research, we study how auditory-visual cues modulate this selective listening. We do so by using immersive Virtual Reality technologies with spatialized audio. Exposing 32 participants to an Information Masking Task with concurrent speakers, we find significantly more errors in the decision-making processes triggered by asynchronous audiovisual speech cues. More precisely, the results show that lips on the Target speaker matched to a secondary (Mask) speaker’s audio severely increase the participants’ comprehension error rates. In a control experiment (n = 20), we further explore the influences of the visual modality over auditory selective attention. The results show a dominance of visual-speech cues, which effectively turn the Mask into the Target and vice-versa. These results reveal a disruption of selective attention that is triggered by bottom-up multisensory integration. The findings are framed in the sensory perception and cognitive neuroscience theories. The VR setup is validated by replicating previous results in this literature in a supplementary experiment.