bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis
Authors: Velthorst Eva , Froudist-Walsh Sean , Stahl Eli , Ruderfer Douglas , Ivanov Ilyan , Buxbaum Joseph ,   iPSYCH-Broad ASD Group, the IMAGEN consortium, Børglum Anders D. , Grove Jakob , Mattheisen Manuel , Werge Thomas , Mortensen Preben Bo , Pedersen Marianne Giørtz , Pedersen Carsten Bøcker , Mors Ole , Nordentoft Merete , Hougaard David M. , Bybjerg-Grauholm Jonas , Bækvad-Hansen Marie , Hansen Christine Søholm , Daly Mark J. , Neale Benjamin M. , Robinson Elise B , Cerrato Felecia , Dumont Ashley , Goldstein Jacqueline , Stevens Christine , Walters Raymond , Churchhouse Claire , Ripke Stephan , Martin Joanna , Banaschewski Tobias , Bokde Arun L. W. , Dipl-Psych Uli Bromberg , Büchel Christian , Quinlan Erin Burke , Desrivières Sylvane , Flor Herta , Frouin Vincent , Garavan Hugh , Gowland Penny , Heinz Andreas , Ittermann Bernd , Martinot Marie-Laure Paillère , Artiges Eric , Nees Frauke , Orfanos Dimitri Papadopoulos , Paus Tomáš , Poustka Luise , Hohmann Sarah , Fröhner Juliane H. , Smolka Michael N. , Walter Henrik , Whelan Robert , Schumann Gunter , Reichenberg Abraham
Published: September 2018

While psychotic experiences (PEs) are assumed to represent psychosis liability, general population studies have not been able to establish significant associations between polygenic risk scores (PRS) and PEs. Previous work suggests that PEs may only represent significant risk when accompanied by social impairment. Leveraging data from the large longitudinal IMAGEN cohort, including 2096 14-year old adolescents that were followed-up to age 18, we tested whether the association between polygenic risk and PEs is mediated by (increasing) impairments in social functioning and social cognitive processes. Using structural equation modeling (SEM) for the subset of participants (n = 643) with complete baseline and follow-up data, we examined pathways to PEs. We found that high polygenic risk for schizophrenia (p = 0.014), reduced brain activity to emotional stimuli (p = 0.009) and social impairments in late adolescence (p < 0.001; controlling for functioning in early adolescence) each independently contributed to the severity of PEs at age 18. The pathway between polygenic risk for autism spectrum disorder and PEs was mediated by social impairments in late adolescence (indirect pathway; p = 0.025). These findings point to multiple direct and indirect pathways to PEs, suggesting that different processes are in play, depending on genetic loading, and environment. Our results suggest that treatments targeting prevention of social impairment may be particularly promising for individuals at genetic risk for autism in order to minimize risk for psychosis.
A pharmacological probe identifies cystathionine β-synthase as a new negative regulator for ferroptosis
Authors: Wang Li , Cai Hao , Hu Youtian , Liu Fan , Huang Shengshuo , Zhou Yueyang , Yu Jing , Xu Jinyi , Wu Fang
Published: September 2018

Cystathionine β-synthase (CBS) is responsible for the first enzymatic reaction in the transsulfuration pathway of sulfur amino acids. The molecular function and mechanism of CBS as well as that of transsulfuration pathway remain ill-defined in cell proliferation and death. In the present study, we designed, synthesized and obtained a bioactive inhibitor CH004 for human CBS, which functions in vitro and in vivo. CH004 inhibits CBS activity, elevated the cellular homocysteine and suppressed the production of hydrogen sulfide in a dose-dependent manner in cells or in vivo. Chemical or genetic inhibition of CBS demonstrates that endogenous CBS is closely coupled with cell proliferation and cell cycle. Moreover, CH004 substantially retarded in vivo tumor growth in a xenograft mice model of liver cancer. Importantly, inhibition of CBS triggers ferroptosis in hepatocellular carcinoma. Overall, the study provides several clues for studying the interplays amongst transsulfuration pathway, ferroptosis and liver cancer.
Inhibition of glioblastoma cell proliferation, invasion, and mechanism of action of a novel hydroxamic acid hybrid molecule
Authors: Zhang Issan , Beus Maja , Stochaj Ursula , Le Phuong Uyen , Zorc Branka , Rajić Zrinka , Petrecca Kevin , Maysinger Dusica
Published: September 2018

Glioblastoma multiforme is one of the most aggressive brain tumors and current therapies with temozolomide or suberoylanilide hydroxamic acid (SAHA, vorinostat) show considerable limitations. SAHA is a histone deacetylase (HDAC) inhibitor that can cause undesirable side effects due to the lack of selectivity. We show here properties of a novel hybrid molecule, sahaquine, which selectively inhibits cytoplasmic HDAC6 at nanomolar concentrations without markedly suppressing class I HDACs. Inhibition of HDAC6 leads to significant α-tubulin acetylation, thereby impairing cytoskeletal organization in glioblastoma cells. The primaquine moiety of sahaquine reduced the activity of P-glycoprotein, which contributes to glioblastoma multiforme drug resistance. We propose the mechanism of action of sahaquine to implicate HDAC6 inhibition together with suppression of epidermal growth factor receptor and downstream kinase activity, which are prominent therapeutic targets in glioblastoma multiforme. Sahaquine significantly reduces the viability and invasiveness of glioblastoma tumoroids, as well as brain tumor stem cells, which are key to tumor survival and recurrence. These effects are augmented with the combination of sahaquine with temozolomide, the natural compound quercetin or buthionine sulfoximine, an inhibitor of glutathione biosynthesis. Thus, a combination of agents disrupting glioblastoma and brain tumor stem cell homeostasis provides an effective anti–cancer intervention.
Patchwork of contrasting medication cultures across the USA
Authors: Melamed Rachel D. , Rzhetsky Andrey
Published: September 2018

Health in the United States is markedly heterogeneous, with large disparities in disease incidence, treatment choices and health spending. Drug prescription is one major component of health care—reflecting the accuracy of diagnosis, the adherence to evidence-based guidelines, susceptibility to drug marketing and regulatory factors. Using medical claims data covering nearly half of the USA population, we have developed and validated a framework to compare prescription rates of 600 popular drugs in 2334 counties. Our approach uncovers geographically separated sub-Americas, where patients receive treatment for different diseases, and where physicians choose different drugs for the same disease. The geographical variation suggests influences of racial composition, state-level health care laws and wealth. Some regions consistently prefer more expensive drugs, even when they have not been proven more efficacious than cheaper alternatives. Our study underlines the benefit of aggregating massive information on medical practice into a summarized and actionable form.
A hierarchical anti-Hebbian network model for the formation of spatial cells in three-dimensional space
Authors: Soman Karthik , Chakravarthy Srinivasa , Yartsev Michael M.
Published: September 2018

Three-dimensional (3D) spatial cells in the mammalian hippocampal formation are believed to support the existence of 3D cognitive maps. Modeling studies are crucial to comprehend the neural principles governing the formation of these maps, yet to date very few have addressed this topic in 3D space. Here we present a hierarchical network model for the formation of 3D spatial cells using anti-Hebbian network. Built on empirical data, the model accounts for the natural emergence of 3D place, border, and grid cells, as well as a new type of previously undescribed spatial cell type which we call plane cells. It further explains the plausible reason behind the place and grid-cell anisotropic coding that has been observed in rodents and the potential discrepancy with the predicted periodic coding during 3D volumetric navigation. Lastly, it provides evidence for the importance of unsupervised learning rules in guiding the formation of higher-dimensional cognitive maps.
Safety and efficacy of novel malaria vaccine regimens of RTS,S/AS01B alone, or with concomitant ChAd63-MVA-vectored vaccines expressing ME-TRAP
Authors: Rampling Tommy , Ewer Katie J. , Bowyer Georgina , Edwards Nick J. , Wright Danny , Sridhar Saranya , Payne Ruth , Powlson Jonathan , Bliss Carly , Venkatraman Navin , Poulton Ian D. , de Graaf Hans , Gbesemete Diane , Grobbelaar Amy , Davies Huw , Roberts Rachel , Angus Brian , Ivinson Karen , Weltzin Rich , Rajkumar Bebi-Yassin , Wille-Reece Ulrike , Lee Cynthia , Ockenhouse Chris , Sinden Robert E. , Gerry Stephen C. , Lawrie Alison M. , Vekemans Johan , Morelle Danielle , Lievens Marc , Ballou Ripley W. , Lewis David J. M. , Cooke Graham S. , Faust Saul N. , Gilbert Sarah , Hill Adrian V. S
Published: September 2018

We assessed a combination multi-stage malaria vaccine schedule in which RTS,S/AS01B was given concomitantly with viral vectors expressing multiple-epitope thrombospondin-related adhesion protein (ME-TRAP) in a 0-month, 1-month, and 2-month schedule. RTS,S/AS01B was given as either three full doses or with a fractional (1/5th) third dose. Efficacy was assessed by controlled human malaria infection (CHMI). Safety and immunogenicity of the vaccine regimen was also assessed. Forty-one malaria-naive adults received RTS,S/AS01B at 0, 4 and 8 weeks, either alone (Groups 1 and 2) or with ChAd63 ME-TRAP at week 0, and modified vaccinia Ankara (MVA) ME-TRAP at weeks 4 and 8 (Groups 3 and 4). Groups 2 and 4 received a fractional (1/5th) dose of RTS,S/AS01B at week 8. CHMI was delivered by mosquito bite 11 weeks after first vaccination. Vaccine efficacy was 6/8 (75%), 8/9 (88.9%), 6/10 (60%), and 5/9 (55.6%) of subjects in Groups 1, 2, 3, and 4, respectively. Immunological analysis indicated significant reductions in anti-circumsporozoite protein antibodies and TRAP-specific T cells at CHMI in the combination vaccine groups. This reduced immunogenicity was only observed after concomitant administration of the third dose of RTS,S/AS01B with the second dose of MVA ME-TRAP. The second dose of the MVA vector with a four-week interval caused significantly higher anti-vector immunity than the first and may have been the cause of immunological interference. Co-administration of ChAd63/MVA ME-TRAP with RTS,S/AS01B led to reduced immunogenicity and efficacy, indicating the need for evaluation of alternative schedules or immunization sites in attempts to generate optimal efficacy.
Renoprotective effect of Zhenwu decoction against renal fibrosis by regulation of oxidative damage and energy metabolism disorder
Authors: Li Shasha , Xiao Xue , Han Ling , Wang Yiming , Luo Guoan
Published: September 2018

Zhenwu decoction (ZWD) is a promising traditional Chinese prescription against renal fibrosis, while its underlying mechanism remains unclear. Rat model of renal fibrosis were established and divided into control group, model group, ZWD treatment group and enalapril maleate treatment group. Metabolic profiles on serum samples from each group were acquired by using ultra performance liquid chromatography coupled with quadrupole time-of-flight high-resolution mass spectrometry. Metabolomics combined with molecular biology were comparatively conducted on samples of various groups. Fifteen potential biomarkers were identified and these biomarkers are mainly phospholipids and fatty acids. The results showed renal fibrosis was associated with oxidative damage and energy metabolism disorder. The results of histopathology, biochemistry and metabolomics demonstrated that ZWD exhibited an efficient renoprotective effect by alleviating oxidative stress, increasing energy metabolism and regulating fibrotic cytokines. This study provided scientific support for the research and development of new drugs from traditional Chinese medicine.
Permissiveness to form pluripotent stem cells may be an evolutionarily derived characteristic in Mus musculus
Authors: Garbutt Tiffany A. , Konneker Thomas I. , Konganti Kranti , Hillhouse Andrew E. , Swift-Haire Francis , Jones Alexis , Phelps Drake , Aylor David L. , Threadgill David W.
Published: September 2018

Mus musculus is the only known species from which embryonic stem cells (ESC) can be isolated under conditions requiring only leukemia inhibitory factor (LIF). Other species are non-permissive in LIF media, and form developmentally primed epiblast stem cells (EpiSC) similar to cells derived from post-implantation, egg cylinders. To evaluate whether non-permissiveness extends to induced pluripotent stem cells (iPSC), we derived iPSC from the eight founder strains of the mouse Collaborative Cross. Two strains, NOD/ShiLtJ and the WSB/EiJ, were non-permissive, consistent with the previous classification of NOD/ShiLtJ as non-permissive to ESC derivation. We determined non-permissiveness is recessive, and that non-permissive genomes do not compliment. We overcame iPSC non-permissiveness by using GSK3B and MEK inhibitors with serum, a technique we termed 2iS reprogramming. Although used for ESC derivation, GSK3B and MEK inhibitors have not been used during iPSC reprogramming because they inhibit survival of progenitor differentiated cells. iPSC derived in 2iS are more transcriptionally similar to ESC than EpiSC, indicating that 2iS reprogramming acts to overcome genetic background constraints. Finally, of species tested for ESC or iPSC derivation, only some M. musculus strains are permissive under LIF culture conditions suggesting that this is an evolutionarily derived characteristic in the M. musculus lineage.
Authenticity and geographic origin of global honeys determined using carbon isotope ratios and trace elements
Authors: Zhou Xiaoteng , Taylor Mark Patrick , Salouros Helen , Prasad Shiva
Published: September 2018

Honey is the world’s third most adulterated food. The addition of cane sugar or corn syrup and the mislabelling of geographic origin are common fraudulent practices in honey markets. This study examined 100 honey samples from Australia (mainland and Tasmania) along with 18 other countries covering Africa, Asia, Europe, North America and Oceania. Carbon isotopic analyses of honey and protein showed that 27% of commercial honey samples tested were of questionable authenticity. The remaining 69 authentic samples were subject to trace element analysis for geographic determination. One-way ANOVA analysis showed a statistical difference (p < 0.05) in trace element concentrations of honey from Australian regions and different continents. Principal component analysis (PCA) and canonical discriminant analysis (CDA) coupled with C5.0 classification modelling of honey carbon isotopes and trace element concentrations showed distinct clusters according to their geographic origin. The C5.0 model revealed trace elements Sr, P, Mn and K can be used to differentiate honey according to its geographic origin. The findings show the common and prevalent issues of honey authenticity and the mislabelling of its geographic origin can be identified using a combination of stable carbon isotopes and trace element concentrations.
Polystyrene microplastics increase microbial release of marine Chromophoric Dissolved Organic Matter in microcosm experiments
Authors: Galgani Luisa , Engel Anja , Rossi Claudio , Donati Alessandro , Loiselle Steven A.
Published: September 2018

About 5 trillion plastic particles are present in our oceans, from the macro to the micro size. Like any other aquatic particulate, plastics and microplastics can create a micro-environment, within which microbial and chemical conditions differ significantly from the surrounding water. Despite the high and increasing abundance of microplastics in the ocean, their influence on the transformation and composition of marine organic matter is largely unknown. Chromophoric dissolved organic matter (CDOM) is the photo-reactive fraction of the marine dissolved organic matter (DOM) pool. Changes in CDOM quality and quantity have impacts on marine microbial dynamics and the underwater light environment. One major source of CDOM is produced by marine bacteria through their alteration of pre-existing DOM substrates. In a series of microcosm experiments in controlled marine conditions, we explored the impact of microplastics on the quality and quantity of microbial CDOM. In the presence of microplastics we observed an increased production of CDOM with changes in its molecular weight, which resulted from either an increased microbial CDOM production or an enhanced transformation of DOM from lower to higher molecular weight CDOM. Our results point to the possibility that marine microplastics act as localized hot spots for microbial activity, with the potential to influence marine carbon dynamics.
Human and mouse albumin bind their respective neonatal Fc receptors differently
Authors: Nilsen Jeannette , Bern Malin , Sand Kine Marita Knudsen , Grevys Algirdas , Dalhus Bjørn , Sandlie Inger , Andersen Jan Terje
Published: September 2018

Albumin has a serum half-life of three weeks in humans and is utilized to extend the serum persistence of drugs that are genetically fused or conjugated directly to albumin or albumin-binding molecules. Responsible for the long half-life is FcRn that protects albumin from intracellular degradation. An in-depth understanding of how FcRn binds albumin across species is of importance for design and evaluation of albumin-based therapeutics. Albumin consists of three homologous domains where domain I and domain III of human albumin are crucial for binding to human FcRn. Here, we show that swapping of two loops in domain I or the whole domain with the corresponding sequence in mouse albumin results in reduced binding to human FcRn. In contrast, humanizing domain I of mouse albumin improves binding. We reveal that domain I of mouse albumin plays a minor role in the interaction with the mouse and human receptors, as domain III on its own binds with similar affinity as full-length mouse albumin. Further, we show that P573 in domain III of mouse albumin is required for strong receptor binding. Our study highlights distinct differences in structural requirements for the interactions between mouse and human albumin with their respective receptor, which should be taken into consideration in design of albumin-based drugs and evaluation in mouse models.
Analysis of the antimicrobial mechanism of porcine beta defensin 2 against E. coli by electron microscopy and differentially expressed genes
Authors: Chen Rui-bo , Zhang Kun , Zhang Heng , Gao Chun-yu , Li Chun-li
Published: September 2018

Porcine beta defensin 2 (pBD2) is a cationic antimicrobial peptide with broad spectrum antibacterial activity, which makes it a potential alternative to antibiotics to prevent and cure diseases of pigs. However, development of pBD2 as an effective antibiotic agent requires molecular understanding of its functional mechanism against pathogens. In this study, we investigated the functional mechanism of pBD2 antibacterial activity. Escherichia coli was incubated with different pBD2 concentrations for different times. Electron microscopy was used to analyze the locations of pBD2 and its induced morphological changes in E. coli. Gene expression analysis was also performed to further understand the molecular changes of E. coli in response to pBD2 incubation. The results demonstrated that E. coli membranes were broken, holed, and wrinkled after treatment with pBD2, and pBD2 was located on the cell membranes and manly in the cytoplasm. Furthermore, 38 differentially expressed genes (DEGs) were detected, successfully sequenced and confirmed by quantitative real-time PCR (qRT-PCR). Most of the known functional DEGs were associated with DNA transcription and translation and located in the cytoplasm. Collectively, the results suggest that pBD2 could have multiple modes of action and the main mechanism for killing E. coli might be influence on DNA transcription and translation by targeting intracellular molecules after membrane damage, although transport and metabolism proteins were also affected.
Defects, Dopants and Sodium Mobility in Na2MnSiO4
Authors: Kuganathan Navaratnarajah , Chroneos Alexander
Published: September 2018

Sodium manganese orthosilicate, Na2MnSiO4, is a promising positive electrode material in rechargeable sodium ion batteries. Atomistic scale simulations are used to study the defects, doping behaviour and sodium migration paths in Na2MnSiO4. The most favourable intrinsic defect type is the cation anti-site (0.44 eV/defect), in which, Na and Mn exchange their positions. The second most favourable defect energy process is found to be the Na Frenkel (1.60 eV/defect) indicating that Na diffusion is assisted by the formation of Na vacancies via the vacancy mechanism. Long range sodium paths via vacancy mechanism were constructed and it is confirmed that the lowest activation energy (0.81 eV) migration path is three dimensional with zig-zag pattern. Subvalent doping by Al on the Si site is energetically favourable suggesting that this defect engineering stratergy to increase the Na content in Na2MnSiO4 warrants experimental verification.
Exposure to heat-stress environment affects the physiology, circulation levels of cytokines, and microbiome in dairy cows
Authors: Chen Siyu , Wang Jian , Peng Dandan , Li Gan , Chen Jian , Gu Xianhong
Published: September 2018

The microbiome has emerged as a new player on behavior, physiology and stress because of its significant effects on the brain-gut axis. The aim of this study was to increase our understanding of brain-gut function in dairy cows. We investigated the effects of a heat-stress (HS) environment and individual differences of heat sensitivity (IH) on bovine physiological characteristics and microbial composition. Results indicate that both HS and IH increased rectal temperature (RT) (P < 0.05). An HS environment increased plasma, as well as milk cortisol and cytokines in plasma; however, it decreased plasma, and milk oxytocin, triiodothyronine, and thyroxine (P < 0.05) levels. Exposure to an HS environment reduced the diversity of the fecal microbial population, and resulted in a higher expression of diseases, the environmental adaptation pathway, and the immune related pathway, whereas it lowered the expression of metabolic pathways (P < 0.05). High heat sensitive cows have upregulated metabolisms, environmental adaptation and cellular process pathways, and a downregulated neurodegenerative disease pathway (P < 0.05). Thus, we conclude that exposure to an HS environment modulates physiological characteristics, which may interplay with microbial activity, and in turn, alter the circulation levels of cytokines, implicating the role of the brain-gut axis in dairy cows. The HS environment affected physiological characteristics, cytokine levels, and microbial composition, but IH influenced RT and fecal microbial functions.
Computerised Dynamic Posturography in Premanifest and Manifest individuals with Huntington’s Disease
Authors: Reyes Alvaro , Salomonczyk Danielle , Teo Wei-Peng , Medina Luis D. , Bartlett Danielle , Pirogovsky-Turk Eva , Zaenker Pauline , Bloom Jody Corey , Simmons Roger W. , Ziman Mel , Gilbert Paul E. , Cruickshank Travis
Published: September 2018

Evidence from small-scale studies indicates that impairments in postural stability are an early and disabling feature of Huntington’s disease (HD) and may be a useful clinical endpoint for disease modifying trials. Larger studies are needed to confirm these preliminary findings and the suitability of postural stability outcomes as clinical endpoints. Static and dynamic postural stability were evaluated in 54 premanifest HD, 36 manifest HD and 45 healthy individuals using the Sensory Organization Test (SOT) and Limits of Stability (LOS) test. Manifest HD displayed significantly lower scores on all SOT conditions and on the SOT composite score and had more falls than healthy and premanifest HD (p < 0.05). Premanifest and manifest HD demonstrated significantly lower endpoint excursion (p < 0.001), maximum excursion (p ≤ 0.001), and directional control (p ≤ 0.004) values than healthy individuals on the LOS test. Deficits in LOS were found to manifest on the left side of premanifest HD. Significant but low associations were observed between UHDRS-TMS, disease burden score, diagnostic confidence level, SOT conditions and SOT composite score. We confirm here that individuals with premanifest and manifest HD display significant impairments in static and dynamic postural stability. Dynamic posturography assessments should be considered as clinical endpoints for future disease modifying trials.
Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo
Authors: Kelly R. D. W. , Chandru A. , Watson P. J. , Song Y. , Blades M. , Robertson N. S. , Jamieson A. G. , Schwabe J. W. R. , Cowley S. M.
Published: September 2018

Proteomic analysis of histones has shown that they are subject to a superabundance of acylations, which extend far beyond acetylation, to include: crotonylation, propionylation, butyrylation, malonylation, succinylation, β-hydroxybutyrylation and 2-hydroxyisobutyrylation. To date, much of the functional data has focussed on histone crotonylation which, similar to acetylation, has been associated with positive gene regulation and is added by the acyltransferase, p300. Although Sirtuins 1–3, along with HDAC3, have been shown to possess decrotonylase activity in vitro, there is relatively little known about the regulation of histone crotonylation in vivo. Here we show that Histone Deacetylase 1 and 2 (HDAC1/2), the catalytic core of numerous co-repressor complexes, are important histone decrotonylase enzymes. A ternary complex of HDAC1/CoREST1/LSD1 is able to hydrolyse both histone H3 Lys18-acetyl (H3K18ac) and H3 Lys18-crotonyl (H3K18cr) peptide substrates. Genetic deletion of HDAC1/2 in ES cells increases global levels of histone crotonylation and causes an 85% reduction in total decrotonylase activity. Furthermore, we mapped H3K18cr in cells using ChIP-seq, with and without HDAC1/2, and observed increased levels of crotonylation, which largely overlaps with H3K18ac in the vicinity of transcriptional start sites. Collectively, our data indicate that HDAC1/2 containing complexes are critical regulators of histone crotonylation in vivo.
Sin3A recruits Tet1 to the PAH1 domain via a highly conserved Sin3-Interaction Domain
Authors: Chandru Aditya , Bate Neil , Vuister Geerten W. , Cowley Shaun M.
Published: September 2018

The Sin3A complex acts as a transcriptional hub, integrating the function of diverse transcription factors with histone modifying enzymes, notably, histone deacetylases (HDAC) 1 and 2. The Sin3A protein sits at the centre of the complex, mediating multiple simultaneous protein-protein interactions via its four paired-amphipathic helix (PAH) domains (PAH1-4). The PAH domains contain a conserved four helical bundle, generating a hydrophobic cleft into which the single-helix of a Sin3-interaction domain (SID) is able to insert and bind with high affinity. Although they share a similar mode of interaction, the SIDs of different repressor proteins bind to only one of four potential PAH domains, due to the specific combination of hydrophobic residues at the interface. Here we report the identification of a highly conserved SID in the 5-methylcytosine dioxygenase, Tet1 (Tet1-SID), which interacts directly with the PAH1 domain of Sin3A. Using a combination of NMR spectroscopy and homology modelling we present a model of the PAH1/Tet1-SID complex, which binds in a Type-II orientation similar to Sap25. Mutagenesis of key residues show that the 11-amino acid Tet1-SID is necessary and sufficient for the interaction with Sin3A and is absolutely required for Tet1 to repress transcription in cells.
3D laser nano-printing on fibre paves the way for super-focusing of multimode laser radiation
Authors: Sokolovskii Grigorii S. , Melissinaki Vasileia , Fedorova Ksenia A. , Dudelev Vladislav V. , Losev Sergey N. , Bougrov Vladislav E. , Sibbett Wilson , Farsari Maria , Rafailov Edik U.
Published: September 2018

Multimode high-power laser diodes suffer from inefficient beam focusing, leading to a focal spot 10–100 times greater than the diffraction limit. This inevitably restricts their wider use in ‘direct-diode’ applications in materials processing and biomedical photonics. We report here a ‘super-focusing’ characteristic for laser diodes, where the exploitation of self-interference of modes enables a significant reduction of the focal spot size. This is achieved by employing a conical microlens fabricated on the tip of a multimode optical fibre using 3D laser nano-printing (also known as multi-photon lithography). When refracted by the conical surface, the modes of the fibre-coupled laser beam self-interfere and form an elongated narrow focus, usually referred to as a ‘needle’ beam. The multiphoton lithography technique allows the realisation of almost any optical element on a fibre tip, thus providing the most suitable interface for free-space applications of multimode fibre-delivered laser beams. In addition, we demonstrate the optical trapping of microscopic objects with a super-focused multimode laser diode beam thus rising new opportunities within the applications sector where lab-on-chip configurations can be exploited. Most importantly, the demonstrated super-focusing approach opens up new avenues for the ‘direct-diode’ applications in material processing and 3D printing, where both high power and tight focusing is required.
Detection and characterization of traumatic bile leaks using Gd-EOB-DTPA enhanced magnetic resonance cholangiography
Authors: Wong Yon-Cheong , Wang Li-Jen , Wu Cheng-Hsien , Chen Huan-Wu , Fu Chen-Ju , Yuan Kuo-Ching , Lin Being-Chuan , Hsu Yu-Pao , Kang Shih-Ching
Published: September 2018

Expanding bile leaks after blunt liver trauma require more aggressive treatment than contained bile leaks. In this retrospective study approved by institution review board, we analyzed if non-invasive contrast-enhanced magnetic resonance cholangiography (CEMRC) using hepatocyte-specific contrast agent (gadoxetic acid disodium) could detect and characterize traumatic bile leaks. Between March 2012 and December 2014, written informed consents from 22 included patients (17 men, 5 women) with a median age of 24.5 years (IQR 21.8, 36.0 years) were obtained. Biliary tree visualization and bile leak detection on CEMRC acquired at 10, 20, 30, 90 minutes time points were independently graded by three radiologists on a 5-point Likert scale. Intraclass Correlation (ICC) was computed as estimates of interrater reliability. Accuracy was measured by area under receiver operating characteristic curves (AUROC). Biliary tree visualization was the best on CEMRC at 90 minutes (score 4.30) with excellent inter-rater reliability (ICC = 0.930). Of 22 CEMRC, 15 had bile leak (8 expanding, 7 contained). The largest AUROC of bile leak detection by three radiologists were 0.824, 0.914, 0.929 respectively on CEMRC at 90 minutes with ICC of 0.816. In conclusion, bile leaks of blunt liver trauma can be accurately detected and characterized on CEMRC.
The Chemokine CCL3 Regulates Myeloid Differentiation and Hematopoietic Stem Cell Numbers
Authors: Staversky Rhonda J. , Byun Daniel K. , Georger Mary A. , Zaffuto Brandon J. , Goodman Alexandra , Becker Michael W. , Calvi Laura M. , Frisch Benjamin J.
Published: September 2018

The chemokine CCL3 is frequently overexpressed in malignancies and overexpression leads to microenvironmental dysfunction. In murine models of chronic myelogenous leukemia (CML), CCL3 is critical for the maintenance of a leukemia stem cell population, and leukemia progression. With CCL3 implicated as a potentially viable therapeutic target, it is important to carefully characterize its role in normal hematopoietic homeostasis. CCL3−/− mice were used to evaluate the role of CCL3 in regulating hematopoietic stem and progenitor cell (HSPC) populations. CCL3−/− mice had loss of mature myeloid populations, while myeloid progenitors and HSPCs were increased, and microenvironmental populations were unchanged. These data show that CCL3 promotes myeloid lineage differentiation and the size of the HSPC pool independent of the supportive bone marrow microenvironment. Our results demonstrate a previously unrecognized role of CCL3 in the maintenance of homeostatic hematopoiesis that should be evaluated when targeting CCL3 signaling for the treatment of hematologic malignancy.
Fast neural learning in dogs: A multimodal sensory fMRI study
Authors: Prichard Ashley , Chhibber Raveena , Athanassiades Kate , Spivak Mark , Berns Gregory S.
Published: September 2018

Dogs may follow their nose, but they learn associations to many types of sensory stimuli. Are some modalities learned better than others? We used awake fMRI in 19 dogs over a series of three experiments to measure reward-related learning of visual, olfactory, and verbal stimuli. Neurobiological learning curves were generated for individual dogs by measuring activation over time within three regions of interest: the caudate nucleus, amygdala, and parietotemporal cortex. The learning curves showed that dogs formed stimulus-reward associations in as little as 22 trials. Consistent with neuroimaging studies of associative learning, the caudate showed a main effect for reward-related stimuli, but not a significant interaction with modality. However, there were significant differences in the time courses, suggesting that although multiple modalities are represented in the caudate, the rates of acquisition and habituation are modality-dependent and are potentially gated by their salience in the amygdala. Visual and olfactory modalities resulted in the fastest learning, while verbal stimuli were least effective, suggesting that verbal commands may be the least efficient way to train dogs.
Genome sequencing of Prototheca zopfii genotypes 1 and 2 provides evidence of a severe reduction in organellar genomes
Authors: Severgnini Marco , Lazzari Barbara , Capra Emanuele , Chessa Stefania , Luini Mario , Bordoni Roberta , Castiglioni Bianca , Ricchi Matteo , Cremonesi Paola
Published: September 2018

Prototheca zopfii (P. zopfii, class Trebouxiophyceae, order Chlorellales, family Chlorellaceae), a non-photosynthetic predominantly free-living unicellular alga, is one of the few pathogens belonging to the plant kingdom. This alga can affect many vertebrate hosts, sustaining systemic infections and diseases such as mastitis in cows. The aim of our work was to sequence and assemble the P. zopfii genotype 1 and genotype 2 mitochondrial and plastid genomes. Remarkably, the P. zopfii mitochondrial (38 Kb) and plastid (28 Kb) genomes are models of compaction and the smallest known in the Trebouxiophyceae. As expected, the P. zopfii genotype 1 and 2 plastid genomes lack all the genes involved in photosynthesis, but, surprisingly, they also lack those coding for RNA polymerases. Our results showed that plastid genes are actively transcribed in P. zopfii, which suggests that the missing RNA polymerases are substituted by nuclear-encoded paralogs. The simplified architecture and highly-reduced gene complement of the P. zopfii mitochondrial and plastid genomes are closer to those of P. stagnora and the achlorophyllous obligate parasite Helicosporidium than to those of P. wickerhamii or P. cutis. This similarity is also supported by maximum likelihood phylogenetic analyses inferences. Overall, the P. zopfii sequences reported here, which include nuclear genome drafts for both genotypes, will help provide both a deeper understanding of the evolution of Prototheca spp. and insights into the corresponding host/pathogen interactions.
Longitudinal analysis of biomarker data from a personalized nutrition platform in healthy subjects
Authors: Westerman Kenneth , Reaver Ashley , Roy Catherine , Ploch Margaret , Sharoni Erin , Nogal Bartek , Sinclair David A. , Katz David L. , Blumberg Jeffrey B. , Blander Gil
Published: September 2018

The trend toward personalized approaches to health and medicine has resulted in a need to collect high-dimensional datasets on individuals from a wide variety of populations, in order to generate customized intervention strategies. However, it is not always clear whether insights derived from studies in patient populations or in controlled trial settings are transferable to individuals in the general population. To address this issue, a longitudinal analysis was conducted on blood biomarker data from 1032 generally healthy individuals who used an automated, web-based personalized nutrition and lifestyle platform. The study had two main aims: to analyze correlations between biomarkers for biological insights, and to characterize the effectiveness of the platform in improving biomarker levels. First, a biomarker correlation network was constructed to generate biological hypotheses that are relevant to researchers and, potentially, to users of personalized wellness tools. The correlation network revealed expected patterns, such as the established relationships between blood lipid levels, as well as novel insights, such as a connection between neutrophil and triglyceride concentrations that has been suggested as a relevant indicator of cardiovascular risk. Next, biomarker changes during platform use were assessed, showing a trend toward normalcy for most biomarkers in those participants whose values were out of the clinically normal range at baseline. Finally, associations were found between the selection of specific interventions and corresponding biomarker changes, suggesting directions for future study.
Solar simulated light exposure alters metabolization and genotoxicity induced by benzo[a]pyrene in human skin
Authors: von Koschembahr Anne , Youssef Antonia , Béal David , Calissi Clément , Bourgart Etienne , Marques Marie , Leccia Marie-Thérèse , Giot Jean-Philippe , Maitre Anne , Douki Thierry
Published: September 2018

Skin is a major barrier against external insults and is exposed to combinations of chemical and/or physical toxic agents. Co-exposure to the carcinogenic benzo[a]pyrene (B[a]P) and solar UV radiation is highly relevant in human health, especially in occupational safety. In vitro studies have suggested that UVB enhances B[a]P genotoxicity by activating the AhR pathway and overexpressing the cytochrome P450 enzymes responsible for the conversion of B[a]P into DNA damaging metabolites. Our present work involved more realistic conditions, namely ex vivo human skin explants and simulated sunlight (SSL) as a UV source. We found that topically applied B[a]P strongly induced expression of cutaneous cytochrome P450 genes and formation of DNA adducts. However, gene induction was significantly reduced when B[a]P was combined with SSL. Consequently, formation of BPDE-adducts was also reduced when B[a]P was associated with SSL. Similar results were obtained with primary cultures of human keratinocytes. These results indicate that UV significantly impairs B[a]P metabolism, and decreases rather than increases immediate toxicity. However, it cannot be ruled out that decreased metabolism leads to accumulation of B[a]P and delayed genotoxicity.
Profiling circRNA and miRNA of radiation-induced esophageal injury in a rat model
Authors: Luo Judong , Zhang Changsong , Zhan Qiang , An Fangmei , Zhu Wenyu , Jiang Hua , Ma Changsheng
Published: September 2018

Evidence has also shown that micro ribonucleic acid (miRNA) plays an important role in many cellular processes. However, it is unclear how ionizing radiation causes the miRNA and circular ribonucleic acid (circRNA) expression levels to change and how this change relates to esophageal injury. We analyzed RNA Sequencing (RNA-seq) data from normal esophageal tissue and irradiated esophageal tissues and used computational approaches to identify and characterize differentially expressed miRNAs and circRNAs. We detected 27 miRNAs and 197 circRNAs that had significantly different expression levels after ionizing radiation treatment compared with normal control.Among the 27 miRNAs, 7 miRNAs were down-regulated, and the other 20 were up-regulated. Their target genes were found to be involved in responses to wound, lipid biosynthesis, cell proliferation, cell migration, chemokine activity, hairpin binding, and the cell membrane system. We also found 197 differentially expressed circRNAs in total, of which 87 were up-regulated and 110 were down-regulated. Notably, we found that differentially expressed circRNAs were enriched in cell differentiation, epithelial cell migration, striatum development, protein binding, extracellular exosome, and focal adhesion functions. Of the related processes, sphingolipid metabolism was notable. Many of the differentially expressed circRNAs were involved in sphingolipid metabolism pathways. Cells responded to ionizing radiation (IR) using multiple pathways, which led to sphingolipid metabolism and other immune responses, ultimately leading to esophageal injury.IR-induced esophageal injury is worth studying, especially the dynamic network of circRNA and miRNA. By knowing the regulatory details of related pathways, radiation-related esophageal injury can be prevented, and the efficiency of radiation therapy can be enhanced.
How phosphorylation influences E1 subunit pyruvate dehydrogenase: A computational study
Authors: Sgrignani Jacopo , Chen JingJing , Alimonti Andrea , Cavalli Andrea
Published: September 2018

Pyruvate (PYR) dehydrogenase complex (PDC) is an enzymatic system that plays a crucial role in cellular metabolism as it controls the entry of carbon into the Krebs cycle. From a structural point of view, PDC is formed by three different subunits (E1, E2 and E3) capable of catalyzing the three reaction steps necessary for the full conversion of pyruvate to acetyl-CoA. Recent investigations pointed out the crucial role of this enzyme in the replication and survival of specific cancer cell lines, renewing the interest of the scientific community. Here, we report the results of our molecular dynamics studies on the mechanism by which posttranslational modifications, in particular the phosphorylation of three serine residues (Ser-264-α, Ser-271-α, and Ser-203-α), influence the enzymatic function of the protein. Our results support the hypothesis that the phosphorylation of Ser-264-α and Ser-271-α leads to (1) a perturbation of the catalytic site structure and dynamics and, especially in the case of Ser-264-α, to (2) a reduction in the affinity of E1 for the substrate. Additionally, an analysis of the channels connecting the external environment with the catalytic site indicates that the inhibitory effect should not be due to the occlusion of the access/egress pathways to/from the active site.
Additive Manufactured and Topology Optimized Passive Shimming Elements for Permanent Magnetic Systems
Authors: Huber Christian , Goertler Michael , Abert Claas , Bruckner Florian , Groenefeld Martin , Teliban Iulian , Suess Dieter
Published: September 2018

A method to create a highly homogeneous magnetic field by applying topology optimized, additively manufactured passive shimming elements is investigated. The topology optimization algorithm can calculate a suitable permanent and nonlinear soft magnetic design that fulfills the desired field properties. The permanent magnetic particles are bonded in a polyamide matrix and they are manufactured with a low-cost, end-user 3D printer. Stray field measurements and an inverse stray field simulation framework can determine printing and magnetization errors. The customized shimming elements are manufactured by a selective melting process which produces completely dense soft magnetic metal parts. The methodology is demonstrated on a simple example of two axial symmetric cylindrical magnets, which generates a high inhomogeneous magnetic field. In this case, the maximum magnetic field density is 25 mT and the the homogeneity can be increased by a factor of 35 or down to 6‰. Simulation and measurement results point out a good conformity. Additional topology optimizations of more than one shimming element layer show the opportunity to make the manufactured magnetic system even more homogeneous.
Robustness of Voltage-induced Magnetocapacitance
Authors: Kaiju Hideo , Misawa Takahiro , Nagahama Taro , Komine Takashi , Kitakami Osamu , Fujioka Masaya , Nishii Junji , Xiao Gang
Published: September 2018

One of the most important achievements in the field of spintronics is the development of magnetic tunnel junctions (MTJs). MTJs exhibit a large tunneling magnetoresistance (TMR). However, TMR is strongly dependent on biasing voltage, generally, decreasing with applying bias. The rapid decay of TMR was a major deficiency of MTJs. Here we report a new phenomenon at room temperature, in which the tunneling magnetocapacitance (TMC) increases with biasing voltage in an MTJ system based on Co40Fe40B20/MgO/Co40Fe40B20. We have observed a maximum TMC value of 102% under appropriate biasing, which is the largest voltage-induced TMC effect ever reported for MTJs. We have found excellent agreement between theory and experiment for the bipolar biasing regions using Debye-Fröhlich model combined with quartic barrier approximation and spin-dependent drift-diffusion model. Based on our calculation, we predict that the voltage-induced TMC ratio could reach 1100% in MTJs with a corresponding TMR value of 604%. Our work has provided a new understanding on the voltage-induced AC spin-dependent transport in MTJs. The results reported here may open a novel pathway for spintronics applications, e.g., non-volatile memories and spin logic circuits.
Spider silk proteome provides insight into the structural characterization of Nephila clavipes flagelliform spidroin
Authors: dos Santos-Pinto José Roberto Aparecido , Arcuri Helen Andrade , Esteves Franciele Grego , Palma Mario Sergio , Lubec Gert
Published: September 2018

The capture spiral of web from N. clavipes spider consists of a single type of spidroin - the flagelliform silk protein, a natural material representing a combination of strength and high elasticity. Flagelliform spider silk is the most extensible silk fibre produced by orb weaver spiders and the structure of this remarkable material is still largely unknown. In the present study we used a proteomic approach to elucidate the complete sequence and the post-translational modifications of flagelliform silk proteins. The long sequence of flagelliform silk protein presents 45 hydroxylated proline residues, which may contribute to explain the mechanoelastic property of these fibres, since they are located in the GPGGX motif. The 3D-structure of the protein was modelled considering the three domains together, i.e., the N- and C-terminal non-repetitive domains, and the central repetitive domain. In the resulting molecular model there is a predominance of random structures in the solid fibres of the silk protein. The N-terminal domain is composed of three α-helices and the C-terminal domain is composed of one small helical section. Proteomic data reported herein may be relevant for the development of novel approaches for the synthetic or recombinant production of novel silk-based spider polymers.