bluuebunny/crossref_metadata_2025 huggingface dataset:
Urban Water Conservation Policies in the United States
Authors: Gilligan Jonathan M. , Wold Christopher A. , Worland Scott C. , Nay John J. , Hess David J. , Hornberger George M.
Published: June 2018

Urban water supply systems in the United States are increasingly stressed as economic and population growth confront limited water resources. Demand management, through conservation and improved efficiency, has long been promoted as a practical alternative to building Promethean energy‐intensive water supply infrastructure. Some cities are making great progress at managing their demand, but study of conservation policies has been limited and often regionally focused. We present a hierarchical Bayesian analysis of a new measure of urban water conservation policy, the Vanderbilt Water Conservation Index, for 195 cities in 45 states in the contiguous United States. This study does not attempt to establish causal relationships but does observe that cities in states with arid climates tend to adopt more conservation measures. Within a state, cities with more Democratic‐leaning voting preferences and large and rapidly growing populations tend to adopt more conservation measures. Economic factors and climatic differences between cities do not correlate with the number of measures adopted, but they do correlate with the character of the measures, with arid cities favoring mandatory conservation actions and cities in states with lower real personal income favoring rebates for voluntary actions. Understanding relationships between environmental and societal factors and cities' support for water conservation measures can help planners and policy makers identify obstacles and opportunities to increase the role of conservation and efficiency in making urban water supply systems sustainable.
Frictional Instabilities and Carbonation of Basalts Triggered by Injection of Pressurized H2O‐ and CO2‐ Rich Fluids
Authors: Giacomel Piercarlo , Spagnuolo Elena , Nazzari Manuela , Marzoli Andrea , Passelegue François , Youbi Nasrrddine , Di Toro Giulio
Published: June 2018

The safe application of geological carbon storage depends also on the seismic hazard associated with fluid injection. In this regard, we performed friction experiments using a rotary shear apparatus on precut basalts with variable degree of hydrothermal alteration by injecting distilled H2O, pure CO2, and H2O + CO2 fluid mixtures under temperature, fluid pressure, and stress conditions relevant for large‐scale subsurface CO2 storage reservoirs. In all experiments, seismic slip was preceded by short‐lived slip bursts. Seismic slip occurred at equivalent fluid pressures and normal stresses regardless of the fluid injected and degree of alteration of basalts. Injection of fluids caused also carbonation reactions and crystallization of new dolomite grains in the basalt‐hosted faults sheared in H2O + CO2 fluid mixtures. Fast mineral carbonation in the experiments might be explained by shear heating during seismic slip, evidencing the high chemical reactivity of basalts to H2O + CO2 mixtures.
Future Changes in Extreme El Niño Events Modulated by North Tropical Atlantic Variability
Authors: Ham Yoo‐Geun , Kug Jong‐Seong , Yang Woo‐Hyun , Cai Wenju
Published: June 2018

The extraordinarily strong El Niño events, such as those of 1982/1983, 1997/1998, and 2015/2016, are known to cause critical socio‐economic impacts worldwide by disrupting global weather patterns, cyclones, drought/floods, and ecosystems. Therefore, it is a critical question how often such extreme El Niño will take place in the future. Although many climate models tend to simulate more frequency extreme El Niño under the greenhouse warming, there is a large intermodel diversity, with a range as large as the multimodel averaged change. The cause for this intermodel uncertainty is not known. Here we show that the north tropical Atlantic (NTA) mean precipitation plays a significant role in controlling changes in the extreme El Niño frequency under global warming; that is, much frequent extreme El Niño events under the greenhouse warming are simulated in the models whose climatological precipitation over the NTA is largely decreased. Relatively drier climatology over the NTA can induce a wetter climatology over the equatorial eastern Pacific through an atmospheric teleconnection, and it provides background condition that the El Niño‐related convective responses are amplified to push El Niño to the extremes.
Ambient Seismic Noise Image of the Structurally Controlled Heat and Fluid Feeder Pathway at Campi Flegrei Caldera
Authors: De Siena L. , Sammarco C. , Cornwell D. G. , La Rocca M. , Bianco F. , Zaccarelli L. , Nakahara H.
Published: June 2018

Earthquakes at Campi Flegrei have been low magnitude and sparse since 1985, denying onshore monitoring observations of their usual source for structural constraint: seismic tomography. Here we used continuous seismic records from 2011–2013 to reconstruct period‐dependent Rayleigh wave group velocity maps of the volcano. The Neapolitan Yellow Tuff rim faults bound high‐velocity intracrater products of historical eruptions, which act as a barrier for deep fluid migration. The anomaly with lowest group velocity is aseismic and corresponds to the portion of a fluid storage zone that was fractured during the 1984 volcanic unrest under Pozzuoli town. Earthquake locations show that fluids migrate from this area toward the Solfatara and Pisciarelli fumaroles along shallower low‐velocity fractures. The aseismic anomaly is likely fed by a deep‐seated offshore magmatic source. Its spatial relation with regional dynamics and observations from historical unrests mark the area as the most likely feeder pathway for fluid and magmatic inputs from depth.
Bone-conditioned medium contributes to initiation and progression of osteogenesis by exhibiting synergistic TGF-β1/BMP-2 activity
Authors: Asparuhova Maria B. , Caballé-Serrano Jordi , Buser Daniel , Chappuis Vivianne
Published: June 2018

Guided bone regeneration (GBR) often utilizes a combination of autologous bone grafts, deproteinized bovine bone mineral (DBBM), and collagen membranes. DBBM and collagen membranes pre-coated with bone-conditioned medium (BCM) extracted from locally harvested autologous bone chips have shown great regenerative potential in GBR. However, the underlying molecular mechanism remains largely unknown. Here, we investigated the composition of BCM and its activity on the osteogenic potential of mesenchymal stromal cells. We detected a fast and significant (P < 0.001) release of transforming growth factor-β1 (TGF-β1) from autologous bone within 10 min versus a delayed bone morphogenetic protein-2 (BMP-2) release from 40 min onwards. BCMs harvested within short time periods (10, 20, or 40 min), corresponding to the time of a typical surgical procedure, significantly increased the proliferative activity and collagen matrix production of BCM-treated cells. Long-term (1, 3, or 6 days)-extracted BCMs promoted the later stages of osteoblast differentiation and maturation. Short-term-extracted BCMs, in which TGF-β1 but no BMP-2 was detected, reduced the expression of the late differentiation marker osteocalcin. However, when both growth factors were present simultaneously in the BCM, no inhibitory effects on osteoblast differentiation were observed, suggesting a synergistic TGF-β1/BMP-2 activity. Consequently, in cells that were co-stimulated with recombinant TGF-β1 and BMP-2, we showed a significant stimulatory and dose-dependent effect of TGF-β1 on BMP-2-induced osteoblast differentiation due to prolonged BMP signaling and reduced expression of the BMP-2 antagonist noggin. Altogether, our data provide new insights into the molecular mechanisms underlying the favorable outcome from GBR procedures using BCM, derived from autologous bone grafts.
Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity
Authors: Fanning S. W. , Hodges-Gallagher L. , Myles D. C. , Sun R. , Fowler C. E. , Plant I. N. , Green B. D. , Harmon C. L. , Greene G. L. , Kushner P. J.
Published: June 2018

Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.
PreDicta chip-based high resolution diagnosis of rhinovirus-induced wheeze
Authors: Niespodziana Katarzyna , Stenberg-Hammar Katarina , Megremis Spyridon , Cabauatan Clarissa R. , Napora-Wijata Kamila , Vacal Phyllis C. , Gallerano Daniela , Lupinek Christian , Ebner Daniel , Schlederer Thomas , Harwanegg Christian , Söderhäll Cilla , van Hage Marianne , Hedlin Gunilla , Papadopoulos Nikolaos G. , Valenta Rudolf
Published: June 2018

Rhinovirus (RV) infections are major triggers of acute exacerbations of severe respiratory diseases such as pre-school wheeze, asthma and chronic obstructive pulmonary disease (COPD). The occurrence of numerous RV types is a major challenge for the identification of the culprit virus types and for the improvement of virus type-specific treatment strategies. Here, we develop a chip containing 130 different micro-arrayed RV proteins and peptides and demonstrate in a cohort of 120 pre-school children, most of whom had been hospitalized due to acute wheeze, that it is possible to determine the culprit RV species with a minute blood sample by serology. Importantly, we identify RV-A and RV-C species as giving rise to most severe respiratory symptoms. Thus, we have generated a chip for the serological identification of RV-induced respiratory illness which should be useful for the rational development of preventive and therapeutic strategies targeting the most important RV types.
Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants
Authors: Wegert Jenny , Vokuhl Christian , Collord Grace , Del Castillo Velasco-Herrera Martin , Farndon Sarah J. , Guzzo Charlotte , Jorgensen Mette , Anderson John , Slater Olga , Duncan Catriona , Bausenwein Sabrina , Streitenberger Heike , Ziegler Barbara , Furtwängler Rhoikos , Graf Norbert , Stratton Michael R. , Campbell Peter J. , Jones David TW , Koelsche Christian , Pfister Stefan M. , Mifsud William , Sebire Neil , Sparber-Sauer Monika , Koscielniak Ewa , Rosenwald Andreas , Gessler Manfred , Behjati Sam
Published: June 2018

Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.
Yu–Shiba–Rusinov screening of spins in double quantum dots
Authors: Grove-Rasmussen K. , Steffensen G. , Jellinggaard A. , Madsen M. H. , Žitko R. , Paaske J. , Nygård J.
Published: June 2018

A magnetic impurity coupled to a superconductor gives rise to a Yu–Shiba–Rusinov (YSR) state inside the superconducting energy gap. With increasing exchange coupling the excitation energy of this state eventually crosses zero and the system switches to a YSR ground state with bound quasiparticles screening the impurity spin by ħ/2. Here we explore indium arsenide (InAs) nanowire double quantum dots tunnel coupled to a superconductor and demonstrate YSR screening of spin-1/2 and spin-1 states. Gating the double dot through nine different charge states, we show that the honeycomb pattern of zero-bias conductance peaks, archetypal of double dots coupled to normal leads, is replaced by lines of zero-energy YSR states. These enclose regions of YSR-screened dot spins displaying distinctive spectral features, and their characteristic shape and topology change markedly with tunnel coupling strengths. We find excellent agreement with a simple zero-bandwidth approximation, and with numerical renormalization group calculations for the two-orbital Anderson model.
Global probabilistic projections of extreme sea levels show intensification of coastal flood hazard
Authors: Vousdoukas Michalis I. , Mentaschi Lorenzo , Voukouvalas Evangelos , Verlaan Martin , Jevrejeva Svetlana , Jackson Luke P. , Feyen Luc
Published: June 2018

Global warming is expected to drive increasing extreme sea levels (ESLs) and flood risk along the world’s coastlines. In this work we present probabilistic projections of ESLs for the present century taking into consideration changes in mean sea level, tides, wind-waves, and storm surges. Between the year 2000 and 2100 we project a very likely increase of the global average 100-year ESL of 34–76 cm under a moderate-emission-mitigation-policy scenario and of 58–172 cm under a business as usual scenario. Rising ESLs are mostly driven by thermal expansion, followed by contributions from ice mass-loss from glaciers, and ice-sheets in Greenland and Antarctica. Under these scenarios ESL rise would render a large part of the tropics exposed annually to the present-day 100-year event from 2050. By the end of this century this applies to most coastlines around the world, implying unprecedented flood risk levels unless timely adaptation measures are taken.
In situ architecture of the algal nuclear pore complex
Authors: Mosalaganti Shyamal , Kosinski Jan , Albert Sahradha , Schaffer Miroslava , Strenkert Daniela , Salomé Patrice A. , Merchant Sabeeha S. , Plitzko Jürgen M. , Baumeister Wolfgang , Engel Benjamin D. , Beck Martin
Published: June 2018

Nuclear pore complexes (NPCs) span the nuclear envelope and mediate nucleocytoplasmic exchange. They are a hallmark of eukaryotes and deeply rooted in the evolutionary origin of cellular compartmentalization. NPCs have an elaborate architecture that has been well studied in vertebrates. Whether this architecture is unique or varies significantly in other eukaryotic kingdoms remains unknown, predominantly due to missing in situ structural data. Here, we report the architecture of the algal NPC from the early branching eukaryote Chlamydomonas reinhardtii and compare it to the human NPC. We find that the inner ring of the Chlamydomonas NPC has an unexpectedly large diameter, and the outer rings exhibit an asymmetric oligomeric state that has not been observed or predicted previously. Our study provides evidence that the NPC is subject to substantial structural variation between species. The divergent and conserved features of NPC architecture provide insights into the evolution of the nucleocytoplasmic transport machinery.
Biosynthesis of thiocarboxylic acid-containing natural products
Authors: Dong Liao-Bin , Rudolf Jeffrey D. , Kang Dingding , Wang Nan , He Cyndi Qixin , Deng Youchao , Huang Yong , Houk K. N. , Duan Yanwen , Shen Ben
Published: June 2018

Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN. We identify a thioacid cassette encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A and sulfur transfer, respectively. ThioPTM and thioPTN bind tightly to β-ketoacyl-ACP synthase II (FabF) and retain strong antibacterial activities. Density functional theory calculations of binding and solvation free energies suggest thioPTM and thioPTN bind to FabF more favorably than PTM and PTN. Additionally, thioacid cassettes are prevalent in the genomes of bacteria, implicating that thiocarboxylic acid-containing natural products are underappreciated. These results suggest that thiocarboxylic acid, as an alternative pharmacophore, and thiocarboxylic acid-containing natural products may be considered for future drug discovery.
Guided morphogenesis through optogenetic activation of Rho signalling during early Drosophila embryogenesis
Authors: Izquierdo Emiliano , Quinkler Theresa , De Renzis Stefano
Published: June 2018

During organismal development, cells undergo complex changes in shape whose causal relationship to individual morphogenetic processes remains unclear. The modular nature of such processes suggests that it should be possible to isolate individual modules, determine the minimum set of requirements sufficient to drive tissue remodeling, and re-construct morphogenesis. Here we use optogenetics to reconstitute epithelial folding in embryonic Drosophila tissues that otherwise would not undergo invagination. We show that precise spatial and temporal activation of Rho signaling is sufficient to trigger apical constriction and tissue folding. Induced furrows can occur at any position along the dorsal–ventral or anterior–posterior embryo axis in response to the spatial pattern and level of optogenetic activation. Thus, epithelial folding is a direct function of the spatio-temporal organization and strength of Rho signaling that on its own is sufficient to drive tissue internalization independently of any pre-determined condition or differentiation program associated with endogenous invagination processes.
Recipes for improper ferroelectricity in molecular perovskites
Authors: Boström Hanna L. B. , Senn Mark S. , Goodwin Andrew L.
Published: June 2018

The central goal of crystal engineering is to control material function via rational design of structure. A particularly successful realisation of this paradigm is hybrid improper ferroelectricity in layered perovskite materials, where layering and cooperative octahedral tilts combine to break inversion symmetry. However, in the parent family of inorganic ABX3 perovskites, symmetry prevents hybrid coupling to polar distortions. Here, we use group-theoretical analysis to uncover a profound enhancement of the number of improper ferroelectric coupling schemes available to molecular perovskites. This enhancement arises because molecular substitution diversifies the range of distortions possible. Not only do our insights rationalise the emergence of polarisation in previously studied materials, but we identify the fundamental importance of molecular degrees of freedom that are straightforwardly controlled from a synthetic viewpoint. We envisage that the crystal design principles we develop here will enable targeted synthesis of a large family of new acentric functional materials.
The 3.3 Å structure of a plant geminivirus using cryo-EM
Authors: Hesketh Emma L. , Saunders Keith , Fisher Chloe , Potze Joran , Stanley John , Lomonossoff George P. , Ranson Neil A.
Published: June 2018

Geminiviruses are major plant pathogens that threaten food security globally. They have a unique architecture built from two incomplete icosahedral particles, fused to form a geminate capsid. However, despite their importance to agricultural economies and fundamental biological interest, the details of how this is realized in 3D remain unknown. Here we report the structure of Ageratum yellow vein virus at 3.3 Å resolution, using single-particle cryo-electron microscopy, together with an atomic model that shows that the N-terminus of the single capsid protein (CP) adopts three different conformations essential for building the interface between geminate halves. Our map also contains density for ~7 bases of single-stranded DNA bound to each CP, and we show that the interactions between the genome and CPs are different at the interface than in the rest of the capsid. With additional mutagenesis data, this suggests a central role for DNA binding-induced conformational change in directing the assembly of geminate capsids.
Formation of self-assembled gold nanoparticle supercrystals with facet-dependent surface plasmonic coupling
Authors: Bian Kaifu , Schunk Hattie , Ye Dongmei , Hwang Austin , Luk Ting Shan , Li Ruipeng , Wang Zhongwu , Fan Hongyou
Published: June 2018

Metallic nanoparticles, such as gold and silver nanoparticles, can self-assemble into highly ordered arrays known as supercrystals for potential applications in areas such as optics, electronics, and sensor platforms. Here we report the formation of self-assembled 3D faceted gold nanoparticle supercrystals with controlled nanoparticle packing and unique facet-dependent optical property by using a binary solvent diffusion method. The nanoparticle packing structures from specific facets of the supercrystals are characterized by small/wide-angle X-ray scattering for detailed reconstruction of nanoparticle translation and shape orientation from mesometric to atomic levels within the supercrystals. We discover that the binary diffusion results in hexagonal close packed supercrystals whose size and quality are determined by initial nanoparticle concentration and diffusion speed. The supercrystal solids display unique facet-dependent surface plasmonic and surface-enhanced Raman characteristics. The ease of the growth of large supercrystal solids facilitates essential correlation between structure and property of nanoparticle solids for practical integrations.
Structure determination from single molecule X-ray scattering with three photons per image
Authors: von Ardenne Benjamin , Mechelke Martin , Grubmüller Helmut
Published: June 2018

Scattering experiments with femtosecond high-intensity free-electron laser pulses provide a new route to macromolecular structure determination. While currently limited to nano-crystals or virus particles, the ultimate goal is scattering on single biomolecules. The main challenges in these experiments are the extremely low signal-to-noise ratio due to the very low expected photon count per scattering image, often well below 100, as well as the random orientation of the molecule in each shot. Here we present a de novo correlation-based approach and show that three coherently scattered photons per image suffice for structure determination. Using synthetic scattering data of a small protein, we demonstrate near-atomic resolution of  3.3 Å using 3.3 × 1010 coherently scattered photons from 3.3 × 109 images, which is within experimental reach. Further, our three-photon correlation approach is robust to additional noise from incoherent scattering; the number of disordered solvent molecules attached to the macromolecular surface should be kept small.
Evolution of thiolate-stabilized Ag nanoclusters from Ag-thiolate cluster intermediates
Authors: Cao Yitao , Guo Jiahao , Shi Run , Waterhouse Geoffrey I. N. , Pan Jinheng , Du Zhenxia , Yao Qiaofeng , Wu Li-Zhu , Tung Chen-Ho , Xie Jianping , Zhang Tierui
Published: June 2018

The synthesis of atomically precise thiolate-stabilized silver (Ag) nanoclusters is the subject of intense research interest, yet the formation mechanism of such nanoclusters remains obscure. Here, electrospray ionization mass spectrometry is successfully applied to monitor the reaction intermediates formed during the sodium-borohydride-reduction of silver 4-tert-butylbenzenethiolate (AgSPh-tBu). We demonstrate a unique evolution route to thiolate-stabilized Ag nanoclusters mediated by Ag-thiolate clusters. The Ag-thiolate clusters form in the initial stage of reduction contain tens of Ag atoms and similar number of ligands, and they are transformed into Ag17(SPh-tBu)123− and Ag44(SPh-tBu)304− nanoclusters in the later reduction process. The number of Ag atoms in the Ag-thiolate clusters determines the reaction path to each final nanocluster product. A similar mechanism is found when silver 2,4-dimethylbenzenethiolate (AgSPhMe2) is used as precursor. This mechanism differs markedly from the long-established bottom-up evolution process, providing valuable new insights into the synthesis of metal nanoclusters.
Antibody targeting of a specific region of Pfs47 blocks Plasmodium falciparum malaria transmission
Authors: Canepa Gaspar E. , Molina-Cruz Alvaro , Yenkoidiok-Douti Lampouguin , Calvo Eric , Williams Adeline E. , Burkhardt Martin , Peng Fangni , Narum David , Boulanger Martin J. , Valenzuela Jesus G. , Barillas-Mury Carolina
Published: June 2018

Transmission-blocking vaccines are based on eliciting antibody responses in the vertebrate host that disrupt parasite development in the mosquito vector and prevent malaria transmission. The surface protein Pfs47 is present in Plasmodium falciparum gametocytes and female gametes. The potential of Pfs47 as a vaccine target was evaluated. Soluble full-length recombinant protein, consisting of three domains, was expressed in E. coli as a thioredoxin fusion (T-Pfs47). The protein was immunogenic, and polyclonal and monoclonal antibodies (mAb) were obtained, but they did not confer transmission blocking activity (TBA). All fourteen mAb targeted either domains 1 or 3, but not domain 2 (D2), and immune reactivity to D2 was also very low in polyclonal mouse IgG after T-Pfs47 immunization. Disruption of the predicted disulfide bond in D2, by replacing cysteines for alanines (C230A and C260A), allowed expression of recombinant D2 protein in E. coli. A combination of mAbs targeting D2, and deletion proteins from this domain, allowed us to map a central 52 amino acid (aa) region where antibody binding confers strong TBA (78-99%). This 52 aa antigen is immunogenic and well conserved, with only seven haplotypes world-wide that share 96–98% identity. Neither human complement nor the mosquito complement-like system are required for the observed TBA. A dramatic reduction in ookinete numbers and ookinete-specific transcripts was observed, suggesting that the antibodies are interacting with female gametocytes and preventing fertilization.
Value of multilocus genetic risk score for atrial fibrillation in end-stage kidney disease patients in a Polish population
Authors: Saracyn Marek , Kisiel Bartłomiej , Bachta Artur , Franaszczyk Maria , Brodowska-Kania Dorota , Żmudzki Wawrzyniec , Szymański Konrad , Sokalski Antoni , Klatko Wiesław , Stopiński Marek , Grochowski Janusz , Papliński Marek , Goździk Zdzisław , Niemczyk Longin , Bober Barbara , Kołodziej Maciej , Tłustochowicz Witold , Kamiński Grzegorz , Płoski Rafał , Niemczyk Stanisław
Published: June 2018

Genetic factors play a key role in the pathogenesis of atrial fibrillation (AF). We would like to establish an association between previously described single-nucleotide polymorphisms (SNPs) and AF in haemodialysed patients with end-stage kidney disease (ESKD-HD) as well as to assess the cumulative effect of all genotyped SNPs on AF risk. Sixteen SNPs were genotyped in 113 patients with AF-ESKD-HD and in 157 controls: without AF (NAF) and with ESKD-HD. The distribution of the risk alleles was compared in both groups and between different sub-phenotypes. The multilocus genetic risk score (GRS) was calculated to estimate the cumulative risk conferred by all SNPs. Several loci showed a trend toward an association with permanent AF (perm-AF): CAV1, Cx40 and PITX2. However, GRS was significantly higher in the AF and perm-AF groups, as compared to NAF. Three of the tested variables were independently associated with AF: male sex, history of myocardial infarction (MI) and GRS. The GRS, which combined 13 previously described SNPs, showed a significant and independent association with AF in a Polish population of patients with ESKD-HD and concomitant AF. Further studies on larger groups of patients are needed to confirm the associations.
Assessment of Lower-limb Vascular Endothelial Function Based on Enclosed Zone Flow-mediated Dilation
Authors: Hirano Harutoyo , Takama Renjo , Matsumoto Ryo , Tanaka Hiroshi , Hirano Hiroki , Soh Zu , Ukawa Teiji , Takayanagi Tsuneo , Morimoto Haruka , Nakamura Ryuji , Saeki Noboru , Hashimoto Haruki , Matsui Shogo , Kishimoto Shinji , Oda Nozomu , Kajikawa Masato , Maruhashi Tatsuya , Kawamoto Masashi , Yoshizumi Masao , Higashi Yukihito , Tsuji Toshio
Published: June 2018

This paper proposes a novel non-invasive method for assessing the vascular endothelial function of lower-limb arteries based on the dilation rate of air-cuff plethysmograms measured using the oscillometric approach. The principle of evaluating vascular endothelial function involves flow-mediated dilation. In the study conducted, blood flow in the dorsal pedis artery was first monitored while lower-limb cuff pressure was applied using the proposed system. The results showed blood flow was interrupted when the level of pressure was at least 50 mmHg higher than the subject’s lower-limb systolic arterial pressure and that blood flow velocity increased after cuff release. Next, values of the proposed index, %ezFMDL, for assessing the vascular endothelial function of lower-limb arteries were determined from 327 adult subjects: 87 healthy subjects, 150 subjects at high risk of arteriosclerosis and 90 patients with cardiovascular disease (CAD). The mean values and standard deviations calculated using %ezFMDL were 30.5 ± 12.0% for the healthy subjects, 23.6 ± 12.7% for subjects at high risk of arteriosclerosis and 14.5 ± 15.4% for patients with CAD. The %ezFMDL values for the subjects at high risk of arteriosclerosis and the patients with CAD were significantly lower than those for the healthy subjects (p < 0.01). The proposed method may have potential for clinical application.
Ab initio inspired design of ternary boride thin films
Authors: Moraes Vincent , Riedl Helmut , Fuger Christoph , Polcik Peter , Bolvardi Hamid , Holec David , Mayrhofer P. H.
Published: June 2018

The demand to discover new materials is scientifically as well as industrially a continuously present topic, covering all different fields of application. The recent scientific work on thin film materials has shown, that especially for nitride-based protective coatings, computationally-driven understanding and modelling serves as a reliable trend-giver and can be used for target-oriented experiments. In this study, semi-automated density functional theory (DFT) calculations were used, to sweep across transition metal diborides in order to characterize their structure, phase stability and mechanical properties. We show that early transition metal diborides (TiB2, VB2, etc.) tend to be chemically more stable in the AlB2 structure type, whereas late transition metal diborides (WB2, ReB2, etc.) are preferably stabilized in the W2B5−x structure type. Closely related, we could prove that point defects such as vacancies significantly influence the phase stability and even can reverse the preference for the AlB2 or W2B5−x structure. Furthermore, investigations on the brittle-ductile behavior of the various diborides reveal, that the metastable structures are more ductile than their stable counterparts (WB2, TcB2, etc.). To design thin film materials, e.g. ternary or layered systems, this study is important for application oriented coating development to focus experimental studies on the most perspective systems.
Genome-wide assessment of gene-by-smoking interactions in COPD
Authors: Park Boram , Koo So-My , An Jaehoon , Lee MoonGyu , Kang Hae Yeon , Qiao Dandi , Cho Michael H. , Sung Joohon , Silverman Edwin K. , Yang Hyeon-Jong , Won Sungho
Published: June 2018

Cigarette smoke exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) and its interactions with genetic variants could affect lung function. However, few gene-smoking interactions have been reported. In this report, we evaluated the effects of gene-smoking interactions on lung function using Korea Associated Resource (KARE) data with the spirometric variables—forced expiratory volume in 1 s (FEV1). We found that variations in FEV1were different among smoking status. Thus, we considered a linear mixed model for association analysis under heteroscedasticity according to smoking status. We found a previously identified locus nearSOX9on chromosome 17 to be the most significant based on a joint test of the main and interaction effects of smoking. Smoking interactions were replicated with Gene-Environment of Interaction and phenotype (GENIE), Multi-Ethnic Study of Atherosclerosis-Lung (MESA-Lung), and COPDGene studies. We found that individuals with minor alleles, rs17765644, rs17178251, rs11870732, and rs4793541, tended to have lower FEV1values, and lung function decreased much faster with age for smokers. There have been very few reports to replicate a common variant gene-smoking interaction, and our results revealed that statistical models for gene-smoking interaction analyses should be carefully selected.
Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse
Authors: Philp Amber R. , Riquelme Texia T. , Millar-Büchner Pamela , González Rodrigo , Sepúlveda Francisco V. , Cid L. Pablo , Flores Carlos A.
Published: June 2018

Nearly 70% of cystic fibrosis (CF) patients bear the phenylalanine-508 deletion but disease severity differs greatly, and is not explained by the existence of different mutations in compound heterozygous. Studies demonstrated that genes other than CFTR relate to intestinal disease in humans and CF-mouse. Kcnn4, the gene encoding the calcium-activated potassium channel KCa3.1, important for intestinal secretion, is present in a locus linked with occurrence of intestinal CF-disease in mice and humans. We reasoned that it might be a CF-modifier gene and bred a CF-mouse with Kcnn4 silencing, finding that lethality was almost abolished. Silencing of Kcnn4 did not improve intestinal secretory functions, but rather corrected increased circulating TNF-α level and reduced intestinal mast cell increase. Given the importance of mast cells in intestinal disease additional double mutant CF-animals were tested, one lacking mast cells (C-kitW-sh/W-sh) and Stat6−/− to block IgE production. While mast cell depletion had no effect, silencing Stat6 significantly reduced lethality. Our results show that Kcnn4 is an intestinal CF modifier gene partially acting through a STAT6-dependent mechanism.
Non-communicable disease risk factor profile among public employees in a regional city in northern Ethiopia
Authors: Gebremariam Lemlem Weldegerima , Chiang Chifa , Yatsuya Hiroshi , Hilawe Esayas Haregot , Kahsay Alemayehu Bayray , Godefay Hagos , Abraham Loko , Hirakawa Yoshihisa , Iso Hiroyasu , Aoyama Atsuko
Published: June 2018

The burden of non-communicable diseases (NCDs) is increasing in Ethiopia. This study aims to describe the prevalence of NCD risk factors of public employees in a regional city in northern Ethiopia. We conducted a cross-sectional epidemiological study targeting men and women aged 25–64 years employed by public offices in Mekelle. The prevalence was age-standardized to the Ethiopian 2007 population. Among the 1380 subjects (823 men and 557 women), 68.7% had less than 1 serving of fruits and vegetables per day, 41.0% were physically inactive, and 57.3% observed religious fast. The age-standardised prevalence of abdominal obesity was 29.3% in men and 58.5% in women, but that of metabolic syndrome was comparable between men (39.2%) and women (39.0%). The prevalence of diabetes was underestimated if only fasting blood glucose (FBG) was used for the diagnosis compared to combination of FBG and glycated haemoglobin (HbA1c) (6.7% in men and 3.8% in women vs. 12.1% in men and 5.6% in women). More than a quarter (26.1%) of men and 8.7% of women had estimated 10-year risk of cardiovascular disease of 10% or more. This study revealed the high prevalence of NCD metabolic risk factors among the urban public employees in the highland of Ethiopia.
Ossification of the Ligamentum Flavum in a Nineteenth-Century Skeletal Population Sample from Ireland: Using Bioarchaeology to Reveal a Neglected Spine Pathology
Authors: Geber Jonny , Hammer Niels
Published: June 2018

Ossification of the ligamentum flavum of the spine (OLF) is rarely reported in individuals of European ancestry. It has, however, been observed in archaeological skeletons from Europe. The aim of this study was to revisit OLF rates, utilising a mid-nineteenth-century skeletal sample from Ireland. The hypothesis was that the OLF prevalence rate was similar to studies on non-Europeans. Spines from 345 individuals were analysed, and the extent of OLF recorded on the cranial and caudal attachment sites of each vertebra using the following classification system: Grade 0 (no change); Grade 1 (<2 mm); Grade 2 (2–4 mm); Grade 3 (≥4 mm). OLF was observed at prevalence rates of 83.6%. There was no disparity in prevalence based on sex, except for individuals aged 36–45 years at death in which the male rate was higher. Advancing age was a determining factor in the OLF occurrence with an onset in young adulthood (18–25 years), and most severe grades occurring over the age of 25 years. OLF coincides with spinal osteoarthritis, spondylosis deformans and Schmorl’s nodes in both sexes, and with intervertebral osteochondrosis in females. The results of this study indicate that OLF is likely to be an understudied rather than rare condition in European populations.
QSAR-based molecular signatures of prenylated (iso)flavonoids underlying antimicrobial potency against and membrane-disruption in Gram positive and Gram negative bacteria
Authors: Araya-Cloutier Carla , Vincken Jean-Paul , van de Schans Milou G. M. , Hageman Jos , Schaftenaar Gijs , den Besten Heidy M. W. , Gruppen Harry
Published: June 2018

Prenylated flavonoids and isoflavonoids are phytochemicals with remarkable antibacterial activity. In this study, 30 prenylated (iso)flavonoids were tested against Listeria monocytogenes and Escherichia coli (the latter in combination with an efflux pump inhibitor). Minimum inhibitory concentrations of the most active compounds ranged between 6.3–15.0 µg/mL. Quantitative structure-activity relationships (QSAR) analysis was performed and linear regression models were proposed with R2 between 0.77–0.80, average R2m between 0.70–0.75, Q2LOO between 0.66–0.69, and relatively low amount of descriptors. Shape descriptors (related to flexibility and globularity), together with hydrophilic/hydrophobic volume and surface area descriptors, were identified as important molecular characteristics related to activity. A 3D pharmacophore model explaining the effect of the prenyl position on the activity of compounds was developed for each bacterium. These models predicted active compounds with an accuracy of 71–88%. With regard to the mode of action, good antibacterial prenylated (iso)flavonoids with low relative hydrophobic surface area caused remarkable membrane permeabilization, whereas those with higher relative hydrophobic surface area did not. Based on the QSAR and membrane permeabilization studies, the mode of action of antibacterial prenylated (iso)flavonoids was putatively rationalized.
Highly accurate model for prediction of lung nodule malignancy with CT scans
Authors: Causey Jason L. , Zhang Junyu , Ma Shiqian , Jiang Bo , Qualls Jake A. , Politte David G. , Prior Fred , Zhang Shuzhong , Huang Xiuzhen
Published: June 2018

Computed tomography (CT) examinations are commonly used to predict lung nodule malignancy in patients, which are shown to improve noninvasive early diagnosis of lung cancer. It remains challenging for computational approaches to achieve performance comparable to experienced radiologists. Here we present NoduleX, a systematic approach to predict lung nodule malignancy from CT data, based on deep learning convolutional neural networks (CNN). For training and validation, we analyze >1000 lung nodules in images from the LIDC/IDRI cohort. All nodules were identified and classified by four experienced thoracic radiologists who participated in the LIDC project. NoduleX achieves high accuracy for nodule malignancy classification, with an AUC of ~0.99. This is commensurate with the analysis of the dataset by experienced radiologists. Our approach, NoduleX, provides an effective framework for highly accurate nodule malignancy prediction with the model trained on a large patient population. Our results are replicable with software available at http://bioinformatics.astate.edu/NoduleX.
Protein and DNA synthesis demonstrated in cell-free Ehrlichia chaffeensis organisms in axenic medium
Authors: Eedunuri Vijay K. , Zhang Yuntao , Cheng Chuanmin , Chen Li , Liu Huitao , Omsland Anders , Boyle Dan , Ganta Roman R.
Published: June 2018

Ehrlichia chaffeensis, a tick-transmitted rickettsial bacterium, is the causative agent of human monocytic ehrlichiosis. Biochemical characterization of this and other related Rickettsiales remains a major challenge, as they require a host cell for their replication. We investigated the use of an axenic medium for E. chaffeensis growth, assessed by protein and DNA synthesis, in the absence of a host cell. E. chaffeensis organisms harvested from in vitro cultures grown in a vertebrate cell line were fractionated into infectious dense-core cells (DC) and the non-infectious replicating form, known as reticulate cells (RC) by renografin density gradient centrifugation and incubated in the axenic medium containing amino acids, nucleotides, and different energy sources. Bacterial protein and DNA synthesis were observed in RCs in response to glucose-6-phosphate, although adenosine triphosphate, alpha-ketoglutarate or sodium acetate supported protein synthesis. The biosynthetic activity could not be detected in DCs in the axenic medium. While the data demonstrate de novo protein and DNA synthesis under axenic conditions for E. chaffeensis RCs, additional modifications are required in order to establish conditions that support bacterial replication, and transition to DCs.
Gallic acid improves cardiac dysfunction and fibrosis in pressure overload-induced heart failure
Authors: Jin Li , Sun Simei , Ryu Yuhee , Piao Zhe Hao , Liu Bin , Choi Sin Young , Kim Gwi Ran , Kim Hyung-Seok , Kee Hae Jin , Jeong Myung Ho
Published: June 2018

Gallic acid is a trihydroxybenzoic acid found in tea leaves and some plants. Here, we report the effect of gallic acid on cardiac dysfunction and fibrosis in a mouse model of pressure overload-induced heart failure and in primary rat cardiac fibroblasts, and compare the effects of gallic acid with those of drugs used in clinics. Gallic acid reduces cardiac hypertrophy, dysfunction, and fibrosis induced by transverse aortic constriction (TAC) stimuli in vivo and transforming growth factor β1 (TGF-β1) in vitro. It decreases left ventricular end-diastolic and end-systolic diameter, and recovers the reduced fractional shortening in TAC. In addition, it suppresses the expression of atrial natriuretic peptide, brain natriuretic peptide, skeletal α-actin, and β-myosin heavy chain. Administration of gallic acid decreases perivascular fibrosis, as determined by Trichrome II Blue staining, and reduces the expression of collagen type I and connective tissue growth factor. However, administration of losartan, carvedilol, and furosemide does not reduce cardiac dysfunction and fibrosis in TAC. Moreover, treatment with gallic acid inhibits fibrosis-related genes and deposition of collagen type I in TGF-β1-treated cardiac fibroblasts. These results suggest that gallic acid is a therapeutic agent for cardiac dysfunction and fibrosis in chronic heart failure.
A pivotal role for starch in the reconfiguration of 14C-partitioning and allocation in Arabidopsis thaliana under short-term abiotic stress
Authors: Dong Shaoyun , Zhang Joshua , Beckles Diane M.
Published: June 2018

Plant carbon status is optimized for normal growth but is affected by abiotic stress. Here, we used14C-labeling to provide the first holistic picture of carbon use changes during short-term osmotic, salinity, and cold stress inArabidopsis thaliana. This could inform on the early mechanisms plants use to survive adverse environment, which is important for efficient agricultural production. We found that carbon allocation from source to sinks, and partitioning into major metabolite pools in the source leaf, sink leaves and roots showed both conserved and divergent responses to the stresses examined. Carbohydrates changed under all abiotic stresses applied; plants re-partitioned14C to maintain sugar levels under stress, primarily by reducing14C into the storage compounds in the source leaf, and decreasing14C into the pools used for growth processes in the roots. Salinity and cold increased14C-flux into protein, but as the stress progressed, protein degradation increased to produce amino acids, presumably for osmoprotection. Our work also emphasized that stress regulated the carbon channeled into starch, and its metabolic turnover. These stress-induced changes in starch metabolism and sugar export in the source were partly accompanied by transcriptional alteration in the T6P/SnRK1 regulatory pathway that are normally activated by carbon starvation.
Liver X receptors regulate hepatic F4/80
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CD11b+ Kupffer cells/macrophages and innate immune responses in mice
Authors: Endo-Umeda Kaori , Nakashima Hiroyuki , Komine-Aizawa Shihoko , Umeda Naoki , Seki Shuhji , Makishima Makoto
Published: June 2018

The liver X receptors (LXRs), LXRα and LXRβ, are nuclear receptors that regulate lipid homeostasis. LXRs also regulate inflammatory responses in cultured macrophages. However, the role of LXRs in hepatic immune cells remains poorly characterized. We investigated the role of LXRs in regulation of inflammatory responses of hepatic mononuclear cells (MNCs) in mice. Both LXRα and LXRβ were expressed in mouse hepatic MNCs and F4/80+ Kupffer cells/macrophages. LXRα/β-knockout (KO) mice had an increased number of hepatic MNCs and elevated expression of macrophage surface markers and inflammatory cytokines compared to wild-type (WT) mice. Among MNCs, F4/80+CD11b+ cells, not F4/80+CD11b− or F4/80+CD68+ cells, were increased in LXRα/β-KO mice more than WT mice. Isolated hepatic MNCs and F4/80+CD11b+ cells of LXRα/β-KO mice showed enhanced production of inflammatory cytokines after stimulation by lipopolysaccharide or CpG-DNA compared to WT cells, and LXR ligand treatment suppressed lipopolysaccharide-induced cytokine expression in hepatic MNCs. Lipopolysaccharide administration also stimulated inflammatory cytokine production in LXRα/β-KO mice more effectively than WT mice. Thus, LXR deletion enhances recruitment of F4/80+CD11b+ Kupffer cells/macrophages and acute immune responses in the liver. LXRs regulate the Kupffer cell/macrophage population and innate immune and inflammatory responses in mouse liver.